boehringer ingelheim pharmaceuticals, inc.
Tipranavir
Anti-viral
Drugs advisory committee (AVDAC)
Briefing
document
NDA
21-814
available for public
disclosure without redaction
TABLE OF
CONTENTS
List of
abbreviations...................................................................... 6
SUMMARY.................................................................................................. 8
1. INTRODUCTION.............................................................................. 13
2. NONCLINICAL
PHARMACOLOGY AND TOXICOLOGY.......... 15
3. MICROBIOLOGY............................................................................. 21
3.1 Mechanism Of Action.............................................................................. 21
3.2 Antiviral Activity In Vitro.................................................................. 21
4. OVERVIEW OF CLINICAL
DEVELOPMENT PROGRAM......... 23
4.1 EARLY DEVELOPMENT.................................................................................. 23
4.2 DOSE-FINDING TRIAL.................................................................................... 23
4.3 PHASE III PIVOTAL TRIAL PROGRAM....................................................... 25
4.3.1 Trial design.............................................................................................. 25
4.3.2 Trial design issues................................................................................... 28
4.3.2.1 Choice of comparator PI............................................................. 28
4.3.2.2 Open-label study design.............................................................. 29
4.3.2.3 Resistance status of study cohort................................................. 30
4.3.2.4 RESIST study amendments and relevant protocol deviations........ 31
4.3.2.5 Non-inferiority testing.................................................................. 32
4.4 ADDITIONAL CLINICAL DATA..................................................................... 33
5. CLINICAL PHARMACOLOGY........................................................ 35
5.1 Clinical Pharmacokinetics................................................................ 35
5.1.1 Demographic subpopulations.................................................................. 37
5.1.2 Absorption, distribution, metabolism, elimination (ADME).................. 38
5.1.2.1 Absorption................................................................................. 38
5.1.2.2 Distribution................................................................................. 40
5.1.2.3 Metabolism................................................................................. 40
5.1.2.4 Excretion.................................................................................... 41
5.1.3 Drug interactions..................................................................................... 42
5.1.3.1 Effect on tipranavir...................................................................... 42
5.1.3.2 Interactions with reverse transcriptase inhibitors........................... 43
5.1.3.3 Interactions with protease inhibitors............................................. 45
5.1.3.4 Interactions with non-ARV medications....................................... 46
5.1.3.5 Potential drug interactions............................................................ 48
5.1.4 Hepatic or renal impairment................................................................... 53
5.2 Pharmacokinetic
Conclusions......................................................... 54
6. EFFICACY......................................................................................... 55
6.1 Early Clinical Data................................................................................. 55
6.2 Dose Selection (BI 1182.52)....................................................................... 56
6.3 Efficacy results of pivotal, active-controlled trials (RESIST Trials)............................................................................................................................... 59
6.3.1 Study population...................................................................................... 59
6.3.1.1 Baseline genotypic resistance....................................................... 62
6.3.1.2 Baseline
phenotypic resistance..................................................... 63
6.3.2 Pre-selection of comparator PI and enfuvirtide..................................... 64
6.3.2.1 Stratification by pre-selected PI and enfuvirtide use...................... 64
6.3.2.2 Use of new vs.
ongoing or susceptible vs. resistant
comparator PIs........................................................................... 67
6.3.3 Differences between RESIST studies.................................................... 67
6.3.4 Patient disposition................................................................................... 68
6.3.5 Analysis of treatment response: primary and secondary endpoints..... 69
6.3.5.1 Treatment response..................................................................... 69
6.3.5.2 Response by pre-selected PI strata............................................. 72
6.3.5.3 Viral load change from baseline at 24 weeks (FAS population).... 74
6.3.5.4 Virologic
response (< 400 and < 50 copies/mL) and immunologic response at 24 weeks
(FAS population)........................................................................ 76
6.3.5.5 New onset of AIDS events......................................................... 78
6.3.6.... Impact of active background antiretroviral drugs................................. 78
6.3.7.... Impact of baseline viral load and CD4+ count....................................... 82
6.3.8 Sensitivity analyses................................................................................. 83
6.4 Efficacy RESULTS IN SPECIAL POPULATIONS..................................... 84
6.5 EFFICACY CONCLUSIONS.............................................................................. 87
7. RESISTANCE.................................................................................... 88
7.1 Development Of Tipranavir Resistance In Vitro................... 88
7.2 Clinical Resistance (In Vivo).............................................................. 88
7.3 GENOTYPIC SCORES....................................................................................... 89
7.3.1 Key
protease mutations (HIV protease codons 33, 82, 84 and 90)...... 90
7.3.2 Tipranavir score...................................................................................... 91
7.3.3 FDA protease gene mutations................................................................ 92
7.4 Relationship of Genotype to Phenotype..................................... 92
7.5 Impact of Genotype on Virologic Response.............................. 94
7.6 Impact of Phenotype on Virologic Response........................... 97
7.7 Predictors OF VIRAL Load RESPONSE at 24 Weeks..................... 99
7.8 RESISTANCE
Conclusions...................................................................... 100
8. SAFETY............................................................................................ 101
8.1 EXPOSURE........................................................................................................ 101
8.2 SAFETY DATA FROM EARLY CLINICAL TRIALS................................... 101
8.3 CLINICAL SAFETY DATA OF PIVOTAL, ACTIVE-CONTROLLED TRIALS (RESIST-1
AND RESIST-2)................................................................................................ 103
8.3.1 Exposure and disposition...................................................................... 105
8.3.2 Adverse Events in RESIST trials......................................................... 106
8.3.3 Serious adverse events......................................................................... 108
8.3.4 Adverse events leading to discontinuation of treatment..................... 110
8.3.5 Exploratory analyses of medically selected terms.............................. 111
8.4 LABORATORY EVALUATIONS OF PIVOTAL, ACTIVE-CONTROLLED TRIALS (RESIST-1 AND RESIST-2)............................................................................................. 114
8.4.1.... Overview of DAIDS Grade 3 and 4 Laboratory Adnormalities in the Safety Update................................................................................................................ 114
8.4.2.... Hepatic Transaminase Elevations in the Safety Update..................... 115
8.4.2.1 Evaluation of ALT and/or AST Abnormalities............................ 115
8.4.2.2 Multivariable Analysis for Risk of LFT Elevations...................... 117
8.4.2.3 Actions Taken with LFT Abnormalities...................................... 118
8.4.2.4 Clinical Hepatic Adverse Events................................................ 120
8.4.2.5 Summary of Hepatic Findings.................................................... 121
8.4.3.... Fasting Lipid Elevations....................................................................... 122
8.4.3.1 Triglyceride Elevations.............................................................. 122
8.4.3.2 Cholesterol Elevations............................................................... 124
8.5 mortality and aids progression.................................................. 125
8.5.1.... Deaths in all TPV Trials....................................................................... 125
8.5.2.... AIDS
Progression Events in RESIST Trials....................................... 126
8.5.3 Deaths in RESIST trials....................................................................... 127
8.5.4.... Adjustment for Exposure in RESIST Trials........................................ 127
8.5.5.... Analysis of Patients who Rolled over to Trial BI 1182.17 from the CPI/r arm of RESIST Trials and Died...................................................................................... 129
8.5.6.... Contrast
of Deaths in the rollover study: Patients from RESIST Clinical Program compared
to Patients from other TPV Trials....................................... 130
8.5.7 Review of hepatic deaths...................................................................... 131
8.5.8.... Summary of Deaths............................................................................... 134
8.6 Safety results in special populations....................................... 135
8.6.1.... Long-term safety from rollover Trial BI 1182.17................................ 135
8.6.2.... Pediatric Trial BI 1182.14..................................................................... 137
8.6.3.... Emergency Use and Expanded Access Programs............................... 138
8.6.4.... Safety in Women and Minorities.......................................................... 140
8.7 safety conclusions................................................................................ 141
9. OVERALL Conclusions........................................................... 142
10. PLANS FOR COMPLETING
REQUIREMENTS FOR TRADITIONAL APPROVAL...................................................................................... 148
APPENDIX 1 NONCLINICAL PHARMACOLOGY AND TOXICOLOGY 149
Appendix 1.1 Overview................................................................................... 149
Appendix 1.2 General and Safety
Pharmacology........................ 150
Appendix 1.3 Absorption,
Distribution, Metabolism, and Excretion 151
Appendix 1.4 Toxicology.............................................................................. 152
Appendix 1.4.1 Single dose toxicity studies (acute toxicity)......................... 152
Appendix 1.4.2 Chronic studies...................................................................... 153
Appendix 1.4.3 TPV-ritonavir co-administration studies.............................. 154
Appendix 1.4.4 Genotoxicity studies............................................................. 157
Appendix 1.4.5 Reproduction toxicology....................................................... 157
Appendix 1.4.6 Other toxicity........................................................................ 158
APPENDIX 2 TPV Clinical Trial Program........................... 161
Appendix 2.1 Biopharmaceutic
Studies............................................... 161
Appendix 2.2 Human
Pharmacokinetic Studies.............................. 164
Appendix 2.3 Human
Pharmacodynamic Studies........................... 172
Appendix 2.4 Clinical Efficacy
and Safety Studies...................... 174
Appendix 3 DRUG INTERACTIONS.............................................. 182
Appendix 4 FATAL EVENTS IN RESIST TRIALS........................ 185
AE Adverse event
ALT Alanine
aminotransferase
APV Amprenavir
ARV Antiretroviral
(agent)
BI Boehringer Ingelheim
BID Twice a day
BLQ Below limit of quantitation
CD4+ Cluster of differentiation 4
(antigen marker on T-lymphocytes)
CI Confidence interval
CPI/r Comparator protease inhibitor
with ritonavir
C12h Plasma concentration of drug
at 12 hours
EFV Efavirenz
ENF Enfuvirtide, also referred to
as T-20
EAP Expanded Access Program
EUP Emergency Use Program (BI Trial 1182.58)
FAS Full analysis set
FC Fold-change
GSS Genotypic sensitivity score
HAART Highly active antiretroviral therapy
HFC Hard filled capsule
HIV Human immunodeficiency virus
IC50 Concentration of drug required
to produce 50% inhibition
IDV Indinavir
ITT Intent-to-treat (population)
IQR Interquartile range; 25th
percentile and 75th percentile around median
KM Kaplan Meier probability
LOCF Last observation carried forward
LPV Lopinavir
mg Milligram
mL Milliliter
mm3 Cubic millimeter
N Number of patients
NCC Non-completer considered
censored
NCF Non-completer considered failure
NRTI Nucleoside reverse transcriptase
inhibitor
NNRTI Non-nucleoside reverse transcriptase
inhibitor
OBR Optimized background regimen
OLSS Open-Label Safety Study
OR Odds ratio
OT On treatment
p Probability
PBMC Peripheral blood mononuclear cells
PCR Polymerase chain reaction
PEY Person exposure years
PI Protease inhibitor
PK Pharmacokinetics
PPS Per protocol set
P&U Pharmacia and Upjohn
RESIST-1 Randomized
Evaluation of Strategic Intervention in multi-drug resistant patients with Tipranavir
[BI Trial 1182.12]
RESIST-2 Randomized
Evaluation of Strategic Intervention in multi-drug resistant patients with Tipranavir
[BI Trial 1182.48]
RNA Ribonucleic acid
RR Relative risk
RTV Ritonavir
SAE Serious adverse event
SCS Summary of Clinical Safety
SEC Soft elastic capsule
SEDDS Self-emulsifying drug delivery system
SQV Saquinavir
SQV/r Saquinavir
with ritonavir
SOC System organ class
TPV Tipranavir
TPV/r Tipranavir co-administered with
ritonavir
TR Treatment response
μM Micromole
VL Viral load
WT Wild type
Highly Active Antiretroviral Therapy
(HAART) has had a marked impact on the course of the HIV epidemic in the
developed world. These potent
antiretroviral combination therapies are able to effectively suppress viral
replication and are associated with reconstitution of the immune system. However, non-adherence to HAART regimens and increased
transmission of drug-resistant HIV-1 are common problems in the clinic, and
this has led to the development of a large patient population with multi-drug
resistant HIV-1 infection. Each of the major classes of antiretroviral agents
(ARVs) is affected by resistance, including protease inhibitors (PI). As a result, novel therapeutic agents are
needed to construct active regimens for PI-experienced patients to reduce viral
replication and decrease HIV-related morbidity and mortality. Tipranavir (TPV) is a non-peptidic protease
inhibitor active against the majority of protease inhibitor resistant HIV-1
seen in clinical practice. Both a soft
gelatin capsule and a liquid formulation have been developed to meet the clinical
needs of HIV-positive patients. The
subject of this document is the capsule formulation only (NDA 21-814). Tipranavir helps to address a continued unmet
clinical need for new drugs to treat patients with multidrug resistant HIV-1.
Patients in the tipranavir clinical development program demonstrated multi-drug resistance with varying degrees of cross-resistance to the currently available PIs. In this briefing document, we present 2- and 24-week data demonstrating the antiviral activity of tipranavir, co-administered with low-dose ritonavir (TPV/r), in PI-experienced patients with established PI-resistant viruses.
As of
The ongoing RESIST[1] trial program, which compares TPV/r to a ritonavir-boosted comparator PI (CPI/r) on an optimized background regimen (OBR), is one of the largest programs undertaken in a PI-experienced population. Comparator PIs in the RESIST trials include ritonavir-boosted lopinavir, indinavir, saquinavir, and amprenavir. The intrinsic activity of TPV/r is demonstrated by the ≥ 1 log10 reduction observed at 2 weeks after the initiation of TPV/r therapy. After 24 weeks of treatment (interim analysis), TPV/r had superior antiviral activity compared to CPI/r as shown below:
Overview of Week 24 efficacy endpoints - combined
RESIST trials
|
|
TPV/r + OBR N=582 |
CPI/r + OBR N=577 |
p-value |
|
Median baseline viral load |
4.83 |
4.82 |
|
|
Median baseline CD4+ count |
155 |
158 |
|
|
|
|
|
|
|
Treatment Response
(confirmed > 1 log10 VL decrease) |
41% |
19% |
<0.0001 |
|
Median HIV VL change from
baseline (log10 copies/mL) |
-0.80 |
-0.25 |
<0.0001 |
|
HIV VL < 400 copies/mL |
34% |
15% |
<0.0001 |
|
HIV VL < 50 copies/mL |
24% |
9% |
<0.0001 |
|
Median increase in CD4+ cell
count (cells/mm3) |
34 |
4 |
<0.0001 |
At 24 weeks, TPV/r
had superior virological and immunological responses which were associated with
a non-significant decrease in AIDS progression events in patients with PI‑resistant
HIV-1. The 24‑week responses were of
greater magnitude when TPV/r is combined with other active antiretroviral
agents, for example enfuvirtide.
It has been shown that TPV must be co-administered with low-dose ritonavir to achieve adequate drug levels. Patients taking TPV/r generally achieve plasma concentrations that are many-fold above the protein-adjusted IC90 for the majority of PI-resistant HIV-1 strains in the clinic. Despite being an inducer of the cytochrome P450 isoenzyme 3A (CYP3A) when given alone, TPV when combined with 200 mg of ritonavir produces a net inhibition of CYP3A. The pharmacokinetic drug interactions for most non-antiretroviral concomitant medications are similar to other ritonavir-boosted PIs.
Drug levels for ritonavir-boosted lopinavir, saquinavir, and amprenavir were significantly reduced when combined with TPV/r, therefore these combinations are not recommended. Protease inhibitor levels for novel dual PI regimens containing TPV/r cannot be predicted without formal drug interaction studies possibly due to the mixed patterns of inhibition and induction of CYP pathways seen with these drug combinations.
While reductions in plasma concentrations
of abacavir and zidovudine have been observed when they are combined with
TPV/r, the clinical relevance of these changes has not been established and no
dose adjustment can be recommended at this time.
We have undertaken an extensive
evaluation of the resistance profile of TPV/r and have defined the genotypic
and phenotypic correlates associated with treatment response. The best correlations of the antiviral
activity of TPV/r with a genotypic score were obtained with (1) the
key mutations in the HIV-1 protease at positions 33, 82, 84, and 90, and (2) a tipranavir
score derived from correlation of mutations in HIV-1 protease to viral
phenotype and viral load responses seen in the Phase II and III programs. Based on these analyses, it takes 3 key mutations
and > 4 TPV-score mutations to produce decreased TPV susceptibility (> 3-fold
wild-type) in vitro or decreased antiviral responses in the clinic. High level resistance (> 10-fold
wild type) usually requires all 4 key mutations or > 7 TPV-score mutations
which are uncommon in clinical HIV-1 isolates from treatment-experienced
patients. These in vitro and clinical data
confirm that there is a high genetic barrier to resistance with TPV.
Many of the mutations which are
associated with decreased susceptibility to TPV have not been associated with
drug resistance to currently available PIs.
While one or more mutations at protease codons 33, 82, 84, 90 can produce
high level resistance to currently available PIs, it takes at least three of
these mutations produce reduced susceptibility to TPV/r. The predominant emerging mutations with
virologic failure in PI-experienced patients receiving TPV/r are 33F/I/V,
82T/L, and 84V; the drug resistance pattern which will result from treatment of
drug naïve patients is not yet established.
The types and rates of adverse events (AEs) and serious AEs reported for TPV/r in the RESIST trials are similar to CPI/r and are consistent with AEs associated with the use of other ritonavir-boosted PIs except for increased rates of Grade 3/4 elevations in ALT/AST, cholesterol and triglycerides which were more common with TPV/r than with CPI/r. The hepatic events were generally asymptomatic and most patients were successfully continued on treatment. These laboratory abnormalities can be managed with routine monitoring except in patients with chronic Hepatitis B or C co‑infection or elevated baseline LFTs where increased monitoring of LFTs is recommended.
There was a nonsignificant difference
in fatalities between the TPV/r and CPI/r arms of the RESIST trials at 24 weeks
(p=0.64). The types and rate of
fatalities in the TPV/r development program are consistent with what has been
described for patients with advanced HIV disease. There
have been a limited number of cases of clinical hepatitis or death due to
hepatic failure in the TPV development program, primarily in patients with
advanced HIV disease taking multiple concomitant medications. A causal relationship to TPV/r could not be
established.
In summary, tipranavir, co-administered with low-dose ritonavir, is a novel HIV protease inhibitor which retains significant antiviral activity in the face of multiple PI mutations. Regimens containing TPV/r in the RESIST population of patients with highly PI-resistant viruses had superior virologic and immunologic activity at 24 weeks compared with the CPI/r‑based regimens. Genotypic resistance testing can assist in the selection of drugs to combine with TPV/r and in determination of which patients are most likely to benefit from a TPV/r-based regimen. Similar to other ritonavir-boosted PIs, pharmacokinetic interactions between TPV/r and other drugs metabolized by CYP3A should be expected. The net effect of TPV/r is CYP3A inhibition. Finally, the safety profile of TPV/r is similar to other ritonavir-boosted PIs in a PI-experienced population, except for increased rates of ALT/AST, cholesterol and triglyceride elevations which were seen for the TPV/r arms in the RESIST trials.
The use of
TPV/r-based regimens in treatment-experienced patients with PI-resistant HIV-1 helps
to meet a large unmet clinical need. The
balance of the benefits and risks of drug regimens containing tipranavir
co-administered with low-dose ritonavir supports the indication for use in PI
treatment-experienced patients with HIV-1 infection.
With the introduction of the new class
of HIV protease inhibitors (PI) in the mid-1990s, the Highly Active
Antiretroviral Therapy (HAART) era began.
This was associated with dramatic decreases in HIV-related morbidity and
mortality and subsequent prolongation of the course of HIV infection.[2] However, the first PIs were associated with
poor bioavailability, complex dosing demands, and/or significant GI
intolerability. These factors led to
development of PI resistance, treatment failure, and an understanding of the
importance of treatment adherence.
The second wave of protease inhibitor
development focused on making agents that were easier to tolerate, had an
improved and more forgiving pharmacokinetic profile, and could overcome
established PI drug resistance. These
newer agents to varying degrees have fulfilled this need. However, concurrent resistance to reverse
transcriptase inhibitors developed during this period to the point where many
antiretroviral-experienced patients have evolved significant three-class HIV
drug resistance. This population of
patients harbouring multi-drug resistant HIV represents a growing difficult to
treat group.[3]
Tipranavir is a novel non-peptidic HIV
protease inhibitor that was developed with the specific goal of being able to
overcome broad PI cross-resistance. It
belongs to the class of 4‑hydroxy‑5,6‑dihydro‑2‑pyrone
sulfonamides. The chemical name of tipranavir is 2-Pyridinesulfonamide,
N-[3-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl).
Its molecular formula is C31H33F3N2O5S with a corresponding molecular weight of
602.7 (Figure 1: 1).
Figure 1: 1 Structural
formula of tipranavir
Early in vitro studies showed that viral isolates cross-resistant to most of the commercially available PIs retained susceptibility to tipranavir.[4] The IC90 for multi-drug resistant clinical HIV isolates ranged from 0.31-0.86 µM, and most clinical HIV isolates had a serum-adjusted IC90 of ≤ 2 µM. This is in contrast to an IC90 of 0.18 µM for WT HIV-1 in PBMC.
Although the
number of new AIDS diagnoses and deaths has fallen since the introduction of
highly active antiretroviral therapy (HAART) in the mid-1990’s, many
HIV-positive patients have not had adequate responses to the regimens, cannot
tolerate the toxic effects, or have difficulty complying with treatment
regimens that involve large numbers of pills.
Up to 50% of patients fail their initial regimens, and there is an
increasing population of patients infected with drug-resistant HIV-1 strains
who need new agents with improved resistance profiles compared to those of
existing ARVs.[5] Thus, the initial tipranavir clinical
development program focused on the study of PI-experienced patients in need of
new therapy.
Phase II and III clinical trials in
patients with a PI-resistant HIV-1 have confirmed that tipranavir has potent
antiviral activity. Thus, tipranavir
represents a significant advance in the treatment armamentarium for clinicians
treating drug-resistant HIV-1 infection.
2. NONCLINICAL PHARMACOLOGY AND TOXICOLOGY
General/Safety pharmacology studies were performed with TPV to assess effects on the cardiovascular, central nervous, pulmonary, renal, and gastrointestinal (GI) systems. These studies indicated that the drug was well-tolerated, with some effects noted in the renal and GI systems. Studies to investigate effects on the cardiovascular system showed an inhibitory effect in vitro on the HERG-associated potassium channel (IC50 = 2.9 µM; U02-1175), but no changes were noted in the guinea pig papillary muscle assay at similar concentrations, nor were any effects noted on QTc prolongation in the ECGs of conscious dogs following single administration of up to 160 mg/kg. Overall, these results suggest that TPV has little potential to prolong the QTc interval. No evidence of cardiovascular effects was noted in toxicity studies of up to 26 weeks in dogs with TPV/r or up to 39 weeks in dogs with TPV, and no prolongation of the QTc interval has been observed in multiple clinical studies.
Pharmacokinetic studies in humans have
demonstrated the requirement for RTV co‑administration with TPV treatment
in order to achieve and maintain required plasma levels of TPV for anti-viral
activity. In humans, TPV is primarily
metabolized by CYP3A and is a substrate for Pgp. The boosting effect of RTV on TPV plasma
levels noted in humans is also observed in animals. However, the boosting effect seen in
nonclinical species does not fully reflect that observed in humans, as there
can be distinct species differences in CYP450 and Pgp selectivities. RTV co-administration resulted in an increase
in TPV systemic exposure in all nonclinical species: mice (12- to 22-fold),
rats (6‑to 7-fold), dogs (3‑to 13‑fold), and monkeys
(2-fold). In rats and dogs, co‑administration
of RTV resulted in a 4- to 5-fold decrease in clearance of TPV, consistent with
inhibition of drug-metabolizing enzymes by RTV.
In toxicity studies in animals at higher dose levels the boosting effect
of RTV is lower in magnitude, perhaps due to a saturation of the boosting
mechanism. In humans, in contrast, the
boosting effect is more pronounced with co-administration of RTV (200 mg)
with TPV (500 mg) at the proposed human dose level resulting in a 45-fold
increase in Cmin,
a 4-fold increase in Cmax, and an 11-fold increase in overall systemic exposure (
). RTV is clearly increasing plasma concentrations of TPV by
inhibiting metabolism, as the levels of metabolites in rats and humans are
negligible following RTV co‑administration.
It has been noted in toxicity studies
that TPV exposure in animals, even at the highest dose levels tested, is
approximately equivalent to or only slightly above that achieved at the human
dose level of 500 mg/200 mg TPV/r BID.
Toxicity testing on TPV commenced with TPV administered as a singular
entity. Once it was recognized that TPV
was to be co‑administered with RTV in humans to achieve therapeutic
plasma levels, co‑administration studies in animals were initiated to
investigate the toxicity of the two compounds given concurrently and to
increase plasma levels of TPV in animals.
Co-administration of TPV with RTV does increase plasma levels of TPV in
animals, notably at lower dose levels.
However, this effect diminishes at higher dose levels, and does not
reach the magnitude of the boosting effect that is achieved in humans. Rats in a 26-week TPV study administered
400 mg/kg/day TPV were exposed to maximum plasma concentrations of 90/209
µM in males/females and plasma exposure levels of 910/2320 µM·h
(M/F). No total exposure was calculated
in the 26-week TPV/r study, but plasma levels measured 8 hours after TPV
administration ranged from 180 to 334 µM at the highest dose level tested of
1200/320 mg/kg/day TPV/r. Highest
exposure in dogs was achieved in a 39‑week study at a dose level of
320 mg/kg/day TPV where Cmax and AUC values of 114 µM and
1155 µM·h (sexes combined), respectively, were achieved. These are in contrast to plasma levels
reached at the human therapeutic dose level of 500/200 mg BID TPV/r, where a Cmax of 103 µM and an AUC0-24 of 1542 µM·h were achieved.
Toxicities seen in repeat-dose studies
in rats and dogs are not considered to preclude chronic administration of TPV
to the intended patient population, even in view of their observance at plasma
levels equivalent to or below human exposure.
The reasons for this are primarily their reversibility, manageability,
species specificity, and correlation with species-specific hepatic
enzyme-inducing effects of TPV in the rodent. Primary target organs identified in rats and
dogs included the liver and GI tract. Co-administration
of TPV and RTV in rats and dogs revealed only signs of toxicity or target organ
effects evident when each compound was administered alone. More importantly, co‑administration did
not exacerbate the toxicity of either drug.
Changes in the GI tract in nonclinical
studies have included emesis, soft stools, diarrhea, and/or excessive
salivation post-dosing. Excessive
salivation after TPV administration was attributed to the bitter taste of TPV,
which animals were exposed to during gavage administration.
In rats and dogs, TPV plasma levels
declined with repeated dosing relative to Day 1, indicative of enzyme
induction. This was supported by
increases in CYP450 isoforms CYP3A and CYP2B in both species, increases in
smooth endoplasmic reticulum, increased liver weights, and hepatocellular
hypertrophy. These increases in enzyme
levels in animals are considered an adaptive response to exposure to a
xenobiotic and not evidence of toxicity.
Hepatic effects of TPV were dose-related, and reversible with
discontinuation of treatment, or transient and of no clinical relevance.
Hepatic microsomal enzyme induction has
resulted in secondary changes during toxicity studies in rodents. These include increased clearance of thyroid
hormones with resultant increased thyroid weight and thyroid follicular
hypertrophy/hyperplasia, slight increases in plasma proteins, and increases in
coagulation parameters. All of these
effects were found to be reversible with termination of treatment. Increases in plasma proteins are considered
to reflect their increased synthesis in the liver due to enzyme induction. Thyroid effects in rats due to hepatic
microsomal enzyme induction are not considered relevant to humans. Reversible
increases in coagulation indices (PT and APTT), observed only in rodents
administered TPV or TPV/r, were judged secondary to hepatic enzyme induction
rather than a direct effect of the drug.
Some increases in PT and fibrinogen were observed in mice, but not
consistently, and no increases in coagulation parameters have been observed in
beagle dogs. In response to these
findings in rodents, monitoring of PT was performed in early clinical trials, but
no increases in PT have been observed in humans.
Other hepatic changes in rodents
included degeneration, vacuolation, necrosis, mineral deposition, and karyomegaly. Karyomegaly was noted at a low incidence in
rats treated with TPV/r over 26-weeks.
In these animals, the incidence of karyomegaly was not related to TPV
dose. A much higher incidence was noted
in RTV‑treated animals, and has been previously observed in rat studies
on RTV performed by Abbott Laboratories.
This finding is therefore an effect of RTV administration and not
considered to be of concern for humans administered TPV/r, as in the
combination therapy, RTV plasma levels are low.
The other hepatic findings, along with elevations of ALT and AST,
appeared predominantly in the mouse and were possibly related to tissue anoxia
from circulatory derangements caused by hepatocellular hypertrophy. These changes were not observed in rats and
dogs and may reflect a species-specific effect.
Based on the disparity between species, the implications for humans are
not clear. As liver function may be
readily monitored, the appearance of increased ALT and AST in one species
should not preclude the use of TPV in humans.
In beagle dogs, mild elevations in
alkaline phosphatase in TPV or TPV/r treated groups may be related to enzyme
induction, but may also be caused by an effect on the biliary system. The alkaline phosphatase increases in dogs
were shown in the 26-week SEDDS safety study to be due to the hepatic
isoform. Based on a lack of other
findings indicating cholestasis, this change raises no concern for humans.
Testicular degeneration and/or atrophy
were observed in long-term studies in rats and dogs at high dose levels. Re-evaluation of these data by an expert
panel indicated that the findings in the beagle dog were within normal limits
of variation. The testicular changes in
rats, seen in only three animals at a high dose level, were morphologically and
pathogenically unrelated and therefore not related to drug treatment. Consequently, testes are not considered to be
a target organ of toxicity.
Genotoxicity studies with TPV have
shown no potential for mutagenicity or clastogenicity in standard assays both in
vitro and in vivo. Carcinogenicity
studies are ongoing; therefore no definitive statements may be made regarding
the potential for TPV to induce tumors. A
lack of genotoxicity suggests that TPV would not induce tumors by a mutagenic
or clastogenic mechanism. The potential
effects of TPV on hepatic enzyme induction with consequent hepatic and/or
thyroid tumors in rodent carcinogenicity has already been discussed and at this
time are not considered to be a risk to humans taking TPV chronically.
Reproductive toxicity of TPV was assessed in standard studies in rats and rabbits. At a maximum plasma concentration in rats of 258 µM (2-fold human Cmax), no effects on spermatogenesis, estrous cycles, copulation, fertility, implantation, or early embryonic development were observed. In studies investigating exposure at the time of organogenesis, the no observed adverse effect levels (NOAEL) in rats and rabbits corresponding to exposures (AUC0-24) of 340 µM·h and 66 µM·h were determined. Maternal toxicity, embryotoxicity, and/or developmental toxicity were observed at greater exposure levels. Human exposure levels, at the recommended dose level, are above these NOAEL exposure levels in animals. Consequently, TPV should be given during pregnancy only if the benefit to the mother and the fetus outweighs the risk to the fetus. The definitive study in rabbits resulted in gross malformations at a maternally toxic dose level. These findings were judged to be due to a litter effect and not a drug effect, as marked maternal toxicity was observed at this dose level, and in a previous study at the same and higher dose levels there were no similar findings. Consequently, TPV was judged not to be a selective developmental toxicant and consequently is not teratogenic. TPV retarded pup growth in rats when administered during gestation and into the postpartum period. Distribution studies in rats administered 14C-TPV have demonstrated that radioactivity is excreted into the milk of rats. Consequently, women should be cautioned to avoid breastfeeding while taking TPV.
The immunotoxic potential of TPV was
assessed in a standard assay testing the functioning of the humoral component
of the immune system, the T-dependent antigen response to sheep red blood cells
(sRBC). Treatment with TPV
co-administered with RTV or TPV alone did not adversely affect the functional
ability of the humoral component of the immune system in female CD-1 mice, as
evaluated in the IgM antibody-forming cell response to the T‑dependent antigen,
sRBC.
Toxicity of impurities in TPV drug
substance and degradation products of TPV in drug product have been evaluated
in general toxicity and genotoxicity studies, as recommended by ICH guidances
Q3A(R) and Q3B(R). Impurities in TPV drug
substance and drug product have been qualified at levels equal to or greater
than the proposed acceptance criteria.
TPV is administered in self-emulsifying
drug delivery system (SEDDS) formulations, with both the bulk fill solution and
the oral solution each containing a special mixture of excipients. A 26-week safety study was designed in dogs
to evaluate the toxicity of the bulk fill solution, with special attention
given to the dose levels of one excipient, Cremophor EL (CrEL). CrEL is also present in the co‑administered
RTV capsule formulation, as it is an excipient included in Norvir® capsules at 60 mg/mL (communication from
Abbott Laboratories). Assessment of the
bulk fill solution formulation in rats and dogs in toxicity studies of 13 and
26 weeks, respectively, confirm its safety at the human dose level of 500/200
mg BID TPV/r.
Literature assessment of components of
the TPV oral solution indicate no toxicity concerns when used as
instructed. Levels of propylene glycol (PG)
in the TPV oral solution co‑administered with RTV oral solution are
considered safe when administered to adults and children greater than 2 years
of age. Due to the low levels of the
PG-metabolizing enzyme alcohol dehydrogenase expressed by young livers, caution
must be exercised when administering this combination to infants or children
less than 2 years of age when administering TPV oral and RTV oral solutions
along with other prescription and/or non‑prescription medications
containing propylene glycol and/or ethanol.
Due to the presence of Vitamin
E TPGS in the TPV oral solution,
Vitamin E supplementation should not be taken along with the oral solution
since the Vitamin E content of this product exceeds the Recommended Daily
Intake. Due to anticoagulant effects of
high dose levels of Vitamin E, the possibility exists that this excipient could
exacerbate coagulation defects in individuals who are deficient in Vitamin K or
are receiving anticoagulant therapy and suggests that caution is warranted.
The nonclinical evaluation of TPV/r has
confirmed the safety, efficacy, and bioavailability of TPV for its use in man for
the treatment of HIV.
In
the course of the development of tipranavir, numerous in vitro and in vivo studies
have been conducted to examine its antiviral activity. Particular focus has been on viral isolates
containing mutations (and the patients who harbor these) that confer protease
inhibitor resistance. These studies have
shown that susceptibility to tipranavir is often maintained despite the development
of broad cross-resistance to currently available PIs. In addition, in vitro passage experiments have shown that selection of mutations
that confer resistance is slow; ongoing studies in antiretroviral naïve patients
should help define whether or not there is a signature mutation that confers
resistance to tipranavir.
Tipranavir is a non-peptidic protease
inhibitor (NPPI) of HIV belonging to the class of 4‑hydroxy‑5,6‑dihydro‑2‑pyrone
sulfonamides. In enzymatic assays, TPV
demonstrates potent inhibition of the cleavage of a peptidic substrate by the
HIV-1 protease with an inhibition constant (Ki) of 8.9 ±
3.2 Antiviral Activity In Vitro
Tipranavir inhibits the replication of
laboratory strains and clinical isolates in acute models of T-cell infection,
with 50% effective concentrations (EC50) ranging from 0.03 to 0.07
µM (18-42 ng/mL). Tipranavir is also effective at inhibiting the replication of
M-tropic strains of HIV (EC90 ADA = 0.75 uM, 452 ng/mL and EC90
DGV = 0.3 µM, 180 ng/mL) and at inhibiting the extracellular accumulation
of the p24 capsid protein from H-9 cells chronically infected with HIV-1 IIIB
(EC50 of 0.39 µM, 235 ng/mL).
Protein binding studies have shown that the antiviral activity of
tipranavir decreases on average 3.75-fold in conditions where human serum is
present. When used in combination with other antiretrovirals, tipranavir shows
synergy to additivity with the NRTI zidovudine, the NNRTI delavirdine and the
PI ritonavir. Activities ranging from synergy to slight antagonism were
reported when tipranavir was used in combination with other currently available
ARV drugs. No evidence of strong
antagonism was seen in any of the drugs combined with TPV, and these data have
been recently confirmed by additional analyses of mixed drug cell cultures for
all currently available PIs.
A large subset of isolates from PI-experienced patients entering the pivotal Phase III RESIST trials were evaluated for the presence of phenotypic susceptibility to commercially available PIs and TPV. Analyses using these samples are presented in Section 7 on TPV resistance.
4. OVERVIEW OF CLINICAL DEVELOPMENT PROGRAM
Tipranavir was
discovered by Pharmacia and Upjohn (P&U) and licensed for development by
Boehringer Ingelheim (BI) in 2000. The
initial development of tipranavir conducted by P&U involved optimizing the
soft gelatin capsule SEDDS formulation and characterizing the
ritonavir-boosting effect, so as to address issues of bioavailability and
plasma exposure typical for PIs.
At BI, the TPV
clinical development program was initially focused on PI-experienced patients,
as this group has the greatest unmet medical needs. To provide additional data on the possible
use of TPV/r in other populations, studies in pediatric and treatment naïve
adult patients are ongoing.
Overall, through
Early
open-label, dose ranging studies (BI 1182.3, 1182.2 and 1182.4) demonstrated
that tipranavir reduces viral load in HIV-positive patients with variable
levels of treatment experience (naïve, single- and multiple-PI-experienced). However, these trials failed to determine the
optimal TPV/r dose, thus a Phase II dose-defining study was designed (BI 1182.52).
BI
1182.52 was the definitive dose-finding study that evaluated three TPV/r doses
(TPV/r 500/100, 500/200, and 750/200 given twice daily). The doses chosen for testing in this study
were based on data from the Phase I and II trial program and were considered
the three best doses for possible further study in the Phase III program.
The
study was conducted in patients very similar to those studied in the Phase III
RESIST trials. All patients were triple
ARV class, two PI-based regimen-experienced and had baseline viral isolates
with at least one primary protease mutation (30N, 46I/L, 48V, 50V, 82A/L/F/T,
84V and 90M), with not more than 2 mutations among 82L/T, 84V or 90M. The presence of a primary protease mutation
was required to support adherence to the previous treatment regimen. The specific primary protease mutations
selected were drawn from a mutation list that had been used in a number of
prior clinical trials including the Genotypic Antiretroviral Resistance Testing
(GART) and Multiple Drug Resistance (MDR-HIV) studies.[7] The requirement to have no more than 2
mutations among 82L/T, 84V and 90M was based on in vitro TPV resistance
selection studies, HIV-1 isolates from early Phase II TPV/r trials and a large
panel of highly PI-resistant clinical isolates.[8]
BI
1182.52 was a double-blind study with three TPV/r doses: TPV/r 500/100 mg, TPV/r 500/200 mg and TPV/r
750/200 mg, all given twice daily with a genotypically optimized background
regimen (OBR) that was individually chosen by investigators. The first 2 weeks of the study were the functional
monotherapy phase, in which patients changed the PI they were taking at entry
to one of the three TPV/r doses, but maintained the same OBR. The antiviral effect observed in the first
2 weeks was likely due to TPV/r, thereby allowing critical analyses of the
activity of the three doses. The study
also tested the PK and safety of the three doses.
Based
on a composite of optimal safety, PK and antiviral activity against
PI-resistant viruses, the TPV/r 500/200 mg dose group was selected for study in
Phase III trials. In addition, BI 1182.52
confirmed that patients with virus containing three or more mutations at HIV
protease positions 33, 82, 84 or 90 were unlikely to obtain a durable response
to TPV/r or the alternative boosted PIs available. These data were discussed with the FDA at an
End-of-Phase II meeting prior to the initiation of the Phase III trial program.
4.3 PHASE III PIVOTAL TRIAL PROGRAM
The Phase III
Trials (BI 1182.12 [RESIST-1] and BI 1182.48 [RESIST-2]) are ongoing, large,
randomized, open-label, multicenter trials designed to evaluate the efficacy
and safety of TPV/r in comparison to ritonavir-boosted comparator PIs
(CPI/r). Similar to the Phase IIB
dose-finding study, patients in the RESIST trials were triple ARV class, two
PI-based regimen experienced with HIV RNA ³1,000 copies/mL at
baseline. The study was originally
designed for 48 weeks, but has now been extended for up to five years of follow
up.
Genotyping was
conducted at screening for the study and patients had to demonstrate at least
one primary protease mutation (30N, 46I/L, 48V, 50V, 82A/L/F/T, 84V or 90M),
with not more than 2 mutations at codons 33, 82, 84 or 90. Patients screening for the RESIST studies
with 3 or more of these key mutations were eligible for the companion dual-booted
PI study, BI 1182.51.
Both the general
design of the tipranavir development program and the protocols in the Phase III
program (BI 1182.12, 1182.48, and 1182.51) were reviewed with the FDA and
important design elements were agreed upon.
The RESIST studies also received a Special Protocol Assessment prior to
initiation.
Figure
4.3.1: 1 General design of the
tipranavir Phase II—III development program
The genotypic
inclusion requirement in both BI 1182.52 and in the RESIST trials was based on
the need to test a documented PI-experienced patient population for proof of
the efficacy of TPV/r in these treatment-experienced patients. Patients were required to have at least one
primary mutation to demonstrate that they had taken and failed a PI-containing
regimen with sufficient adherence to select for a mutation. Importantly, any
one of the mutations on the list would have been insufficient to develop
resistance to all of the 4 comparator PIs used in RESIST.
In earlier in vitro and clinical data (BI 1182.52),
the presence of multiple mutations at protease codons 33[9],
82, 84, or 90 had been associated with reduced VL responses to TPV/r and shown to produce high level resistance to
currently available PIs (specifically LPV, IDV, SQV, and APV). By allowing a
maximum of two mutations at positions 33, 82, 84, or 90, patients who had clear
evidence of PI resistance but still had a sufficient chance to respond to
either study arm were selected for the RESIST trials.
Since it was
anticipated that patients with three or more mutations at codons 33, 82, 84, or
90 would be unlikely to achieve a durable 1 log10 response with
either TPV/r or any of the CPI/r treatments, a dual boosted PI companion study
(BI 1182.51) was designed. The objective
of this study was to evaluate the PK, safety and preliminary efficacy of a
dual-boosted PI regimen containing TPV in patients with 3 or 4 mutations at
codons 33, 82, 84, or 90.
To ensure that
both arms of the RESIST trials had a balanced number of patients with similar
characteristics, the OBR had to be pre-selected prior to randomization. Specifically, using baseline genotyping
results and patient treatment history, investigators had to pre-select the PI
their patients would receive if they were randomized to the CPI/r arm. In addition, investigators had to pre-select
the OBR and decide whether they would choose enfuvirtide as part of the
OBR.
Following the
selection of the preferred PI and the OBR, patients in the RESIST trials were
then randomized 1:1 to either TPV/r or to the comparator arm (CPI/r) Patients in the CPI/r would receive the PI
that had been pre-selected (lopinavir [LPV], indinavir [IDV], saquinavir [SQV]
or amprenavir [APV]). Importantly, the
randomizations were stratified according to both the pre-selected PI and on
whether or not they intended to use enfuvirtide.
It was intended
that all patients receive the best possible treatment available. If the patient's treatment history and
genotype indicated that the PI that was part of the screening regimen was the
best option for the patient (an ‘ongoing PI’), this could be the pre-selected
PI chosen by the investigator for the RESIST trial.
In general, the
designs of the two RESIST trials are similar except for the timing of the
interim trial endpoints, the statistical hypotheses, and the resistance testing
methods used. The primary endpoint for
both trials is treatment response after 48 weeks. As defined in the protocol,
the analysis for accelerated approval submission was to be performed at Week
24.
In the two RESIST
studies, the key efficacy endpoint for the 24-week analysis was
‘treatment response,’ a composite endpoint of the proportion of patients
with two consecutive viral load measurements ³1 log10 below baseline without evidence of: confirmed
virological failure to < 1 log10 reduction, introduction of a new
ARV (for reasons other than toxicity or intolerance to a background drug), permanent
discontinuation of study drug, loss to follow-up, or death.
It is the 24-week
interim analyses of the RESIST studies that form the foundation of the data
provided in the TPV NDA package submitted for accelerated approval.
4.3.2.1 Choice of comparator PI
The comparator
arm treatments in the RESIST studies were selected as an “optimized standard of
care.” Following the 1:1 randomization,
patients could be treated with any of four RTV-boosted comparator PIs along
with an OBR. The choice of both the
comparator PI and the OBR was made prior to randomization by each investigator
and was based on individual treatment history and the screening genotype data
provided. As noted above, the objective
of the pre‑randomization selection of all medications was to ensure
balance between the two treatment arms, to provide the optimal treatment
response for patients who were randomized to the comparator arm, and to
eliminate a potential source of bias.
If needed,
investigators were offered the use of an external panel of resistance experts
to assist with drug selection (as needed) and to optimize the PI treatments
chosen for use in the CPI/r arm. The use
of enfuvirtide was allowed if it was pre‑declared prior to randomization
and could be made available from the start of treatment. The randomization was stratified on both the
choice of comparator PI and the use of enfuvirtide.
The use of a
single RTV-boosted PI in the comparator arm (e.g., LPV/r) would have simplified
the study analyses and allowed for blinding, and BI carefully considered this
approach. BI concluded that the
limitations of this approach outweighed the benefits. First, the trial would have been very slow to
enroll; if there had been just one PI option in the CPI/r arm, patients and
investigators might have considered the trial less attractive since that CPI/r
option may not have been optimal for their treatment. Second, use of a single RTV-boosted PI in the
CPI/r arm would have limited the amount of comparative data in this
treatment-experienced population. Third,
patients in the comparator arm would not necessarily be taking an “optimized
standard of care” regimen, and a large number of comparator arm drop-outs might
have resulted that could have invalidated the study efficacy endpoints. Finally, providing the best possible
individualized option for each patient who randomized to the comparator arm
appeared to be the most ethical approach for such patients since this optimized
the opportunity for a treatment response in the CPI/r arm.
4.3.2.2 Open-label study design
BI recognizes the
advantages of conducting pivotal registrational trials in a randomized,
double-blind study design. However, the
open-label design of the two RESIST trials allowed the use of the best possible
RTV-boosted PI for patients randomized to the CPI/r arm. Using blinded drug supplies in the study
would have required patients to take more capsules and this might have reduced
patient adherence in both treatment arms; this would have also required a
complex, time-consuming set of blinded drug supply agreements between
five different pharmaceutical companies.
The open-label nature of the RESIST studies was discussed with the FDA
and concurrence was achieved on these important design elements.
To help overcome potential biases in this open‑label
study design, BI took multiple precautions.
First, an objectively defined composite primary endpoint—one log viral
load reduction from baseline—was chosen which would be unlikely to be subject
to bias. Second, the conservative intent-to-treat, non-completer considered
failure approach has been used for the primary analysis, and multiple
sensitivity analyses have been performed[10]. Third, investigators were required to
pre-select both the CPI/r and OBR to be used.
Finally, BI statistical, data management, and clinical teams were
internally blinded to individual patient treatment assignment during the
conduct of the study until after database lock. In spite of these precautions,
BI was aware that the open-label study design might have a higher rate of
discontinuations in the comparator arm since patients were knowingly not
receiving TPV/r, a potentially preferred treatment option.
It is important to note that patients in the comparator arm
could leave the study after Week 8 if they had confirmed virologic failure in
order to receive TPV treatment outside of the RESIST program (in the BI 1182.17
long-term safety follow-up study). To reduce the number of patients who might
not strictly adhere to the comparator arm treatments, all RESIST investigators
were required to carefully document virologic failure and to provide confirmed
comparator PI plasma concentrations prior to patients being able to receive TPV
in BI 1182.17. Due to the subjective
nature of adverse event reporting, patients leaving the comparator arm of
RESIST for safety reasons were not considered for participation in BI 1182.17.
4.3.2.3 Resistance
status of study cohort
The RESIST study population was chosen as a representative
sample of patients with PI treatment-experience who demonstrated PI resistance.
Prior to patient randomization in the two RESIST studies,
the study protocol was amended (Amendment 2) to allow investigators to
pre-select a comparator PI that was interpreted as “resistant” on the baseline
genotype report.
This important protocol amendment was necessary because
initial genotype reports indicated that 57.4-73.8% of patients had resistance
to the selected PI, making it impossible to enroll eligible
patients and complete the trial within a reasonable time period. Patients with pan-resistance to available PIs
and very limited treatment options would at least have a 50% chance of
receiving TPV/r. Additional
considerations included the knowledge that the genotype report gives an interpretation
of resistance primarily based on unboosted PIs, while RTV-boosted PIs were
exclusively used in the comparator PI arm.
BI encouraged investigators to review the actual mutations listed on the
resistance report (in addition to the interpretation) and to make use of the
expert resistance consultant panel[11].
Finally, BI recognized the importance of providing TPV/r to patients in the
RESIST studies if they had virologic failure on the CPI/r arm, and this was
made available through BI 1182.17, the long term rollover trial.
4.3.2.4 RESIST
study amendments and relevant protocol deviations
There were six RESIST protocol amendments by the time of the
24-week interim analysis. These
amendments did not fundamentally change the study objectives, nor did their
implementation have a clinically relevant impact on patients participating in
the study (with the exception of Amendment 2).
The primary goals of each amendment are described in the following
paragraph.
Amendment 1 was implemented
prior to the start of patient treatment to allow the use of tenofovir in
The relevant
protocol deviations were broadly characterized in the trial protocols and
specified in more detail in the trial statistical analysis plans. Final decisions about relevant protocol
violations were made independently by the trial teams in the blinded report
planning meetings held for each study, and these take place prior to internal
unblinding of the data base. It is
important to point out that each trial team was permitted to make their own decisions
about relevant protocol deviations and reconciliations between the two RESIST
study teams was not required. During the
review process by the international TPV project team, relevant protocol
deviations were re-assessed using the same fundamental criteria as used by each
individual trial. As a result, a
modified per-protocol set was derived that is slightly smaller than the
per-protocol set report analyzed at 24 weeks in the individual RESIST clinical
trial reports. This modified
per-protocol set reduces the TPV/r group by six patients and the CPI/r group by
14 patients, leaving no substantive impact on the conclusion of superiority for
the TPV/r arm.
4.3.2.5 Non-inferiority testing
For the
pre-planned analyses at 24 weeks, both RESIST clinical trial protocols had
planned to use a test of non-inferiority of TPV/r to CPI/r, followed by a test
of superiority of TPV/r to CPI/r if non-inferiority was confirmed. Both tests were to be performed by the
calculation of the same 95% confidence interval for the differences in response
rates, taking into account the stratified randomization in the two arms of the
trials.
The test of
non-inferiority was originally included in the protocol statistical analysis
plans because the control group was expected to show a response rate comparable
to that of the TPV/r arm, at least in a large sub-group of the participating
patients who would have viruses sensitive to both TPV and their chosen CPI. However, after Amendment #2 was implemented
and it was recognized from the analysis of the composition of the trial population
and the response rate of the CPI/r group, it became obvious that the response
rate in the CPI/r group was incompatible with a response of a fully active
control arm. As a result, BI concluded
that a demonstration of non-inferiority was insufficient to demonstrate the
antiviral efficacy of TPV/r and that a demonstration of superiority was
required.
In support of the
RESIST pivotal program, further extensive clinical data have been generated.
These include an initial study of the impact of TPV in very highly treatment
experienced patients, too resistant for participation in the RESIST trials (BI
1182.51).
In addition, a
large amount of data on the resistance profile of TPV, evaluating the clinical
impact of TPV resistance on treatment response and identifying predictors of
TPV treatment response, has been generated, providing a resistance profile
database superior to that of any currently available ARV.
In parallel, an
extensive and highly detailed analysis and characterization of the
pharmacokinetic and drug interaction profile of TPV/r has been performed.
At the time of
NDA submission, data on 37 pediatric patients with up to four weeks of TPV/r
exposure was available. This 48-week, 100-patient pediatric study in HIV-infected
children and adolescents between 2 and 18 years of age now has been fully
accrued and will be the subject of a future efficacy supplement.
Finally, a Phase
III study of TPV/r versus LPV/r in antiretroviral naïve patients has recently
completed enrolment.
All studies in the TPV development program have used standard research approaches to design, conduct, and analysis that are consistent with other ARV drug development programs. A listing of all 39 clinical trials conducted in support of TPV may be found in Appendix 2.
To achieve effective tipranavir plasma concentrations using a twice-daily (BID) dosing regimen, co-administration of tipranavir with low-dose ritonavir twice-daily is essential. Ritonavir acts by inhibiting hepatic cytochrome P450 3A (CYP 3A), the intestinal P‑glycoprotein (Pgp) efflux pump, and possibly intestinal cytochrome P450 3A as well. As demonstrated in a dose‑ranging evaluation in 113 HIV-negative healthy male and female volunteers (BI 1182.5), ritonavir increases tipranavir AUC0-12h, Cmax and Cmin by decreasing its clearance.
Tipranavir 500 mg, co-administered
with low-dose ritonavir 200 mg (TPV/r 500/200 mg), BID for 21 days was
associated with a 48-fold increase in the geometric mean morning steady-state
trough plasma concentrations of tipranavir as compared with tipranavir
500 mg given BID without ritonavir for 11 days (Figure 5.1: 1).
Figure 5.1: 1 Steady
state plasma tipranavir concentrations on the 11th-day of 500 mg BID
administration without ritonavir (open circles) and following the addition of
200 mg ritonavir BID for 14 days (closed circles)
Given alone, TPV induces hepatic CYP 3A and RTV inhibits CYP 3A. To understand the net effect of coadministration of tipranavir and ritonavir on hepatic CYP 3A, a single 200 mg dose of ritonavir co-administered with 500 mg tipranavir was studied using an erythromycin breath test (ERMBT).
Tipranavir rapidly induced CYP 3A when given alone. When ritonavir was added the expected inhibitory effect on CYP 3A was predominant. This net inhibition of CYP 3A for the TPV/r combination was nearly complete on Study Day 1. Following withdrawal of drug administration, CYP 3A activity returned to baseline levels by Study Day 3, likely due to hepatic enzyme turnover.
These data confirm that tipranavir and
ritonavir must be taken together and doses should not be missed. Patients should be cautioned to take their
tipranavir and ritonavir together as prescribed and to not run out of the
booster drug, ritonavir. Full hepatic enzyme
inhibition is necessary to deliver adequate exposure to tipranavir.
The recommended dose of tipranavir is
500 mg (two 250 mg capsules or 5 mL of oral solution), co-administered
with 200 mg ritonavir (low-dose ritonavir), twice daily. Steady state is attained in patients after 7
days of dosing. TPV/r exhibits linear
pharmacokinetics at steady state and the half-life is 6.0 hours in HIV‑positive
patients. Trough concentrations 60‑fold
above the protein-adjusted IC50 for protease inhibitor-resistant
HIV-1 clinical isolates (i.e., IQ ³ 60) are achieved at doses of TPV/r 500/200 mg, and have been
associated with a 1 log10 viral load reduction in clinical studies
of treatment-experienced patients.
5.1.1 Demographic subpopulations
Demographic subpopulations were also analyzed. For example, evaluation of steady-state plasma trough tipranavir concentrations at 10-14 h after dosing from the RESIST studies demonstrated that there was no change in median trough tipranavir concentrations as age increased for either gender through 65 years of age. The trend of consistent trough tipranavir concentrations with increasing age through 80 years for men was supported.
In addition, females generally had higher tipranavir concentrations than males. After 4 weeks of TPV/r 500 mg/200 mg BID, the median plasma trough concentration of tipranavir was 43.9 mM for females and 31.1 mM for males.
Finally, white males generally had more variability in tipranavir concentrations than black males, but the median concentration and the range making up the majority of the data are comparable between the races. Table 5.1.1: 1 summarizes pharmacokinetic parameters by gender and HIV status.
Table 5.1.1: 1 Population
pharmacokinetic assessment by gender and HIV status
|
Pharmacokinetic parameter |
HIV+ patients |
HIV- subjects |
||
|
Females (N = 14) |
Males (N = 106) |
Females (N = 25) |
Males (N = 42) |
|
|
Cp0h,12h (mM) |
30.94 |
31.63 |
43.26 |
32.97 |
|
Cmax
(mM) |
92.33 |
75.87 |
114.71 |
90.08 |
|
Tmax
(h) |
2.9 |
2.9 |
3.0 |
2.9 |
|
AUC0-12h
(h•mM) |
792.8 |
681.0 |
1005.3 |
781.8 |
|
|
|
|
|
|
|
CL
(L/h) |
1.05 |
1.22 |
0.83 |
1.06 |
|
V
(L) |
7.7 |
10.2 |
5.3 |
7.0 |
|
|
|
|
|
|
|
t1/2
(h) |
6.0 |
4.8 |
||
|
|
5.5 |
6.0 |
4.7 |
4.8 |
|
|
|
|
|
|
|
Ka
(h-1) |
0.5142 |
0.5291 |
0.4406 |
0.4780 |
|
Ke
(h-1) |
0.1354 |
0.1200 |
0.1560 |
0.1510 |
|
free
fraction protein binding |
0.015% ± 0.006% |
0.019% ± 0.076% |
||
5.1.2 Absorption,
distribution, metabolism, elimination (ADME)
Because tipranavir is a Biopharmaceutics
Classification Scheme (BCS) Class II compound, with low solubility and high
permeability, absorption of tipranavir in humans is limited, though no
quantification of absolute absorption is available.
A self-emulsifying drug delivery system (SEDDS) to create a microemulsion environment in the gastrointestinal tract upon agitation with water is required to get maximum dispersion of tipranavir in the gastrointestinal tract as a solution.
Food
Tipranavir capsules, administered under high fat
meal conditions or with a light snack of toast and skim milk, were tested in a
multiple dose study. Food enhanced the extent
of bioavailability (AUC point estimate 1.31, confidence interval 1.23‑1.39),
but had minimal effect on peak tipranavir concentrations (Cmax point estimate 1.16, confidence interval 1.09‑1.24). Based on these data, tipranavir may be safely
taken with standard or high-fat meals and food appears to improve GI
tolerability and aid in the emulsification of the drug.
Antacid
When TRV/r was co-administered with 20 mL of
aluminium and magnesium-based liquid antacid, tipranavir AUC0®12h, Cmax and C12h were reduced by 25-29%. Consideration should be given to separating TPV/r
dosing from antacid administration to prevent reduced absorption of
tipranavir.
The effect of a proton pump inhibitor
on tipranavir absorption has not been studied in a formal drug interaction
trial. However, for the 80 patients on
proton pump inhibitors in the RESIST studies, the median trough tipranavir
concentration was 41 µM compared to a median 34 µM concentration
observed in the group of 570 patients not on proton pump inhibitors.
Formulation
Excipients
Despite the significant amounts of the emulsifier Cremophor
EL® ingested each day with tipranavir and
ritonavir capsules, systemic ricinoleic acid concentrations have not been
detected after 6 months of chronic therapy demonstrating that the large
molecular weight excipient is not absorbed.
Loperamide
Loperamide is often co-administered with TPV/r to control
diarrhea. A pharmacodynamic interaction
study in healthy volunteers demonstrated that administration of loperamide 16mg
and TPV/r 750 mg/200 mg does not cause any clinically relevant change in the
respiratory response to carbon dioxide, a surrogate marker for CNS entry of
loperamide and its metabolite.
The pharmacokinetic analysis showed
that the AUC and Cmax of loperamide and its
metabolite were reduced by greater than 50%, whereas the AUC and Cmax
for tipranavir remained unchanged and the Cmin decreased by 26%. Since the primary
pharmacologic activity of loperamide is local, lower systemic loperamide
concentrations are not of clinical concern.
This data does suggest that TPV/r has an inductive effect on efflux
transporters in vivo.
Tipranavir is extensively bound to
plasma proteins (>99.9%). From
clinical samples of healthy volunteers and HIV-1 positive subjects who received
tipranavir the mean fraction of tipranavir unbound in plasma was similar in
both populations (healthy volunteers 0.015% ± 0.006%; HIV-positive subjects 0.019% ± 0.076%). Total plasma tipranavir concentrations for these samples
ranged from
Since tipranavir is highly protein
bound, dialysis is unlikely to be beneficial in significant removal of this
medicine in an overdose situation.
In
vitro
In an in
vitro drug interaction assessment using tipranavir alone the I/Ki
ratios, based on in vivo maximum plasma tipranavir concentrations (bound
and free) following ritonavir-boosted tipranavir administration, were greater
than 1 (interaction likely) for the inhibition of CYP1A2, CYP2C9, CYP2C19,
CYP2D6, and CYP3A4. Follow-up in vivo evaluations using probe
substrate drugs for these isoforms have not yet been conducted to rule out
these potential interactions. During the
conduct of the RESIST trials, patients were on co-medications that were
substrates for these major human isoforms.
A review of the case reports for patients co-prescribed a CYP2C19
substrate carisoprodol (n=5), a CYP1A2 substrate olanzapine (n=6), and a CYP2C9
substrate phenytoin (n=9) failed to show a need for dose adjustment of the
substrate drug. For the CYP1A2, CYP2C19,
CYP2C9, CYP3A4 substrate warfarin (n=3), frequent INR monitoring due to the
ritonavir component of tipranavir therapy is warranted.
In
vitro metabolism studies with human liver
microsomes indicated that CYP3A is the predominant CYP isoform involved in
tipranavir metabolism.
In
vivo
Tipranavir is a substrate of intestinal and hepatic
CYP3A activity and Pgp, and appears to be both an inhibitor and an inducer of
these metabolic and transport systems, but the clinical significance of these
findings is not yet established. Steady
state is attained after 7 days of dosing. TPV/r exhibits linear
pharmacokinetics at steady state.
As noted above, the ERMBT data
confirmed in vitro analyses indicating that tipranavir induces the
cytochrome P450 CYP3A enzyme system after multiple doses. Hepatic CYP3A activity, as measured by the
ERMBT, increased from basal levels following oral administration of 500 mg
tipranavir alone for 11 days, thus indicating hepatic CYP3A enzyme
auto-induction. With the addition of 200
mg of ritonavir, the percent of erythromycin metabolised per hour dropped to negligible
values. This indicates that the net
systemic effect of TPV/r is inhibition of the hepatic CYP3A enzyme system.
The oral clearance of tipranavir decreased after the addition of ritonavir which may represent diminished first-pass clearance of the drug at the gastrointestinal tract and the liver. With repeated dosing, tipranavir plasma concentrations are lower than predicted from single dose data, presumably due to efflux transporter induction as the metabolism of tipranavir in the presence of low-dose ritonavir is minimal.
In a 14C-tipranavir human
study (BI 1182.24) radio-labelled tipranavir (14C‑tipranavir)
given with unlabelled RTV 200 mg, unchanged tipranavir was the predominant form
detected, accounting for 98.4% or
greater of the total plasma radioactivity circulating at 3, 8, or 12 hours
after dosing. Only a few TPV metabolites
were found in plasma, and all were at trace levels (0.2% or less of the plasma
radioactivity).
Administration of 14C-tipranavir to subjects (n = 8) who received TPV/r 500/200 mg BID dosed to steady-state demonstrated that the majority of radioactivity (median 82.3%) was excreted in feces. Only a median of 4.4% of the radioactive dose administered was recovered in urine.
In addition, 56% was excreted between 24 and
96 hours after dosing. A minor
fraction of the dose, attributed to colonic bacteria, was detected as
metabolites in the feces; the overwhelming majority of the dose was excreted
unchanged.
The effective mean elimination
half-life of tipranavir/ritonavir in healthy volunteers (n = 67) and
HIV-infected adult patients (n = 120) was 4.8 and 6.0 hours, respectively, at
steady state following a dose of TPV/r 500/200 mg BID with a light meal.
Since tipranavir and ritonavir are both metabolized by CYP3A, studies evaluating the TPV/r co-administration with agents that induce CYP3A (e.g., efavirenz) or inhibit CYP3A (e.g., fluconazole) were performed.
The analyses in Table 5.1.3.1: 1 demonstrate that if ritonavir 200 mg is chronically co-administered with tipranavir, then the CYP3A enzyme induction effect of efavirenz will not decrease the systemic tipranavir or ritonavir exposure. However, both fluconazole and clarithromycin increased the tipranavir concentration even in the presence of 200 mg ritonavir. When only ritonavir 100 mg is co-administered with tipranavir enzyme induction by efavirenz produces significant decreases in tipranavir exposure.
Table 5.1.3.1: 1 Mean Pharmacokinetic Ratios* of
Tipranavir in the Presence of Co-administered Drug Based on Historical
Tipranavir Data for
|
Regimen |
Cmax |
AUC |
Cmin |
|
TPV/r 500/200 mg BID & |
1.40 |
1.66 |
2.00 |
|
TPV/r 500/200 mg BID & |
1.32 |
1.50 |
1.69 |
|
TPV/r 500/100 mg BID & |
0.79 |
0.69 |
0.58 |
|
TPV/r 750/200 mg BID & |
0.97 |
1.01 |
0.97 |
* Mean pharmacokinetic ratios with 90% confidence intervals (5 and 95
percentiles) following 2000 bootstrap samples.
Design did not permit a true cross-over comparison.
5.1.3.2 Interactions with reverse transcriptase
inhibitors
When administered
alone, tipranavir is an inducer of hepatic CYP3A. TPV/r at the recommended
dosage, is a net inhibitor of the hepatic CYP3A. TPV/r may therefore increase plasma
concentrations of agents that are primarily metabolised by CYP3A similar to
other ritonavir-boosted PIs. These increases in plasma concentrations of
co-administered agents could increase or prolong their therapeutic effect and
adverse effects.
The systemic exposures of stavudine,
lamivudine, tenofovir, efavirenz, and nevirapine are not affected by TPV/r
(Table 5.1.3.2:
1).
Zidovudine systemic exposure decreases by >40%, with no impact on glucuronidated-ZDV levels. Similarly, TPV/r decreases the extent of abacavir systemic exposure by approximately 40% and co-administration with enteric-coated didanosine is associated with a 10-20% reduction in didanosine levels. Based on the metabolic pathways for NRTIs, an interaction with TPV/r of this magnitude was unexpected and the mechanism(s) is unknown.
It should be noted that the prescribing information for zidovudine states that routine dose adjustment is not warranted for decreases of 25-47% in zidovudine exposure. It is possible that the drug interaction between didanosine and TPV/r was due to food and may be minimized by separating the didanosine administration by at least 2 hours from the dose of TPV/r taken with food. The clinical relevance of the decreases in exposure to ZDV, abacavir, and ddI are not known. No recommendation for dose adjustment of ZDV, abacavir or ddI can be made at this time. No dosage adjustments are necessary when the NNRTIs nevirapine or efavirenz are co-administered with TPV/r at the 500/200 mg dose.
Most NRTIs, without significant changes
in plasma concentrations, may be safely co-administered with TPV/r. For ZDV and ABC, the clinical relevance of
the reductions in plasma concentrations is not established and further studies
are needed. As these drug-drug
interaction studies between TPV/r and NRTIs measured only plasma concentrations
of the NRTIs, studies to measure intracellular triphosphorylated drug levels of
ZDV and abacavir are currently being planned.
Table 5.1.3.2: 1 Comparison of NRTI and NNRTI levels
when combined with TPV/r, ritonavir alone, or ritonavir-boosted lopinavir.
|
Substrate Drug |
Ritonavir-boosted
tipranavir result |
Ritonavir
alone |
Ritonavir
boosted lopinavir result |
|
Abacavir |
¯ 40% AUC |
NR |
NR |
|
Zidovudine |
¯ 43% AUC |
¯ 25% AUC |
NR |
|
Didanosine |
¯ 10% AUC |
¯ 13% AUC |
NR |
|
Stavudine |
¯
0-20% |
NR |
NR |
|
Lamivudine |
¯
5-15% |
NR |
NR |
|
Tenofovir |
no
change in AUC, |
NR |
NR |
|
Efavirenz |
0-12% |
NR |
¯ 10-15% |
|
Nevirapine |
¯
3-14% |
NR |
5-15% |
NR =
not reported in prescribing information for Norvir® or Kaletra®
5.1.3.3 Interactions with protease inhibitors
Protease inhibitor (PI) levels for
dual-boosted protease inhibitor regimens containing TPV/r cannot be predicted
without a formal drug interaction study due to the mixed patterns of inhibition
and induction of CYP pathways seen with these boosted-drug combinations.
In a clinical study (BI 1182.51) of dual-boosted PI combination therapy in multiple-treatment experienced HIV-positive adults, TPV/r, was combined with ritonavir-boosted lopinavir, saquinavir, or amprenavir. When tipranavir, lopinavir, and ritonavir were co-administered, there was a 55% reduction in lopinavir systemic exposure and a 70% reduction in the Cmin of lopinavir. When tipranavir, saquinavir, and ritonavir were co-administered, there was a 76% reduction in saquinavir exposure and >80% reduction in the Cmin of saquinavir. When tiparanavir, amprenavir, and ritonavir were co-administered, there was a 45% reduction in amprenavir systemic exposure and a 55% reduction in the Cmin of amprenavir[14].
In the absence of having established
appropriate doses for the combination of TPV/r and LPV, SQV, or APV, these
combinations are not recommended.
5.1.3.4 Interactions with non-ARV medications
Interactions between TPV/r and medications commonly used by patients with HIV were also performed.
Fluconazole
TPV/r does not substantially affect (< 10%
decrease) the steady-state pharmacokinetics of fluconazole (Table 5.1.3.4: 1). As previously noted, fluconazole increases
the AUC and Cmin of tipranavir by over 50% when compared to
historical data. Fluconazole doses >200 mg/day are not recommended as an
initial dose to be combined with TPV/r[15].
Atorvastatin
TPV/r increases the plasma concentrations of
atorvastatin (Table 5.1.3.4: 1) by approximately 8-10 fold and reduces the
extents of exposures of the hydroxyl-metabolites by >85%. This observed interaction is comparable to the
interactions observed with other ritonavir-boosted protease inhibitors. Atorvastatin
does not significantly change the AUC, Cmax or Cmin of tipranavir. It is recommended to initiate
atorvastatin treatment with the lowest possible dose with careful monitoring or,
alternatively, to consider the use of other HMG-CoA reductase inhibitors such
as pravastatin, fluvastatin or rosuvastatin[16].
Rifabutin
TPV/r increases plasma concentrations of rifabutin
(Table 5.1.2.4: 1) by up to 3 fold, and the 25-O-desacetyl-rifabutin active
metabolite by up to 20 fold. Rifabutin
increases the Cmin of tipranavir by 16%. Dosage reductions of rifabutin
by at least 75% of the usual 300 mg/day are recommended (i.e., 150 mg three
times per week). Further dosage reduction may be necessary for some individuals.
Clarithromycin
TPV/r increases the AUC and Cmin of clarithromycin by 19% and 68%, respectively,
and decreases the extent of exposure of the 18‑hydroxy active metabolite
by over 95%. These changes are not
considered clinically relevant unless treating Haemophilus influenzae.
As described earlier, clarithromycin 500 mg doubles the Cmin of tipranavir.
This large increase in Cmin may be clinically relevant.
Patients should therefore use the 500 mg BID dose of clarithromycin and should
be carefully monitored if higher doses are required. Because the metabolic pathway for
clarithromycin elimination has been altered, the renal pathway is expected to
predominate. For patients with renal
impairment the following dosage adjustments should be considered: For patients
with CLCR 30 to 60 ml/min the dose of clarithromycin should be
reduced by 50%. For patients with CLCR <30 ml/min the dose of clarithromycin should be decreased by 75%. No
dosage adjustments for patients with normal renal function are necessary.
Ethinyl
Estradiol
TPV/r decreases the AUC and Cmax of ethinyl estradiol by 50% (Table 5.1.3.4:1),
but does not significantly alter the pharmacokinetic behavior of
norethindrone. As a result of the
reduction in estrogen levels, alternative or additional contraceptive measures should
be used when estrogenic-based oral contraceptives are co-administered with TPV/r. Women using ethinyl estradiol co-administered
with TPV/r may have an increased rate of nonserious rash.
Table 5.1.3.4: 1 Comparison
of non-ARV levels when combined with TPV/r, ritonavir alone, or
ritonavir-boosted lopinavir.
|
Substrate
Drug |
TPV/r |
RTV alone |
LPV/r |
|
Clarithromycin |
AUC 19%,
Cmin 68%, |
AUC 77%,
Cmax 31%, |
NR |
|
Fluconazole |
¯
6-10% |
NR |
NR |
|
Rifabutin |
3
x, |
4
x, |
3
x, |
|
Atorvastatin |
9.4 x |
NR |
5.9 x |
|
Ethinyl
Estradiol |
¯
45-50% |
¯
40% |
¯
42% |
NR =
not reported in prescribing information for Norvir® or Kaletra®
5.1.3.5 Potential drug interactions
Theoretical
Based on the drug interaction
studies conducted to date and the similarity of the results between
ritonavir-boosted tipranavir, ritonavir alone, and other ritonavir-boosted protease
inhibitors, the following drugs are contraindicated or
not recommended for co-administration with tipranavir (Table 5.1.3.5: 1). These
recommendations are based on predicted interactions due to the expected
magnitude of interaction and potential for serious events or loss of efficacy
and specific studies with TPV/r have not been performed.
Table 5.1.3.5: 1 Drugs
that should not be co-administered with TPV/r.
|
Drug Class/Drug Name |
Clinical Comment |
|
Antiarrhythmics: Amiodarone, bepridil,
flecainide, propafenone, quinidine |
CONTRAINDICATED due
to potential for serious and/or life-threatening reactions such as cardiac
arrhythmias secondary to increases in plasma concentrations of
antiarrhythmics. |
|
Antihistamines: Astemizole, terfenadine |
CONTRAINDICATED due
to potential for serious and/or life-threatening reactions such as cardiac
arrhythmias. |
|
Antimycobacterials: rifampin |
May lead to loss of
virologic response and possible resistance to tipranavir or to the class of
protease inhibitors. |
|
Ergot derivatives: Dihydroergotamine,
ergonovine, ergotamine, methylergonovine |
CONTRAINDICATED due
to potential for serious and/or life-threatening reactions such as acute
ergot toxicity characterized by peripheral vasospasm and ischemia of the
extremities and other tissues. |
|
GI motility agents: Cisapride |
CONTRAINDICATED due
to potential for serious and/or life-threatening reactions such as cardiac
arrhythmias. |
|
Herbal products: |
May lead to loss of
virologic response and possible resistance to tipranavir or to the class of
protease inhibitors. |
|
HMG CoA reductase
inhibitors: Lovastatin, simvastatin |
Potential for serious
reactions such as risk of myopathy including rhabdomyolysis. |
|
Neuroleptics: Pimozide |
CONTRAINDICATED due
to potential for serious and/or life-threatening reactions such as cardiac
arrhythmias. |
|
Sedatives/hypnotics: Midazolam, triazolam |
CONTRAINDICATED due
to potential for serious and/or life threatening reactions such as prolonged
or increased sedation or respiratory depression. |
Empirical
Based on the drug interaction
studies conducted to date and the similarity of the results between
ritonavir-boosted tipranavir, ritonavir alone, and other ritonavir-boosted protease
inhibitors, the following interactions, which may require dose adjustments or
clinical monitoring when TPV/r is co-administered, are
summarized in the Table 5.1.3.5: 2. Many
of these studies have been performed, but those not performed are indicated in
the table.
Table
5.1.3.5: 2 Established and
Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be
Recommended Based on Drug Interaction Studies or Predicted Interactions
|
Concomitant Drug Class: Drug name |
Effect on Concentration of Tipranavir or Concomitant Drug |
Clinical Comment |
|
HIV-Antiviral
Agents |
||
|
Nucleoside reverse
transcriptase inhibitors: Abacavir Didanosine (EC) Zidovudine |
¯ Abacavir concentrations by
approx. 40% ¯ Didanosine by 10-20% ¯ Zidovudine concentrations
by approx. 50%. ZDV glucuronide concentrations were unaltered. |
Clinical relevance of
reduction in abacavir levels not established.
No dose adjustment recommended. Clinical relevance of
reduction in didanosine levels not established. For optimal absorption, didanosine should
be separated from TPV/r dosing by at least 2 hours. No dose adjustment recommended. Clinical relevance of
reduction in zidovudine levels not established. No dose adjustment recommended. |
|
Protease inhibitors
(co-administered with low-dose ritonavir): Amprenavir Lopinavir Saquinavir |
¯ Amprenavir Cmin by 55%, ¯ Lopinavir Cmin by 70%, ¯ Saquinavir Cmin by >80%,
|
In the absence of having
established appropriate doses for the combination of tipranavir/ritonavir and
ritonavir-boosted amprenavir, saquinavir, or lopinavir, these combinations
cannot be recommended. |
|
Other Agents for Opportunistic Infections |
||
|
Antifungals: Fluconazole Itraconazole Ketoconazole Voriconazole |
Tipranavir >50%, ↔ Fluconazole Itraconazole (not studied),
Ketoconazole
(not studied), |
Fluconazole increases TPV
concentrations, but dose adjustments are not needed. Fluconazole doses >200
mg/day are not recommended. Based on theoretical
considerations itraconazole and ketoconazole should be used with caution.
High doses (200 mg/day) are not recommended. |
|
Antimycobacterials: Rifampin Rifabutin Clarithromycin |
¯ Tipranavir (not studied) Tipranavir not
changed, Rifabutin 3-fold Desacetyl-rifabutin 21-fold Tipranavir 2-fold, Clarithromycin 20-68%, ¯ 18-hydroxy metabolite >97% |
Concomitant use
of tipranavir and rifampin is contraindicated. Alternate antimycobacterial agents
such as rifabutin should be considered. Dosage reductions of
rifabutin by 75% are recommended (e.g., 150 mg three times a week).
Increased monitoring for adverse events in patients receiving the combination
is warranted. Further dosage reduction
may be necessary. No dose adjustment of
tipranavir or clarithromycin for patients with normal renal function is
necessary. For patients with renal
impairment the following dosage adjustments should be considered: ·
For patients with CLCR 30 to 60
mL/min the dose of clarithromycin should be reduced by 50%. ·
For patients with CLCR < 30
mL/min the dose of clarithromycin should be decreased by 75%. |
|
Other Agents Commonly Used |
||
|
PDE5 inhibitors: Sildenafil Tadalafil Vardenafil |
Combinations
with TPV/r not studied. Sildenafil Tadalafil Vardenafil expected |
Concomitant use
of PDE5 inhibitors with tipranavir and ritonavir should be used with caution and in no case should
the starting dose of: ·
sildenafil exceed 25 mg within 48 hours ·
tadalafil exceed 10 mg every 72 hours ·
vardenafil exceed 2.5 mg every 72 hours |
|
HMG-CoA reductase
inhibitors: Atorvastatin |
Tipranavir unchanged Atorvastatin 9.4‑fold ¯ Hydroxy-metabolites >85% |
Start with the lowest
possible dose of atorvastatin with careful monitoring, or consider other
HMG-CoA reductase inhibitors. |
|
Narcotic
analgesics: Methadone Meperidine |
¯ Methadone by 50% Combinations
with TPV/r not studied ¯ Meperidine, Normeperidine |
Dosage of
methadone may need to be increased when co-administered with tipranavir and
low-dose ritonavir. Dosage increase and
long-term use of meperidine are not recommended due to increased
concentrations of the metabolite normeperidine which has both analgesic
activity and CNS stimulant activity (e.g. seizures) |
|
Oral
contraceptives/Estrogens Ethinyl-estradiol |
¯ Ethinyl-estradiol concentrations by 50% |
Alternative
methods of non-hormonal contraception should be used when estrogen based oral
contraceptives are co-administered with tipranavir and low-dose
ritonavir. Women using estrogens may
have an increased risk of non serious rash. |
|
Immunosuppressants: Tacrolimus Sirolimus Cyclosporine |
Combination with
TPV/r not studied Tacrolimus Sirolimus Cyclosporine |
More frequent concentration
monitoring of these medicinal products is recommended until blood levels have
been stabilized. |
|
Warfarin |
Combination with
TPV/r not studied ¯ R- and
S warfarin metabolized by different isozymes |
Frequent INR
(international normalized ratio) monitoring upon initiation of
tipranavir/ritonavir therapy. |
|
Hypoglycemics: Tolbutamide Glyburide Glipizide Glimepiride Repaglinide Pioglitazone |
Combination with
TPV/r not studied ¯ Tolbutamide ¯ Glyburide ¯ Glipizide ¯ Glimepiride Repaglinide Pioglitazone |
Because of the
potential for ritonavir CYP3A inhibition or CYP2C9 induction with chronic
therapy, careful glucose monitoring is warranted. |
|
SSRIs: fluoxetine paroxetine sertaline |
Combination with
TPV/r not studied fluoxetine paroxetine sertaline |
Antidepressants
have a wide therapeutic index, but doses may need to be adjusted upon
initiation of TPV/r therapy. |
|
Calcium Channel Blockers: verapamil nisoldepine felodipine |
Combination with
TPV/r not studied verapamil nisoldepine felodipine |
Combinations of
TPV/r and calcium channel blockers should be avoided because of the CYP3A
activity of both agents. |
|
Desipramine |
Combination with
TPV/r not studied Desipramine |
Dosage reduction
and concentration monitoring of desipramine is recommended. |
|
Disulfiram/Metronidazole |
Combination with
TPV/r not studied |
Tipranavir
capsules contain alcohol they can produce disulfiram-like reactions when
co-administered with disulfiram or other drugs which produce this reaction
(e.g. metronidazole). |
5.1.4 Hepatic or renal impairment
The pharmacokinetic profiles of single-dose and steady-state TPV/r 500/200 mg in subjects with mild to moderate hepatic insufficiency were investigated in an open label trial (BI 1182.32). Mildly and moderately hepatically-impaired patients were paired with control patients according to age, weight, and other demographics.
Following 7 days of TPV/r
500/200 mg BID dosing in a study comparing 9 patients with mild
(Child-Pugh A) hepatic impairment to 9 healthy volunteer controls, the single
and multiple dose pharmacokinetic dispositions of tipranavir and ritonavir were
found to be increased in patients with hepatic impairment, but still within the
range observed in clinical trials. The geometric mean ratios for the population
were 1.30 (AUC0‑12h), 1.14 (Cmax) and 1.84 (Cp12h). No dosing adjustment is required in patients
with mild hepatic impairment.
The influence of moderate hepatic impairment (Child-Pugh B) on the pharmacokinetics of either tipranavir or ritonavir has not been evaluated at steady state. Further studies are planned. Because greater than 80% of the doses of both drug entities are excreted in the feces as unchanged drug moieties, close clinical and laboratory monitoring of patients with moderate impaired liver (e.g. Child-Pugh B) function is important.
The use of TPV/r in Child-Pugh C
patients is contraindicated, and studies in this population are not planned.
Tipranavir pharmacokinetics has not
been studied in patients with renal dysfunction. However, since the renal
clearance of tipranavir is negligible, a decrease in total body clearance is
not expected in patients with renal insufficiency.
5.2 Pharmacokinetic Conclusions
•
In treatment-experienced HIV-positive patients, TPV 500 mg
must be given simultaneously with ritonavir 200 mg to obtain the desired drug
levels with BID dosing.
•
Despite TPV being an inducer of CYP3A, when combined with 200
mg of ritonavir TPV/r produces a net hepatic inhibition of CYP3A. The
pharmacokinetic drug interactions for most concomitant medications are
consistent with other ritonavir-boosted PIs.
•
Reductions in zidovudine, abacavir, and didanosine plasma
drug levels have been observed with TPV/r, but the clinical relevance of these
reductions has not been established. No
dose adjustments can be recommended at this time.
•
No dosage adjustments of the NNRTIs nevirapine or efavirenz
are required when co-administered with TPV/r at the 500/200 mg dose.
•
Drug levels for ritonavir-boosted lopinavir, saquinavir, and
amprenavir were significantly reduced when combined with TPV/r, therefore these
combinations are not recommended. PI
levels for novel dual PI regimens containing TPV/r cannot be predicted without
formal drug interaction studies possibly due to the mixed patterns of
inhibition and induction of CYP pathways seen with these drug combinations.
•
Based on the interactions observed with TPV/r, the following
additional drug interaction studies are planned: atazanavir, buprenorphine,
bupropion, tadalafil, omeprazole, Peg-interferon/ribavirin, carbamazepine,
methadone, new investigational antiretrovirals, and a CYP/Pgp-cocktail study.
Since the discovery of tipranavir by
Pharmacia and Upjohn (P&U) and its licensing for development by Boehringer
Ingelheim (BI) in 2000, 39 tipranavir clinical trials have been conducted. This summary of efficacy presents tipranavir
efficacy data from nine clinical
trials conducted primarily in treatment-experienced HIV-positive patients.
Early open-label,
dose ranging studies (Trials BI 1182.3, 1182.2 and 1182.4, Tables 6.1: 1 and
6.1: 2) showed that TPV reduces viral load in HIV-positive patients with different
levels of treatment experience (naïve [BI 1182.3], single- [BI 1182.4] and
multiple-PI experienced [BI 1182.2]).
In BI 1182.3,
treatment naïve HIV-positive adults were given tipranavir alone or tipranavir
with low dose ritonavir for 14 days.
These 14 day viral activity data (Table 6.1: 1) clearly demonstrate that
the addition of low dose ritonavir is required for an optimal treatment
response.
Table 6.1: 1 Median
change from baseline in HIV-1 RNA values over 14 days of monotherapy treatment
in ARV Treatment
Naïve Trial BI
1182.3
|
|
TPV
1200 mg |
TPV/r 300
mg/200 mg |
TPV/r
1200 mg/200 mg |
|
Baseline VL |
4.90 |
5.20 |
4.79 |
|
Day 14 or 15 |
-0.77 (10) |
-1.43 (7) |
-1.64 (10) |
In BI 1182.2, multiple PI regimen-experienced patients
(NNRTI-naïve) were given two doses of TPV/r with efavirenz. The 48 week treatment response was similar
between both dose groups but generally favored the lower dose used (TPV/r
500/100mg) over the high dose (TPV/r 1000/100mg). In BI 1182.4, single PI regimen-experienced
patients were given two doses of TPV/r and this was compared against a standard
of care regimen containing SQV/RTV 400/400mg.
The 48 week treatment response was similar for both of the two TPV/r
dose groups but appeared to slightly favour the higher dose (TPV/r 1250/100mg)
over the lower dose (TPV/r 500/100mg) (Table 6.1: 2).
Table 6.1: 2 Virologic
efficacy data in Trials BI 1182.2 and 1182.4 - FAS (LOCF or NCF), using
combination therapy
|
|
BI 1182.2 |
BI 1182.4 |
|||
|
|
Multiple PI
Failure |
Single PI
Failure |
|||
|
|
TPV/r 500 /100mg NRTI and NNRTI |
TPV/r 1000 /100mg |
TPV/r 500 /100mg |
TPV/r 1250 /100mg |
SQV/r 400 /400mg 2 NRTIs |
|
Median
Baseline VL [log10 copies/mL] |
4.43 |
4.45 |
4.44 |
4.35 |
4.19 |
|
24-week
analysis: |
|
|
|
|
|
|
Median VL
change from baseline [log10 copies/mL] |
|
|
|
|
|
|
Patients <
400 copies/mL [%] |
79 |
50 |
38 |
29 |
24 |
|
Patients < 50 copies/mL [%] |
58 |
50 |
17 |
21 |
14 |
|
48-week analysis: |
|
|
|
|
|
|
Median VL change from baseline [log10
copies/mL] |
|
|
|
|
|
|
Patients < 400 copies/mL [%] |
79 |
50 |
16 |
32 |
17 |
|
Patients < 50 copies/mL [%] |
68 |
41 |
8 |
27 |
10 |
While these trials provided data on the
efficacy of TPV/r in patients with variable treatment experience, no definitive
dose was established. As a result, BI
designed and conducted a dose-finding study (BI 1182.52) using three doses of
TPV/r.
6.2 Dose
Selection (BI 1182.52)
As noted previously, BI designed and conducted a dose-finding study (BI 1182.52) to determine the optimal dose for use in the Phase III trial program.
Similar to the RESIST study cohort,
these patients had two PI-based regimen experience, and baseline viral isolates
with at least one primary protease mutation (30N, 46I/L, 48V, 50V, 82A/L/F/T,
84V and 90M), and not more than 2 mutations among 82L/T, 84V or 90M. This was a double-blind study evaluating 3
TPV/r doses: 500/100 mg, 500/200 mg and 750/200 mg, all given BID with a
genotypically optimized background regimen (OBR).
The first 2 weeks of the study were a functional
monotherapy phase in which patients changed the PI they were taking at study entry
to one of three TPV/r doses, but maintained the same OBR. The antiviral effect from these first 2 weeks
was therefore predominantly due to only TPV/r.
During this 2-week functional monotherapy phase, the viral load
reductions from baseline to Week 2 were: TPV/r 500/100 mg, 0.85 log10
copies/mL; TPV/ r 500/200 mg, 0.93 log10 copies/mL; and TPV/r 750/200
mg, 1.18 log10 copies/mL.
For the full study cohort, there was an inverse relationship between the number of mutations at codons 33, 82, 84, or 90 and viral load reduction at Week 24. Patients with no mutations at these codons demonstrated a -1.51 log10 copies/mL reduction; one mutation, -0.76 log10 copies/mL reduction; two mutations, -0.62 log10 copies/mL reduction; three mutations, -0.13 log10 copies/mL reduction[17].
For patients with virus containing mutations at three of these key positions, the antiviral activity for all three doses was reduced. Across treatment groups, patients with up to two mutations at codons 33, 82, 84, or 90 showed a strong dose-related response at Week 24 in the LOCF analysis (Table 6.2: 1); there was a statistically significant difference between the TPV/r 750/200 and 500/100 doses but not between TPV/r 750/200 and 500/200. This was confirmed when the viral load responses at 24 weeks were stratified by the number of mutations at codons 33, 82, 84 or 90. The 500/100 group showed a significant drop in antiviral activity with 1 mutation while the 500/200 and the 750/200 doses required more mutations before antiviral activity was diminished. Thus, the 500/100 dose underperformed against the drug resistant viruses to be evaluated in the TPV pivotal trial program.
Table 6.2: 1 Median log10
change from baseline in viral load at 2 and 24 Weeks of TPV/r treatment
(FAS-LOCF) by number of baseline mutations at codons 33, 82, 84, or 90
|
Number of
Mutations at codons 33, 82, 84, or 90 at Baseline/ Weeks of
Treatment |
Treatment
Group |
|||||||||||
|
TPV/r |
TPV/r |
TPV/r |
|
|||||||||
|
Log10
Change from Baseline in RNA Copies/mL |
||||||||||||
|
N |
Meda |
IQR |
N |
Meda |
IQR |
N |
Meda |
IQR |
N |
Meda |
IQR |
|
|
None |
|
|
|
|
|
|
|
|
|
|
|
|
|
2 weeks |
5 |
-1.32 |
-1.51,
-1.04 |
1 |
-0.60 |
-0.60,
-0.60 |
5 |
-1.35 |
-1.35,
-1.02 |
11 |
-1.32 |
-1.51,
-0.82 |
|
24 weeks |
5 |
-1.92 |
-2.42,
-1.51 |
1 |
-1.82 |
-1.82,
-1.82 |
5 |
-1.16 |
-1.20,
-0.33 |
11 |
-1.51 |
-2.26,
-0.97 |
|
1 |
|
|
|
|
|
|
|
|
|
|
|
|
|
2 weeks |
19 |
-1.21 |
-1.48,
-0.73 |
25 |
-1.15 |
-1.67,
-0.60 |
31 |
-1.25 |
-1.81,
-0.58 |
75 |
-1.21 |
-1.61,
-0.60 |
|
24 weeks |
19 |
-0.29 |
-1.72, 0.42 |
25 |
-1.05 |
-2.39,
-0.14 |
31 |
-1.07 |
-2.17,
-0.18 |
75 |
-0.76 |
-2.28, 0.00 |
|
2 |
|
|
|
|
|
|
|
|
|
|
|
|
|
2 weeks |
36 |
-0.68 |
-1.07,
-0.18 |
25 |
-1.28 |
-1.84,
-0.78 |
19 |
-1.24 |
-1.62,
-0.49 |
80 |
-0.93 |
-1.65,
-0.26 |
|
24 weeks |
36 |
-0.20 |
-1.68, 0.22 |
25 |
-0.59 |
-2.72,
-0.25 |
19 |
-1.84 |
-2.36,
-0.42 |
80 |
-0.62 |
-2.28,
-0.03 |
|
0, 1, or
2 |
|
|
|
|
|
|
|
|
|
|
|
|
|
2 weeks |
60 |
-0.91 |
-1.41,
-0.32 |
51 |
-1.16 |
-1.73,
-0.60 |
55 |
-1.24 |
-1.68,
-0.58 |
166 |
-1.13 |
-1.61,
-0.46 |
|
24 weeks |
60 |
-0.44 |
-1.99, 0.17 |
51 |
-1.05 |
-2.62,
-0.24 |
55 |
-1.49 |
-2.26,
-0.28 |
166 |
-0.87 |
-2.26,
-0.06 |
|
3 |
|
|
|
|
|
|
|
|
|
|
|
|
|
2 weeks |
13 |
-0.19 |
-0.98, 0.20 |
21 |
-0.33 |
-1.10, -0.09 |
16 |
-0.54 |
-1.14, -0.04 |
50 |
-0.32 |
-1.10, 0.12 |
|
24 weeks |
13 |
0.23 |
-1.09, 0.29 |
21 |
0.05 |
-0.63, 0.29 |
16 |
-0.25 |
-0.91, -0.13 |
50 |
-0.13 |
-1.09, 0.27 |
a Median.
Safety analyses of BI 1182.52
demonstrated a dose relationship with higher frequency of severe adverse
events, discontinuations due to adverse events and DAIDS Grade 3 or 4 ALT
elevations observed with increasing dose.
Specifically, 21.2% of patients in the TPV/r 750/200 mg dose group had
Grade 3 or 4 ALT elevations over the course of 24 weeks of therapy as compared
to 5.5% for the TPV/r 500/100 mg dose group and 11.1% for the TPV/r 500/200 mg
dose group. Thus, from the standpoint of
optimal safety, PK and efficacy, the TPV/r 500/200 mg dose group was selected
for study in Phase III trials, and these data were reviewed with the FDA at the
End-of-Phase II meeting in December 2002.
6.3 Efficacy results of pivotal, active-controlled trials
(RESIST Trials)
Using a treatment population that was
very similar to the cohort studied in BI 1182.52, the RESIST study program
studied HIV-positive adults with
triple ARV class experience, including at least two PI-based regimens. All patients had to be virologically failing on
their current PI-based regimen at the time of study screening in order to get
an accurate analysis of PI resistance; no treatment interruptions prior to
study entry were allowed.
A total of 3309
patients were screened for participation in the two RESIST studies, and
1816/3309 (54.9%) of these patients failed screening. Of the 1816 patients who failed screening,
the most common reasons for screening failure were: failure to meet baseline
resistance criteria (66.4%), failure to meet baseline safety lab criteria
(26.7%), unacceptable medical history (15.3%), and failure to have a viral load
of at least 1000 copies/mL (12.9%).
A total of 1483
patients were randomized and treated in the combined RESIST trials
(Table 6.3.1: 1). By
Table 6.3.1: 1 Summary
of population sets for the RESIST trials
|
|
RESIST-1 BI 1182.12 |
RESIST-2 BI 1182.48 |
Combined RESIST Trials |
|||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
TPV/r |
CPI/r |
|
|
N (%) |
N (%) |
N (%) |
N (%) |
N (%) |
N (%) |
|
All treated patients; achieve 16 weeks
of efficacy by interim cut-off |
311 (100.0) |
309 (100.0) |
435 (100.0) |
428 (100.0) |
746 (100.0) |
737 (100.0) |
|
Full analysis set (FAS); achieve 24
weeks of efficacy by interim cut-off |
311 (100.0) |
309 (100.0) |
271 (62.3) |
268 (62.6) |
582 (78.0) |
577 (78.3) |
|
Per protocol set (PPS); subset of FAS
without any protocol deviations |
191 (61.4) |
193 (62.5) |
180 (41.4) |
167 (39.0) |
371 (49.7) |
360 (48.8) |
The integrated
RESIST trial population included in the interim 24-week efficacy analyses
consisted of 1159 patients, 582 randomized to TPV/r and 577 to CPI/r. Demographic characteristics were comparable
between the two treatment groups (Table 6.3.1: 2).
Patients in the RESIST-1
trial had a lower CD4+ cell count (median 123 cells/mm3 in both
treatment groups) than the RESIST-2 trial (median 175 cells/mm3 for
TPV/r and 200 cells/mm3 for CPI/r), potentially reflective of
geographic differences in the treatment strategies of investigators.
Table 6.3.1: 2 Baseline
demographic data, HIV-1 RNA values, and CD4+ cell counts – RESIST trials (FAS a)
|
|
RESIST-1 BI 1182.12 |
RESIST-2 BI 1182.48 |
Combined RESIST Trials |
|||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
TPV/r |
CPI/r |
|
Total treated |
311 |
309 |
271 |
268 |
582 |
577 |
|
Age [years] |
|
|
|
|
|
|
|
N |
311 |
309 |
271 |
268 |
582 |
577 |
|
Median |
45.0 |
43.0 |
42.0 |
42.0 |
43.0 |
43.0 |
|
Range |
24-80 |
28-70 |
17-76 |
21-72 |
17-80 |
21-72 |
|
Subgroups [N (%)] |
|
|
|
|
|
|
|
<18 |
0 |
0 |
1
(0.4) |
0 |
1 (0.2) |
0 |
|
18 – 40 |
86
(27.7) |
94 (30.4) |
115 (42.4) |
118 (44.0) |
201
(34.5) |
212 (36.7) |
|
41 – 55 |
191 (61.4) |
190 (61.5) |
128 (47.2) |
122 (45.5) |
319
(54.8) |
312 (54.1) |
|
56 – 64 |
29
(9.3) |
23
(7.4) |
25
(9.2) |
21
(7.8) |
54
(9.3) |
44
(7.6) |
|
> 65 |
5
(1.6) |
2
(0.6) |
2
(0.7) |
7
(2.6) |
7
(1.2) |
9
(1.6) |
|
Gender [N (%)] |
|
|
|
|
|
|
|
Male |
278 (89.4) |
287 (92.9) |
225 (83.0) |
229 (85.4) |
503
(86.4) |
516 (89.4) |
|
Female |
33 (10.6) |
22
(7.1) |
46 (17.0) |
39 (14.6) |
79
(13.6) |
61 (10.6) |
|
Race [N (%)] |
|
|
|
|
|
|
|
White |
241 (77.5) |
235 (76.1) |
189 (69.7) |
179 (66.8) |
430
(73.9) |
414 (71.8) |
|
Black |
68 (21.9) |
69 (22.3) |
15
(5.5) |
11
(4.1) |
83
(14.3) |
80 (13.9) |
|
Asian |
2
(0.6) |
5
(1.6) |
2
(0.7) |
3
(1.1) |
4
(0.7) |
8
(1.4) |
|
Not Collectedb |
0 |
0
|
65 (24.0) |
75 (28.0) |
65 (11.2) |
75 (13.0) |
|
Median
baseline HIV-1 RNA [log10 copies/mL] |
4.81 |
4.84 |
4.84 |
4.81 |
4.83 |
4.82 |
|
Median baseline
CD4+ cell count [cells/mm3] |
123 |
123 |
175 |
200 |
155 |
158 |
a FAS, full
analysis set of patients in 24-week efficacy analyses. The reader is cautioned against making
comparison to the Summary of Clinical Safety Module 2.7.4 since the FAS used
here includes patients who could have achieved 24 weeks of treatment
whereas the Summary of Clinical Safety uses the all treated population.
b In
Patients enrolled
in the RESIST trials were highly treatment experienced, with a history of using
a median of 12 ARVs before entry into the trial (Table 6.3.1: 3). More than 70%
of patients had used four or more PIs, although PI use was slightly lower in RESIST-2. The median number of NRTIs that had been used
was 6 (range 2-8) and the median number of NNRTIs was 1 (range 0-3), thus
representing a population of patients with extensive ARV treatment experience
and few ARV options with which to construct a viable regimen. Enfuvirtide had been previously used by 12%
of patients. There were no differences
between treatment groups in past ARV use within the combined study population.
Table 6.3.1: 3 Number
of antiretroviral agents used prior to study randomization, by class – RESIST
trials (FAS a)
|
|
RESIST-1 BI 1182.12 |
RESIST-2 BI 1182.48 |
Combined RESIST Trials |
|||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
TPV/r |
CPI/r |
|
Total treated |
311 |
309 |
271 |
268 |
582 |
577 |
|
Total of all ARVs |
|
|
|
|
|
|
|
Median |
12 |
12 |
12 |
12 |
12 |
12 |
|
Range |
3-19 |
4-20 |
4-18 |
3-18 |
3-19 |
3-20 |
|
ENF |
|
|
|
|
|
|
|
N (%) |
39 (12.5) |
37 (12.0) |
30 (11.1) |
31 (11.6) |
69 (11.9) |
68 (11.8) |
|
PIs b |
|
|
|
|
|
|
|
Median |
4 |
4 |
4 |
4 |
4 |
4 |
|
Range |
1-7 |
1-7 |
1-7 |
1-7 |
1-7 |
1-7 |
|
Subgroups |
|
|
|
|
|
|
|
1 |
2
(0.6) |
6
(1.9) |
3
(1.1) |
4
(1.5) |
5
(0.9) |
10
(1.7) |
|
2 |
25
(8.0) |
18
(5.8) |
26
(9.6) |
34 (12.7) |
51
(8.8) |
52
(9.0) |
|
3 |
50 (16.1) |
54 (17.5) |
54 (19.9) |
52 (19.4) |
104 (17.9) |
106 (18.4) |
|
4 |
87 (28.0) |
77 (24.9) |
76 (28.0) |
66 (24.6) |
163 (28.0) |
143 (24.8) |
|
> 5 |
147 (47.3) |
154 (49.8) |
112 (41.3) |
112 (41.8) |
259 (44.5) |
266 (46.1) |
|
NRTIs |
|
|
|
|
|
|
|
Median |
6 |
6 |
6 |
6 |
6 |
6 |
|
Range |
2-8 |
2-8 |
2-8 |
2-8 |
2-8 |
2-8 |
|
NNRTIs |
|
|
|
|
|
|
|
Median |
2 |
1 |
1 |
1 |
1 |
1 |
|
Range |
0-3 |
0-3 |
0-3 |
0-3 |
0-3 |
0-3 |
a FAS, full analysis set of patients in
24-week efficacy analyses
b RTV was only counted if given
at a therapeutic dose.
6.3.1.1 Baseline genotypic resistance
The combined RESIST population was well
balanced between treatment groups for the frequencies of protease gene
mutations, per-protocol primary protease mutations, and number of mutations at
codons 33, 82, 84, or 90 (Table 6.3.1: 4).
The median number of protease gene mutations, defined as any change
deviation from the
Table 6.3.1: 4 Distribution
of baseline protease gene mutations – RESIST trials (FAS a)
|
|
RESIST-1 BI 1182.12 |
RESIST-2 BI 1182.48 |
Combined RESIST Trials |
|||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
TPV/r |
CPI/r |
|
Total treated |
311 (100.0) |
309 (100.0) |
271 (100.0) |
268 (100.0) |
582 (100.0) |
577 (100.0) |
|
No. of protease gene mutations b |
|
|
|
|
|
|
|
Median |
15 |
15 |
16 |
16 |
16 |
16 |
|
Subgroups [N (%)] |
|
|
|
|
|
|
|
< 12 |
70 (22.5) |
79 (25.6) |
47 (17.3) |
42 (15.7) |
117 (20.1) |
121 (21.0) |
|
13 – 15 |
90 (28.9) |
86 (27.8) |
70 (25.8) |
74 (27.6) |
160 (27.5) |
160 (27.7) |
|
16 – 18 |
93 (29.9) |
78 (25.2) |
88 (32.5) |
76 (28.4) |
181 (31.1) |
154 (26.7) |
|
> 19 |
57 (18.3) |
66 (21.4) |
66 (24.4) |
76 (28.4) |
123 (21.1) |
142 (24.6) |
|
Missing |
1 (0.3) |
0 |
0 |
0 |
1 (0.2) |
0 |
|
No. of protease mutations at 33, 82, 84,
90 [N (%)] |
|
|
|
|
|
|
|
0 |
11
(3.5) |
13
(4.2) |
12
(4.4) |
7
(2.6) |
23
(4.0) |
20
(3.5) |
|
1 |
91 (29.3) |
77 (24.9) |
74 (27.3) |
83 (31.0) |
165 (28.4) |
160 (27.7) |
|
2 |
192 (61.7) |
204 (66.0) |
182 (67.2) |
174 (64.9) |
374 (64.3) |
378 (65.5) |
|
Subtotal < 2 |
294 (94.5) |
294 (95.1) |
268 (98.9) |
264 (98.5) |
562 (96.6) |
558 (96.7) |
|
3 |
16
(5.1) |
15
(4.9) |
2
(0.7) |
4
(1.5) |
18
(3.1) |
19
(3.3) |
|
4 |
0 |
0 |
1
(0.4) |
0 |
1
(0.2) |
0 |
|
Missing |
1
(0.3) |
0 |
0 |
0 |
1
(0.2) |
0 |
a FAS, full analysis set of patients in
24-week efficacy analyses
b Protease gene mutations include
any deviation from
6.3.1.2 Baseline phenotypic resistance
Although baseline
phenotypic testing was not performed in real time and results were therefore
not available to investigators to determine patient eligibility or to make
baseline drug choices, these data were later obtained on a randomly selected
sub-set of the patients participating in the RESIST studies. These data showed high level phenotypic
resistance of the baseline HIV-1 isolates against each of the currently
marketed PIs with the majority of isolates remaining sensitive to TPV.
The median IC50
fold-change for each PI tested was:
ü Tipranavir (n=454) 1.7
ü Lopinavir (n=452) 87.4
ü Indinavir (n=423) 41.0
ü Saquinavir (n=450) 20.1
ü Amprenavir (n=445) 12.2
ü Nelfinavir (n=452) 40.7
ü Ritonavir (n=449) 194.7
ü Atazanavir (n=456) 55.3.
6.3.2 Pre-selection of comparator PI and enfuvirtide
6.3.2.1 Stratification by pre-selected PI and enfuvirtide
use
In the RESIST studies, investigators had the option to pre-select a comparator PI that was either new or ongoing. A new PI was one that was not in use at the time of randomization, but could have been recycled from a previous regimen. Investigators also had the option to pre-select a genotypically available or a genotypically resistant PI. Where possible, investigators pre-selected a genotypically available PI for use in the CPI/r arms, but when the baseline genotype report provided an interpretation that there was no PI that was genotypically available, investigators could pre-select a PI that was considered genotypically resistant.
The resistance expert consultant panel was made available to assist investigators in interpreting the actual mutation pattern provided on the genotype report and to select an optimal PI for use in the CPI/r arm in context with the patient's treatment history.
The comparator PIs pre-selected by investigators and the use of a “new” CPI/r is provided in Table 6.3.2.1: 1. LPV/r was the most common comparator PI pre-selected (50.3%), followed by APV/r (25.8%), SQV/r (20.5%), and IDV/r (3.5%). Nearly two thirds of patients had a “new” CPI/r pre-selected, indicating that it was not the PI that the patient had been taking at the time of randomization. Of those who actually received treatment in the CPI/r arms, the PI used was “new” for 122/290 (42.1%) of those receiving LPV/r, 17/20 (85.0%) of those receiving IDV/r, 97/118 (82.2%) of those receiving SQV/r, and 127/149 (85.2) of those receiving APV/r.
Table 6.3.2.1: 1 Summary
of patient treatment with respect to PI strata and use of a new PI – RESIST
trials (FAS)
|
|
Total |
|
|
|
TPV/r |
CPI/r |
|
|
N (%) |
N (%) |
|
Total |
582 (100.0) |
577 (100.0) |
|
PI strata |
|
|
|
LPV |
293 (50.3) |
290 (50.3) |
|
IDV |
21 (3.6) |
20 (3.5) |
|
SQV |
117 (20.1) |
118 (20.5) |
|
APV |
151 (25.9) |
149 (25.8) |
|
New pre-selected PI |
375 (64.4) |
363 (62.9) |
|
New pre-selected PI by strata |
|
|
|
LPV |
128 (22.0) |
122 (21.1) |
|
IDV |
20 (3.4) |
17 (2.9) |
|
SQV |
96 (16.5) |
97 (16.8) |
|
APV |
131 (22.5) |
127 (22.0) |
The pre-selected use of enfuvirtide by investigators is provided in Table 6.3.2.1: 2. Overall, 158/582 (27.1%) of patients receiving TPV/r also used enfuvirtide and 128/577 (22.2%) of patients receiving CPI/r also used enfuvirtide.
Table 6.3.2.1: 2 Summary
of patient treatment with respect to enfuvirtide use by PI strata – RESIST
trials (FAS)
|
|
Total |
|
|
|
TPV/r |
CPI/r |
|
|
N (%) |
N (%) |
|
Total |
582 (100.0) |
577 (100.0) |
|
Total ENF use |
158 (27.1) |
128 (22.2) |
|
ENF use by strata |
|
|
|
LPV |
85 (14.6) |
71 (12.3) |
|
IDV |
8 (1.4) |
3 (0.5) |
|
SQV |
37 (6.4) |
32 (5.5) |
|
APV |
28 (4.8) |
22 (3.8) |
It is important to note that patients who pre-selected
enfuvirtide had different baseline characteristics than those patients who did
not. Table 6.3.2.1: 3 provides the
baseline data of those patients who pre-selected enfuvirtide and those who did
not. In general, patients pre-selected
enfuvirtide had higher baseline viral load, lower CD4 count, more prior ARV
drug use, and more baseline drug resistance than patients who did not
pre-select enfuvirtide.
Table 6.3.2.1: 3 Baseline
demographic data and HIV characteristics of patients receiving or not receiving
enfuvirtide – RESIST trials (FAS)
|
|
Receiving ENF |
Not Receiving ENF |
||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
|
Total treated |
158 |
128 |
424 |
449 |
|
Median
baseline HIV-1 RNA [log10 copies/mL] |
5.07 |
5.10 |
4.74 |
4.75 |
|
Median baseline CD4+ cell count
[cells/mm3] |
72 |
77 |
177 |
182 |
|
Median ARV use (range) |
13 (8-19) |
14 (4-20) |
11 (3-18) |
11 (3-19) |
|
Median prior PI use (range) |
5 (2-7) |
5 (1-7) |
4 (1-7) |
4 (1-7) |
|
Median NRTI use (range) |
6 (3-8) |
6 (2-8) |
6 (2-8) |
6 (2-8) |
|
Median NNRTI use (range) |
2 (0-3) |
2 (0-3) |
1 (0-3) |
1 (0-3) |
|
Median number of protease gene mutations a |
17 |
17 |
15 |
15 |
|
Mutations at 33, 82, 84, 90 [N, (%)] |
|
|
|
|
|
0 |
4 (2.5) |
1 (0.8) |
19 (4.5) |
19 (4.2) |
|
1 |
31 (19.6) |
25 (19.5) |
134 (31.6) |
135 (30.1) |
|
2 |
114 (72.2) |
95 (74.2) |
260 (61.3) |
283 (63.0) |
|
3 |
9 (5.7) |
7 (5.5) |
9 (2.1) |
12 (2.7) |
|
4 |
0 (0.0) |
0 (0.0) |
1 (0.2) |
0 (0.0) |
a Protease gene mutations include any deviation from
6.3.2.2
Use
of new vs. ongoing or susceptible vs. resistant comparator PIs
Overall, most patients who randomized to the CPI/r
arms (62.9%) of the RESIST studies used a new PI, one that was not being used
at the time of randomization. These data
are shown in table 6.3.2.2: 1. In
contrast, most patients who randomized to the CPI/r arms (66.7%) of the RESIST
studies used a PI that was considered “resistant” in the interpretation of the
baseline genotype report. These data are
also shown in Table 6.3.2.2: 1.
Table 6.3.2.2: 1 Choice
of pre-selected PI as new or ongoing and resistance interpretation from the
genotype report – RESIST trials (FAS)
|
|
TPV/r |
CPI/r |
||
|
|
N |
(%) |
N |
(%) |
|
Total treated |
582 |
(100.0) |
577 |
(100.0) |
|
New or ongoing pre-selected
PI |
|
|
|
|
|
New PI |
375 |
(64.4) |
363 |
(62.9) |
|
Ongoing PI |
207 |
(35.6) |
214 |
(37.1) |
|
Resistance to pre-selected PI |
|
|
|
|
|
Susceptible a |
76 |
(13.1) |
80 |
(13.9) |
|
Possibly Resistant b |
135 |
(23.2) |
112 |
(19.4) |
|
Resistant c |
369 |
(63.4) |
385 |
(66.7) |
|
Missing |
2 |
(0.3) |
0 |
|
|
Genotypically available and
new pre-selected PI |
152 |
(26.1) |
140 |
(24.3) |
a TruGene®: No evidence of resistance. Virtual Phenotype™: within normal
susceptibility range or resistance unlikely; for IDV < 3.0, for SQV <
2.5, for APV < 2.0, and for LPV <10.
b TruGene®: Possible resistance.
Virtual Phenotype™: for LPV only 10 to <40.
c TruGene®: Resistance.
Virtual Phenotype™: resistance or resistance likely as defined by being
above normal susceptibility range; for IDV >3.0, for SQV >2.5, for APV
>2.0, and for LPV > 40.
6.3.3 Differences between RESIST studies
There were several noteworthy
differences between the RESIST trials.
One difference was a higher frequency of new pre-selected PIs in the RESIST-2
study (70.3% for both treatment groups combined) than in the RESIST-1 study
(57.9% for both treatment groups combined).
The difference might have been a result of more patients in the RESIST-2
trial not having exhausted all of their PI options; whereas more patients in
the RESIST-1 trial had used five or more PIs before screening. Another difference between the trials
concerned the genotypic resistance interpretation, with more patients in the RESIST-2
trial (73.8%) than patients in the RESIST-1 trial (57.4%) testing resistant to
the pre-selected PI. This difference may
be attributed to geographic differences in treatment strategies or due to the different
algorithms used by the resistance testing laboratories, TruGene® (exclusively
used in RESIST-1) and Virtual Phenotype™ (primarily used in RESIST-2). In addition, the VIRCO Virtual Phenotype™
interpretation used only one cut-off for all PIs except LPV.
Enfuvirtide was used more frequently in the RESIST-1 trial (38.3% of
the TPV/r group and 34.0% of the CPI/r group) than in the RESIST-2 trial (only
14.4% in the TPV/r group and 8.6% in the CPI/r group). In the integrated analyses, 27.1% of TPV/r
patients and 22.2% of CPI/r patients received E concomitantly with study
medication. Enfuvirtide was most
frequently co-administrated with LPV in the comparator arm. The lower use of enfuvirtide in the RESIST-2
trial was due to the limited access to the drug in
Of the 1,159 randomized
patients, 475 (81.6%) in the TPV/r group and 247 (42.8%) in the CPI/r group
completed Week 24 (Table 6.3.4: 1).
This difference between treatment groups was driven by early trial
discontinuation because of lack of virologic response in the CPI/r group.[18]
A higher level of
patients in the CPI/r arms had missing or incomplete data at Week 24 than in
the TPV/r arms. This higher number of
patients with missing or incomplete data appears to reflect the fact that more
patients in the CPI/r discontinued than patients in the TPV/r arms.
Table
6.3.4: 1 Patient disposition – RESIST
trials (FAS)
|
|
RESIST-1 Trial BI 1182.12 |
RESIST-2 Trial BI 1182.48 |
Combined RESIST Trials |
|||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
TPV/r |
CPI/r |
|
|
N (%) |
N (%) |
N (%) |
N (%) |
N (%) |
N (%) |
|
Total treated |
311 (100.0) |
309 (100.0) |
271 (100.0) |
268 (100.0) |
582 (100.0) |
577 (100.0) |
|
Completing to |
263 (84.6) |
151 (48.9) |
212 (78.2) |
96 (35.8) |
475 (81.6) |
247 (42.8) |
|
Missing or incomplete data at Week 24 a |
0 (0.0) |
19 (6.1) |
9 (3.3) |
48 (17.9) |
9 (1.5) |
67 (11.6) |
|
Study drug discontinued prematurely |
48 (15.4) |
139 (45.0) |
50 (18.5) |
124 (46.3) |
98 (16.8) |
263 (45.6) |
a Missing or incomplete at Week
24 consists of two subgroups of patients. The first subgroup had a premature
discontinuation of the study based on the end of treatment case report form
page filled out with a date up to Day 196, but no date or reason for the stop
of study medications was indicated on the protease inhibitor case report form
page. The second subgroup did neither have a documentation of a premature
discontinuation nor did it have documentation of continued use of the study
medication on the protease inhibitor case report form page because this page
was not received by BI for the Week 24 visit.
6.3.5 Analysis
of treatment response: primary and secondary endpoints
The primary endpoint for accelerated
approval is treatment response through Week 24.
Treatment response is a composite primary endpoint of the proportion of
patients with two consecutive VL measurements >1 log10 below
baseline after 24 weeks of treatment without prior (1) evidence of a confirmed virological failure, (2) introduction of a
new ARV to the regimen for reasons other than toxicity or intolerance to
a background drug, (3) permanent discontinuation of the study drug, (4) death,
or (5) loss to follow-up.
The primary endpoint treatment response is shown below in Table 6.3.5.1: 1. At 24 weeks, 41.2% of TPV/r patients achieved this confirmed treatment response as compared with 18.9% of CPI/r patients (p <0.0001). This difference, adjusted for the stratification by PI strata and enfuvirtide strata was 21.3%, with a lower limit of the two-sided 95% CI of 16.3% superiority (Table and Figure 6.3.2.1: 1).
The proportion of treatment responders
in the TPV/r group was similar across both the RESIST-1 and RESIST-2 studies,
though a lower proportion of CPI/r patients in RESIST-2 (14.9%) achieved a
treatment response at Week 24 than CPI/r patients in RESIST-1 (22.3%), which
resulted in a larger weighted treatment difference favoring TPV/r in RESIST-2 (Table 6.3.5.1:
1).
Table 6.3.5.1: 1 Primary
endpoint treatment response (2 consecutive VL measurements >1 log10
below baseline) at Week 24 – RESIST trials (FAS)
|
|
Treatment Response a by
Treatment Group |
Treatment Difference b |
||||||||
|
|
TPV/r |
CPI/r |
Weighted |
95% CI |
||||||
|
Trial |
Analysis |
n |
(%) |
N |
n |
(%) |
N |
Diff. |
LL |
UL |
|
1182.12 |
FAS (NCF) |
129 |
(41.5) |
311 |
69 |
(22.3) |
309 |
(18.4) |
(11.4) |
(25.3) |
|
1182.48 |
FASS24 (NCF) |
111 |
(41.0) |
271 |
40 |
(14.9) |
268 |
(25.0) |
(17.8) |
(32.2) |
|
Total |
FAS (NCF) |
240 |
(41.2) |
582 |
109 |
(18.9) |
577 |
(21.3) |
(16.3) |
(26.4) |
a Treatment response is the composite endpoint of
the proportion of patients with two consecutive VL measurements >1 log10
below baseline after 24 weeks without prior (1) evidence of a confirmed
virological failure, (2) introduction of a new ARV to the regimen for reasons
other than toxicity or intolerance to a background drug, (3) permanent
discontinuation of the study drug, (4) death, or (5) loss to follow-up
b Treatment difference and confidence interval weighted
for the sizes of ENF strata and PI strata.
n = number of responders, N = number of evaluable
patients.
Figure 6.3.5.1: 1 Treatment
response over time through 24 weeks – Combined RESIST trials, (FAS [NCF])
24-week difference:
p <0.0001
For patients in the TPV/r treatment
arms, the proportion of treatment responders reached a peak at Week 4. At each time point the proportion of
treatment responders was larger among TPV/r patients than CPI/r patients (p <0.0001). At Week 24 the proportion of treatment
responders in the TPV/r group was larger than the peak proportion of responders
in the CPI/r group during the 24 weeks.
The primary reason for a lack of treatment response was lack of a confirmed 1 log10 reduction below baseline, which occurred in 45.9% of TPV/r patients and 71.4% of CPI/r patients (Table 6.3.5.1: 2). Specific reasons that led to failure were (1) a 1 log10 drop from baseline without confirmation; (2) viral load never being suppressed ;( 3) rebound; and (4) a drug change or discontinuation due to virologic failure. The two treatment groups differed especially for drug change or discontinuation due to virologic failure, which occurred in 37.3% of CPI/r patients and 6.4% of TPV/r patients and for viral rebound, which occurred in 15.3% of TPV/r patients and 10.9% of CPI/r patients.
The higher rate of rebound in the TPV/r
group is likely due to the fact that there were more virologic responders in
the TPV/r group and only responders can show rebound.
Discontinuations of study medication
due to AEs were more frequent in the TPV/r group (8.1%) than CPI/r group (3.8%). The RESIST study design may have contributed
to this imbalance, as patients in the CPI/r arms could leave the study to
receive TPV/r in BI 1182.17 for virologic failure, but not due to AEs. The rate of discontinuation for reasons other
than AEs (e.g., consent withdrawn, lost to follow-up) were comparable between
the two treatment groups, with 5.0% in the CPI/r group and 3.8% in the TPV/r
group.
Table 6.3.5.1: 2 Treatment
outcomes at Week 24 – RESIST trials (FAS [NCF])
|
|
RESIST-1 BI 1182.12 |
RESIST-2 BI 1182.48 |
Combined RESIST Trials |
|||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
TPV/r |
CPI/r |
|
Total treated |
311 (100.0) |
309 (100.0) |
271 (100.0) |
268 (100.0) |
582 (100.0) |
577 (100.0) |
|
Primary endpoint treatment response at
Week 24 |
129 (41.5) |
69 (22.3) |
111 (41.0) |
40 (14.9) |
240 (41.2) |
109 (18.9) |
|
No confirmed 1 log10 drop
from baseline |
140 (45.0) |
209 (67.6) |
127 (46.9) |
203 (75.7) |
267 (45.9) |
412 (71.4) |
|
1 log10 drop from baseline
without confirmation |
31 (10.0) |
16 (5.2) |
19 (7.0) |
16 (6.0) |
50 (8.6) |
32 (5.5) |
|
Rebound a |
51 (16.4) |
39 (12.6) |
38 (14.0) |
24 (9.0) |
89 (15.3) |
63 (10.9) |
|
Never suppressed through Week 24 |
45 (14.5) |
45 (14.6) |
46 (17.0) |
57 (21.3) |
91 (15.6) |
102 (17.7) |
|
Drug change or discontinuation due to
virologic failure b |
13 (4.2) |
109 (35.3) |
24 (8.9) |
106 (39.6) |
37 (6.4) |
215 (37.3) |
|
Death c |
5 (1.6) |
3 (1.0) |
1 (0.4) |
2 (0.7) |
6 (1.0) |
5 (0.9) |
|
Study drug discontinuation due to
adverse events d |
25 (8.0) |
9 (2.9) |
22 (8.1) |
13 (4.9) |
47 (8.1) |
22 (3.8) |
|
Study drug discontinuation due to other
reasons |
12 (3.9) |
19 (6.1) |
10 (3.7) |
10 (3.7) |
22 (3.8) |
29 (5.0) |
|
Consent withdrawn |
3 (1.0) |
3 (1.0) |
3 (1.1) |
2 (0.7) |
6 (1.0) |
5 (0.9) |
|
Loss to follow-up |
4 (1.3) |
4 (1.3) |
0 |
0 |
4 (0.7) |
4 (0.7) |
|
Non-adherence |
3 (1.0) |
9 (2.9) |
1 (0.4) |
0 |
4 (0.7) |
9 (1.6) |
|
Pregnancy |
1 (0.3) |
0 |
1 (0.4) |
0 |
2 (0.3) |
0 |
|
Protocol violation |
1 (0.3) |
1 (0.3) |
2 (0.7) |
0 |
3 (0.5) |
1 (0.2) |
|
Other |
0 |
2 (0.6) |
3 (1.1) |
8 (3.0) |
3 (0.5) |
10 (1.7) |
a Confirmed loss of virologic
response or loss of virologic response and missing confirmatory visit.
b Includes premature
discontinuation of the study PI due to virologic failure and the addition of a
drug to the background regimen (if not introduced to replace a background drug
discontinued due to AEs attributable to the discontinued background drug).
c Death as primary reason for
treatment failure.
d The reader is cautioned against
making comparison to the Summary of Clinical Safety Module 2.7.4 since the
count used here is discontinuation as reason for virologic failure and is based
on the FAS population whereas the Summary of Clinical Safety counts all treated
patients.
6.3.5.2 Response by
pre-selected PI strata
Data from each of the two RESIST trials were combined to analyze treatment response within each pre-selected PI stratum.
To evaluate the impact of the extensive treatment experience of patients in the RESIST trials, analyses were conducted according to choice of the pre-selected PI: whether the pre-selected PI was new to the study regimen constructed at randomization (new PI), whether the virus was susceptible to the PI or the PI was genotypically available based on genotypic report interpretation of susceptible or possibly resistant, or whether the PI was both new to the study regimen and virus was susceptible or PI was genotypically available.
The
TPV/r group had significantly greater treatment responses than LPV/r, SQV/r, or
APV/r groups and these data are provided in Table 6.3.5.2: 1. The IDV stratum had too few patients to make
a valid definitive comparison.
Table 6.3.5.2: 1 Treatment
response at Week 24 by PI strata - RESIST trials (FAS)
|
|
Treatment Group |
Treatment Difference a |
||||||||
|
|
TPV/r |
CPI/r |
Weighted |
95% CI |
||||||
|
PI Strata |
Analysis |
n |
(%) |
N |
n |
(%) |
N |
Diff. (%) |
LL |
UL |
|
LPV |
FAS (NCF) |
116 |
(39.6) |
293 |
62 |
(21.4) |
290 |
(17.7) |
(10.5) |
(25.0) |
|
IDV |
FAS (NCF) |
10 |
(47.6) |
21 |
1 |
(5.0) |
20 |
b |
b |
b |
|
SQV |
FAS (NCF) |
51 |
(43.6) |
117 |
18 |
(15.3) |
118 |
(27.4) |
(16.5) |
(38.3) |
|
APV |
FAS (NCF) |
63 |
(41.7) |
151 |
28 |
(18.8) |
149 |
(22.0) |
(12.1) |
(31.9) |
n = Number of responders; N = Number of evaluable patients
a Treatment
difference and confidence interval weighted for the size of ENF strata and PI
strata.
b Weighted difference and confidence interval not presented for the
IDV stratum due to small sample size.
It is important for the reviewer to interpret these data cautiously. While the treatment response for patients receiving TPV/r was superior to the treatment response of those receiving LPV/r, SQV/r, or APV/r, the comparator PI being used was not always “new” and was not always considered “genotypically available” on the baseline resistance report. In the LPV/r stratum, for example, if the LPV/r was “new” the treatment response was 45.3% in the TPV/r arm and 36.1% in the CPI/r arm (p=NS). Alternatively, in the LPV/r stratum, if the LPV/r was “ongoing” the treatment response was 35.2% in the TPV/r arm and 10.7% in the CPI/r arm, a statistically significant result.
The response by status of pre-selected PI (new or ongoing) and whether or not it was genotypically available[19] for the aggregate CPI/r population was examined and these data are provided in Table 6.3.5.2: 2. These data demonstrate that patients who pre-selected a “new” PI had a superior treatment response if they received TPV/r than if they received CPI/r. In addition, the data show that those patients who pre-selected a “genotypically available” PI had a superior treatment response if they received TPV/r than if they received CPI/r.
Table 6.3.5.2: 2 Treatment responses at Week 24 by choice of and
resistance to pre-selected PIs for the
aggregate CPI/r population – RESIST trials (FAS)
|
|
Treatment Group |
Treatment Difference a |
|||||||
|
|
TPV/r |
CPI/r |
Weighted |
95% CI |
|||||
|
|
n |
(%) |
N |
n |
(%) |
N |
Diff. |
LL |
UL |
|
Pre-selected PI |
|
|
|
|
|
|
|
|
|
|
New PI |
165 |
(44.0) |
375 |
88 |
(24.2) |
363 |
(18.4) |
(11.9) |
(24.9) |
|
Ongoing PI |
75 |
(36.2) |
207 |
21 |
(9.8) |
214 |
(25.1) |
(17.6) |
(32.7) |
|
Resistance to pre-selected PI |
|
|
|
|
|
|
|
|
|
|
Genotypically available a |
92 |
(43.6) |
211 |
55 |
(28.6) |
192 |
(14.2) |
(5.0) |
(23.3) |
|
Genotypically resistant |
147 |
(39.8) |
369 |
54 |
(14.0) |
385 |
(24.3) |
(18.4) |
(30.2) |
|
Missing |
1 |
(50.0) |
2 |
0 |
|
0 |
|
|
|
|
Genotypically available and new
pre-selected CPI/r |
70 |
(46.1) |
152 |
46 |
(32.9) |
140 |
(11.7) |
(1.1) |
(22.4) |
n = number of responders, N =
number of evaluable patients
a Treatment difference and
confidence interval weighted for the size of PI strata
Pre-specified secondary efficacy endpoints included viral load change from baseline, proportion of patients with undetectable viral load (BLQ 400 copies/mL, BLQ 50 copies/mL, CD4 count change, and AIDS progression events). These data are described in the following sections.
6.3.5.3 Viral load change from baseline at 24 weeks (FAS population)
Viral load
reduction from baseline was rapid and substantial in the TPV/r group
(Figure 6.3.5.3: 1). For the
TPV/r group, the peak median change from baseline (LOCF) was ‑1.53 log10
copies/mL at Week 4. After 24 weeks
of treatment, the median change in VL from baseline in the combined RESIST
trials was -0.80 log10 copies/mL for the TPV/r group compared to -0.25
for the CPI/r group (p <0.0001).
Table 6.3.5.3: 1 VL change from baseline at Week 24 – RESIST trials (FAS)
|
|
RESIST-1 BI 1182.12 |
RESIST-2 BI 1182.48 |
Combined RESIST Trials |
|||||||||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
TPV/r |
CPI/r |
||||||
|
|
N |
Median |
N |
Median |
N |
Median |
N |
Median |
N |
Median |
N |
Median |
|
Baseline VL [log10
copies/mL] |
311 |
4.81 |
309 |
4.84 |
271 |
4.84 |
268 |
4.81 |
582 |
4.83 |
577 |
4.82 |
|
VL change (LOCF) |
311 |
-0.88 |
309 |
-0.28 |
271 |
-0.72 |
268 |
-0.22 |
582 |
-0.80 |
577 |
-0.25 |
Figure 6.3.5.3: 1 Median
log10 copies/mL change from baseline in viral load through Week 24 in combined
RESIST trials – (FAS [LOCF])
24-week difference:
p <0.0001
6.3.5.4 Virologic response (< 400 and < 50
copies/mL) and immunologic response at 24 weeks (FAS population)
At Week 24, the proportion of patients
who achieved a VL < 400 copies/mL was greater among TPV/r patients (34.2%)
than CPI/r patients (14.9%), and the proportion of patients who achieved a VL
< 50 copies/mL was also greater among TPV/r patients (23.9%) than CPI/r
patients (9.4%) (p <0.0001) (Table 6.3.5.4: 1; Figures 6.3.5.4: 1, 6.3.5.4:
2). Slightly larger proportions of
CPI/r patients in RESIST-1 achieved responses of < 400 copies/mL and < 50
copies/mL compared with CPI/r patients in RESIST-2.
Table 6.3.5.4: 1 Summary
of Week 24 virologic response (< 400 and < 50 HIV RNA copies/mL) and
immunologic response – RESIST trials (FAS)
|
|
RESIST-1 BI 1182.12 |
RESIST-2 BI 1182.48 |
Combined RESIST Trials |
|||||||||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
TPV/r |
CPI/r |
||||||
|
|
N |
(%) |
N |
(%) |
N |
(%) |
N |
(%) |
N |
(%) |
N |
(%) |
|
Total treated |
311 |
(100.0) |
309 |
(100.0) |
271 |
(100.0) |
268 |
(100.0) |
582 |
(100.0) |
577 |
(100.0) |
|
VL < 400 copies/mL (NCF) |
108 |
(34.7) |
51 |
(16.5) |
91 |
(33.6) |
35 |
(13.1) |
199 |
(34.2) |
86 |
(14.9) |
|
VL < 50 copies/mL (NCF) |
78 |
(25.1) |
31 |
(10.0) |
61 |
(22.5) |
23 |
(8.6) |
139 |
(23.9) |
54 |
(9.4) |
|
|
N |
Median |
N |
Median |
N |
Median |
N |
Median |
N |
Median |
N |
Median |
|
Baseline CD4+ cell count [cells/mm3] |
310 |
123 |
309 |
123 |
269 |
175 |
265 |
200 |
579 |
155 |
574 |
158 |
|
Absolute change CD4+ cell count
[cells/mm3] (LOCF) |
310 |
36 |
309 |
6 |
269 |
31 |
265 |
1 |
579 |
34 |
574 |
4 |
Figure 6.3.5.4: 1 Virologic
response (VL < 400 copies/mL) over time through 24 weeks in combined RESIST
trials – (FAS [NCF])
24-week difference:
p <0.0001
Figure 6.3.5.4: 2 Virologic
response (VL < 50 copies/mL) over time through 24 weeks in combined RESIST
trials – (FAS [NCF])
24-week difference:
p <0.0001
In the
combined RESIST trials, TPV/r patients achieved a larger median increase in
CD4+ cell count (34 cells/mm3) than CPI/r patients (4 cells/mm3)
at Week 24 (p <0.0001) (Figure 6.3.5.4: 3).
The mean increase in the patients receiving TPV/r was 52 cells/mm3.
Figure 6.3.5.4: 3 Median
change from baseline in CD4+ cell count (cells/mm3) in combined RESIST
trials – (FAS [LOCF])
24-week difference:
p <0.0001
6.3.5.5 New onset of AIDS events
In the combined RESIST study population, the proportion of patients who developed a new AIDS event was a secondary efficacy endpoint. The frequency of AIDS events was 3.4% for patients in the TPV/r arms and 4.6% for patients in the CPI/r arms, despite a greater duration of exposure in the TPV/r group. This difference did not achieve statistical significance, an anticipated result as the study was not powered to discriminate between treatment arms for this outcome.
6.3.6 Impact of active
background antiretroviral drugs
The OBR of patients in the RESIST trials consisted predominantly of two NRTIs, although some patients received up to 5 NRTIs. Overall, 52-57% of the patients in the RESIST trials had 2 or more genotypically available background ARVs to support the RTV-boosted protease (tipranavir or comparator) in the regimen.
The genotypic sensitivity score (GSS)
was the total number of drugs in the OBR to which a patient’s viral isolate
showed genotypic sensitivity according to the algorithmic interpretations of
the TruGene® or Virtual Phenotype™. By pre-established definition, enfuvirtide
was always considered genotypically available, even if enfuvirtide had been previously
administered, and it therefore counts in the calculation of GSS for those
patients who chose to use it as part of their ARV regimen.
Table 6.3.6: 1 Genotypic
sensitivity score of the background regimen in patients treated – RESIST trials
(FAS)
|
|
Total |
|
|
|
TPV/r |
CPI/r |
|
Total treated |
582 |
577 |
|
Genotypic sensitivity score for OBR |
N (%) |
N (%) |
|
0 |
61 (10.5) |
77 (13.3) |
|
1 |
190 (32.6) |
186 (32.2) |
|
2 |
236 (40.5) |
206 (35.7) |
|
> 3 |
95 (16.3) |
108 (18.7) |
As noted previously, enfuvirtide use was
declared by investigators prior to randomization and it could not be added
after study treatment had already been initiated. A total of 286 patients in the RESIST studies
used enfuvirtide in their treatment regimen; 27.1% in the TPV/r group (158 of
582) and 22.2% in the CPI/r group (128 of 577).
For patients who used enfuvirtide, there was a higher treatment response than for those who did not use it. The treatment response increased to 58.2% for those on TPV/r who used enfuvirtide and to 25.8% for those on CPI/r who used the drug. For those not taking enfuvirtide, the proportion of treatment responders was also twice as high in the TPV/r group (34.9%) than in the CPI/r group (16.9%).
Even in the absence of enfuvirtide, a
treatment response was achieved with TPV/r in more than 40% of patients when
used with 2 or more background ARV drugs that were considered genotypically
available at baseline to the patient. A
comparable response in patients treated with CPI/r was achieved when the CPI/r
drug was used with at least three other genotypically available ARVs (GSS > 3).
Table 6.3.6: 2 Treatment
responses at Week 24 according to enfuvirtide use and number of sensitive
background ARVs - RESIST trials (FAS [NCF])
|
|
ENF
strata |
|||||||||||
|
|
With ENF |
Without
ENF |
||||||||||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
||||||||
|
|
n |
(%) |
N |
n |
(%) |
N |
n |
(%) |
N |
n |
(%) |
N |
|
Total |
92 |
(58.2) |
158 |
33 |
(25.8) |
128 |
148 |
(34.9) |
424 |
76 |
(16.9) |
449 |
|
Genotypic sensitivity score for OBR a |
|
|
|
|
|
|
|
|
|
|
|
|
|
0 |
34 |
(57.6) |
59 |
6 |
(13.6) |
44 |
8 |
(13.1) |
61 |
7 |
(9.1) |
77 |
|
1 |
37 |
(55.2) |
67 |
10 |
(23.8) |
42 |
37 |
(28.2) |
131 |
18 |
(12.7) |
142 |
|
2 |
17 |
(68.0) |
25 |
12 |
(38.7) |
31 |
72 |
(42.6) |
169 |
31 |
(18.9) |
164 |
|
> 3 |
4 |
(57.1) |
7 |
5 |
(45.5) |
11 |
31 |
(49.2) |
63 |
20 |
(30.3) |
66 |
n = number of responders, N = number of evaluable
patients.
a ENF
not counted; always considered susceptible.
Co-administration of enfuvirtide
influenced other categories of virologic response. Within both treatment
groups, patients taking enfuvirtide had higher proportions of responders
achieving a reduction in VL >
1 log10, a VL of < 400 copies/mL, or a VL <
50 copies/mL than patients not taking enfuvirtide.
Changes in VL and CD4+ cell count from baseline to Week 24 were also influenced by enfuvirtide use even though these patients had a higher baseline VL and lower CD4+ cell count. For patients taking enfuvirtide, the median reduction in VL at Week 24 was -2.06 log10 copies/mL in the TPV/r group and -0.40 log10 copies/mL in the CPI/r group; and for patients not taking enfuvirtide the median reduction in VL at Week 24 was -0.57 log10 copies/mL in the TPV/r group and -0.20 log10 copies/mL in the CPI/r group. TPV/r patients taking enfuvirtide had a median increase of 55 cells/mm3, while TPV/r patients not taking enfuvirtide had a median increase of 27 cells/mm3; and CPI/r patients taking enfuvirtide had a median increase of 6 cells/mm3, while CPI/r patients not taking enfuvirtide had a median increase of 3 cells/mm3.
Table 6.3.6: 3 Summary
of secondary efficacy endpoints at Week 24 according to enfuvirtide use -
RESIST trials (FAS)
|
Endpoint / |
ENF Strata |
|||||||
|
With ENF |
Without ENF |
|||||||
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
|||||
|
n/N |
(%) |
n/N |
(%) |
n/N |
(%) |
n/N |
(%) |
|
|
VL > 1 log10
reduction (NCF) |
93/158 |
(58.9) |
35/128 |
(27.3) |
161/424 |
(38.0) |
83/449 |
(18.5) |
|
0 |
0 |
|
0 |
|
9/61 |
(14.8) |
7/77 |
(9.1) |
|
1 |
34/59 |
(57.6) |
6/44 |
(13.6) |
41/131 |
(31.3) |
19/142 |
(13.4) |
|
2 |
38/67 |
(56.7) |
10/42 |
(23.8) |
79/169 |
(46.7) |
35/164 |
(21.3) |
|
> 3 |
21/32 |
(65.6) |
19/42 |
(45.2) |
32/63 |
(50.8) |
22/66 |
(33.3) |
|
VL < 400 copies/mL (NCF) |
71/158 |
(44.9) |
26/128 |
(20.3) |
128/424 |
(30.2) |
60/449 |
(13.4) |
|
0 |
0 |
|
0 |
|
7/61 |
(11.5) |
4/77 |
(5.2) |
|
1 |
24/59 |
(40.7) |
5/44 |
(11.4) |
31/131 |
(23.7) |
13/142 |
(9.2) |
|
2 |
28/67 |
(41.8) |
9/42 |
(21.4) |
66/169 |
(39.1) |
24/164 |
(14.6) |
|
> 3 |
19/32 |
(59.4) |
12/42 |
(28.6) |
24/63 |
(38.1) |
19/66 |
(28.8) |
|
VL < 50 copies/mL (NCF) |
48/158 |
(30.4) |
16/128 |
(12.5) |
91/424 |
(21.5) |
38/449 |
(8.5) |
|
0 |
0 |
|
0 |
|
3/61 |
(4.9) |
2/77 |
(2.6) |
|
1 |
18/59 |
(30.5) |
4/44 |
(9.1) |
21/131 |
(16.0) |
9/142 |
(6.3) |
|
2 |
16/67 |
(23.9) |
3/42 |
(7.1) |
48/169 |
(28.4) |
16/164 |
(9.8) |
|
> 3 |
14/32 |
(43.8) |
9/42 |
(21.4) |
19/63 |
(30.2) |
11/66 |
(16.7) |
|
|
N |
Median |
N |
Median |
N |
Median |
N |
Median |
|
Baseline VL [log10 copies/mL] |
158 |
5.07 |
128 |
5.10 |
424 |
4.74 |
449 |
4.75 |
|
VL change [log10
copies/mL] (LOCF) |
158 |
-2.06 |
128 |
-0.40 |
424 |
-0.57 |
449 |
-0.20 |
|
Baseline CD4+ cell count [cells/mm3] |
158 |
72 |
127 |
77 |
421 |
177 |
447 |
182 |
|
Absolute change in CD4+ cell count
[cells/mm3] (LOCF) |
158 |
55 |
127 |
6 |
421 |
27 |
447 |
3 |
a ENF not
counted; always considered susceptible.
The number of patients with prior enfuvirtide treatment experience was 69/582 (11.9%) in the TPV/r arms and 68/577 (11.8%) in the CPI/r arms. A greater percentage of those patients without prior enfuvirtide experience achieved a treatment response.
The greatest response was seen in
patients who were enfuvirtide naïve and received the combination of TPV/r and enfuvirtide
where nearly 70% achieved a treatment response.
Table 6.3.6: 4 Treatment
response by prior enfuvirtide use
|
|
TPV/r |
CPI/r |
||||
|
ENF Use |
N |
% |
N |
N |
% |
N |
|
ENF Naive |
80 |
69.6% |
115 |
27 |
28.7% |
94 |
|
ENF Experienced |
12 |
27.9% |
43 |
6 |
17.6% |
34 |
|
No ENF Use |
|
|
|
|
|
|
|
ENF Naive |
146 |
36.7% |
398 |
73 |
17.6% |
415 |
|
ENF Experienced |
2 |
7.7% |
26 |
3 |
8.8% |
34 |
For most participants in the RESIST
trials enfuvirtide was a drug from a new class of antiretroviral agents. To characterize the relative contribution of
the different components of the regimen started after randomization into
RESIST, an ANOVA analysis of the Week 24 viral load change considering
treatment group, preselected PI, enfuvirtide use, and genotypic susceptibility
to background drugs (other than enfuvirtide) was performed. This analysis confirmed the superiority of
TPV/r compared to CPI/r after adjustment for the other factors. The Week 24 viral load reduction
attributable to TPV/r over and above the Week 24 viral load reduction
attributable to CPI/r was 0.64 log10 copies/mL. Similarly, after controlling for other
factors including treatment group, the magnitude of Week 24 viral load
reduction attributable to a new class of drug (enfuvirtide) was of
approximately the same order of magnitude as that for TPV/r, i.e., 0.67 log10
copies/mL.
6.3.7 Impact of baseline
viral load and CD4+ count
In the TPV/r group, the proportion with
a treatment response increased from 34.9% in patients with high baseline VL
(>100,000-1,000,000 copies/mL) to 56.3% in patients with low baseline VL
(1,000-10,000 copies/mL). In the CPI/r
group, the proportion of patients with a treatment response was 13.7% and 31.5%
in patients with high and low baseline viral loads respectively. In the TPV/r group, the proportion of
patients with a treatment response increased from 26.3% for patients in the <
50 cells/mm3 baseline CD4+ group to 46.0% for patients in
the >350 cells/mm3 group. In the CPI/r group, the response rate
increased from 9.5% for patients in the < 50 cells/mm3 baseline CD4+ group to 21.2% for patients in
the >350 cells/ mm3 group.
6.3.8 Sensitivity
analyses
Multiple sensitivity analyses were
conducted to evaluate the potential for bias.
One sensitivity analysis explored the influence of protocol violations
on the Week 24 treatment responses (PPS [NCF]).
In this analysis, only patients who did not have protocol violations or
relevant protocol deviations[20]
(PPS) were considered in the assessment of Week 24 treatment responses. Consistent with the primary analysis, this
analysis showed that a larger proportion of TPV/r patients (44.7%) achieved a
treatment response than did CPI/r patients (22.5%). The weighted difference in the proportion of
treatment responders was 21.3% and the lower bound of the 95% CI was 14.7%
superiority, which again indicated a large treatment effect.
Table 6.3.8: 1 Sensitivity
analyses of treatment response at Week 24 – RESIST trials (FAS and PPS[21])
|
|
Treatment Group |
Treatment Difference |
||||||||
|
|
TPV/r |
CPI/r |
Weighted |
95% CI |
||||||
|
Trial |
Analysis |
n |
(%) |
N |
n |
(%) |
N |
Diff. |
LL |
UL |
|
1182.12 |
FAS (NCC) |
129 |
(42.3) |
305 |
69 |
(23.7) |
291 |
(17.7) |
(10.5) |
(24.8) |
|
|
FAS |
129 |
(41.5) |
311 |
69 |
(23.7) |
291 |
(17.0) |
(9.9) |
(24.1) |
|
|
PPS24 (NCF) |
86 |
(45.0) |
191 |
50 |
(25.9) |
193 |
(18.5) |
(9.3) |
(27.6) |
|
1182.48 |
FASS24, (NCC) |
111 |
(42.4) |
262 |
40 |
(15.3) |
261 |
(26.1) |
(18.7) |
(33.4) |
|
|
FAS |
111 |
(41.0) |
271 |
40 |
(15.3) |
261 |
(24.6) |
(17.4) |
(31.9) |
|
|
PPSS24 (NCF) |
80 |
(44.4) |
180 |
31 |
(18.6) |
167 |
(24.6) |
(15.4) |
(33.8) |
|
Total |
FAS (NCC) |
240 |
(42.3) |
567 |
109 |
(19.7) |
552 |
(21.4) |
(16.3) |
(26.6) |
|
|
FAS |
240 |
(41.2) |
582 |
109 |
(19.7) |
552 |
(20.4) |
(15.3) |
(25.5) |
|
|
PPS (NCF) |
166 |
(44.7) |
371 |
81 |
(22.5) |
360 |
(21.3) |
(14.7) |
(27.8) |
6.4 Efficacy RESULTS IN SPECIAL POPULATIONS
Within the TPV/r clinical development
program, the highly treatment experienced adult patients in BI 1182.51, who by
design harbored more resistant virus (more than 2 mutations at codons 33, 82,
84, or 90), represent an important treatment population. Efficacy results for this trial are summarized
here. Direct comparison to the RESIST
trials cannot be made, however, due to the fact that different primary
endpoints were used. BI 1182.51 was
primarily a PK and safety trial with 2- and 4-week efficacy results. Patients in BI 1182.51 were allowed to have
background medication adjustments at 4 weeks (after completing the PK portion
of the trial), thus interpretation of 24-week efficacy results is limited.
Patients who screened for either of the
two RESIST studies but were not able to enrol because they had more than 2 key
mutations at codons 33, 82, 84, or 90 in the protease gene were offered TPV/r
in a study evaluating the safety and pharmacokinetics of TPV/r of dual boosted
PI regimens. Of those who failed
screening for the RESIST studies, 315 patients were randomized into BI 1182.51
and received at least one dose of study medication.
At baseline, all patients received an
individually selected OBR and were randomized to receive either TPV/r (n = 67)
or LPV/r (n = 83), SQV/r (n = 82), or APV/r (n = 83). Fourteen percent of patients pre-selected enfuvirtide
as part of the background regimen.
After 2 weeks using one of the four
single RTV-boosted regimens, TPV/r was added to patients in the LPV/r, SQV/r,
and APV/r treatment arms; patients in the TPV/r control arm either maintained
their same drug regimen or had a second PI added to their treatment regimen
although the primary trial objective was to evaluate the safety and
pharmacokinetics of dual boosted PI regimens the first 4 weeks of the trial
allow for comparison of intrinsic activity of the individual PIs.
Patients in BI 1182.51 tended to have a
lower baseline CD4+ count (median 138 compared with 155 cells/mm3
in the TPV/r group of the combined RESIST trials), a higher baseline viral load
(4.97 compared with 4.83 log10 copies/mL in the TPV/r group of the
combined RESIST trials), and had been exposed to more antiretroviral agents (13
compared with 12 in the TPV/r group of the combined RESIST trials).
During the first 2 weeks of therapy in
which patients received a single boosted PI, the median viral load reduction
among patients randomized to TPV/r was 1.06 log10 copies/mL, while
it was below 0.4 log10 copies/mL in the 3 other arms (Table 6.4.1: 1
and Figure 6.4.1: 1).
Table 6.4.1: 1 Median
Baseline VL [log10 copies/mL] change in BI 1182.51 - FAS (LOCF/NCF)
|
|
TPV/r a |
LPV/r b |
SQV/r b |
APV/r b |
|
Week |
N = 67 |
N = 83 |
N = 82 |
N = 83 |
|
Baseline VL |
4.78 |
4.97 |
5.02 |
4.99 |
|
2 |
-1.06 |
-0.38 |
-0.19 |
-0.15 |
|
4 c |
-1.27 |
-1.19 |
-0.96 |
-1.12 |
|
8 |
-0.76 |
-0.63 |
-0.54 |
-0.69 |
|
24 |
-0.28 |
-0.43 |
-0.24 |
-0.47 |
a Enrollment
into the TPV/r arm was halted when the trial monitoring team found that >25%
of patients on the TPV/r arm had at Week 4 VL reduction below 0.5 log10.
Since the sample size for the primary PK objective was 60, enrollment into the
TPV/r arm was stopped.
b TPV/r added
after 2 weeks.
c Patients
were allowed to switch both background ARVs and PIs after Week 4.
At Week 2, TPV/r was added to the
individual PIs and, the virologic response at Week 4 was similar for each of
the four treatment arms to that seen for TPV alone during the first 2 weeks of
the study. After Week 4, the virologic
response began to decay across all treatment
arms and after 8 weeks of therapy, there was no significant
difference in virologic response across all four treatment arms. Viral load responses diminish after 4 weeks
due to a combination of impaired TPV activity and limited active background
drugs available to support the TPV/r resulting in the development of viruses
resistant to TPV. (Figure 6.4.1: 1).
Figure 6.4.1: 1 Reduction
in HIV-1 viral load from baseline in each of the four treatment arms in BI
1182.51 during the single boosted and dual boosted PI treatment phases (Weeks
0-8)
·
TPV/r has proved to be a potent PI in patients who have been
previously exposed to 2 or more PI-containing antiretroviral regimens.
·
In multiple PI-experienced patients, TPV/r was virologically
and immunologically superior to CPI/r across multiple efficacy analyses
confirmed by sensitivity analyses of the overall results and for individual
randomized CPI comparisons.
·
For patients with PI-resistant virus, superior efficacy was
demonstrated for TPV/r compared to the best available alternate
ritonavir-boosted PI.
· The superior virological and immunological responses seen with TPV/r at 24 weeks were associated with a nonsignificant decrease in AIDS progression events in patients with PI-resistant HIV-1.
· The antiviral effect seen with regimens containing TPV/r is greater in regimens with additional active ARVs (e.g. other genotypically available background drugs, for example enfuvirtide). TPV/r had potent early antiviral responses despite high-level protease inhibitor resistance, but to obtain a durable response with TPV/r additional active background drugs are needed.
· Consistent with established NIH and IAS guidelines for the use of ARV drugs in treatment-experienced patients, knowledge of baseline resistance can be used to choose the optimal background regimen to combine with TPV/r to obtain a durable antiviral response.
7.1 Development Of Tipranavir Resistance In Vitro
The development of
resistance to tipranavir in vitro is
slow and complex. In one in vitro
resistance experiment starting with wild type HIV-1, an HIV-1 isolate that was
87-fold resistant to tipranavir was selected after 9 months and contained 10
mutations in the protease: L10F, I13V, V32I, L33F, M36I, K45I, I54V/T, A71V,
V82L, I84V as well as a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic experiments showed that the
presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L, I84V)
was required to confer >10-fold resistance to tipranavir while the full
10-mutation genotype conferred 69‑fold resistance to tipranavir.
In vitro, there is an inverse correlation between the
degree of resistance to tipranavir and the capacity of viruses to replicate.
Recombinant viruses showing > 3-fold resistance to tipranavir
grow at less than 1% of the rate detected for wild type HIV-1 in the same
conditions. Tipranavir-resistant viruses which emerged in vitro from
wild-type HIV-1 showed decreased susceptibility to the protease inhibitors
amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but
remained sensitive to saquinavir.
7.2 Clinical Resistance (In
Vivo)
Current treatment
of HIV-1 infection involves the concomitant administration of at least three
ARV medications among the classes of non-nucleoside reverse transcriptase
inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), PIs,
and to a lesser extent HIV entry inhibitors. There are currently eight PIs
approved for the treatment of HIV infection.
Varying degrees of cross resistance among the PIs approved for HIV
therapy have been observed and have resulted in limited options for patients
with PI-resistant virus. There is
clearly a need for novel PIs with activity against PI-resistant HIV-1 and
distinct patterns of PI cross resistance.
Tipranavir (TPV) demonstrates unique resistance characteristics that
offer potential therapeutic advantages to PI-experienced patients. In a study of 105 highly PI‑resistant
viruses at VIRCO, Larder, et. al. showed that 90% remained sensitive to TPV (< 4-fold
WT) while only 2% showed high level resistance (> 10-fold WT).[22]
Experiments by Larder, et al also demonstrated
that clinical HIV-1 strains resistant to TPV had a high frequency of mutations
V82T and
I84V. Specifically, two clusters of
mutation patterns were identified: V82T with I84V and I84V with L90M (both with
numerous secondary mutations). In Phase
II and III clinical trials, 276 patients with on-treatment genotypes have
demonstrated that the predominant emerging mutations with TPV/r treatment are
L33F/I/V, V82T/L and I84V. Combination of all three of these mutations is
usually required for reduced TPV susceptibility. Mutations at position 82 occur
via two pathways: one from pre-existing mutation 82A selecting to 82T, the
other from V82-wild type selecting to 82L.
These in vitro observations led BI to emphasize analyses of patient responses according to the presence of multiples of mutations at four protease codons: 33, 82, 84, and 90 which were associated with decreased viral load responses to TPV/r in Phase II studies and broad, high level resistance to other available PIs in in vitro studies. At various times, these positions have been called "key TPV-associated mutations", "universal protease-associated mutations" (UPAMs), or "protease resistance-associated mutations" (PRAMs). This section will provide a comprehensive review of resistance data obtained from all TPV clinical trials, including evaluation of effect of the genotype on susceptibility phenotype and genotype or phenotype on antiviral responses.
7.3 GENOTYPIC SCORES
HIV drug susceptibility genotyping and phenotyping are the two methods
currently in use to determine whether an HIV-1 isolate has decreased
susceptibility to ARV agents. With
either of these methods, physicians can construct regimens for
treatment-experienced patients that provide enhanced antiviral response compared
with regimens designed using treatment history alone.
In the context of
the RESIST trials, genotypic resistance testing was performed at screening for
all patients. Phenotyping was conducted
in a subset of 500 randomly selected baseline plasma samples (400 for patients
randomized to TPV/r and 100 for patients randomized to CPI/r). A total of 454 paired genotypic and
phenotypic results of screening samples were available for analyses of the
relationship between protease mutations and phenotype (phenotyping was
unsuccessful for 46 samples). To broaden
the range of TPV susceptibilities evaluated, 356 samples from patients in the
Phase II program (Trials BI 1182.52 and 1182.51) were added to some
analyses. Virologic responses of
patients on the 500/200 mg dose of TPV/r in Phase II trials were also included
in some response analyses.
To examine the relationship between protease mutations detected by
genotypic resistance testing and TPV phenotypic susceptibility results, several
patterns of protease inhibitor resistance mutations were
investigated:
·
Key protease
mutations: protease codons 33,
82, 84, 90
·
TPV score mutations:
protease codons 10V, 13V, 20M/R/V, 33F,
35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V
·
FDA protease mutations: protease
codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88, 90
7.3.1 Key protease mutations
(HIV protease codons 33, 82, 84 and 90)
The relationship between the presence of key mutations (mutations at HIV-1
protease codons 33, 82, 84, and 90) and associated change in phenotypic
susceptibility to available protease inhibitors was evaluated using the
clinical samples from the TPV development program (Table 7.3.1: 1). HIV-1
isolates with one key mutation showed resistance to lopinavir, indinavir,
nelfinavir, ritonavir and atazanavir, and decreased susceptibility to
saquinavir and amprenavir while TPV had a median susceptibility of 1.1-fold WT.
HIV-1 isolates with 2 key mutations demonstrated high level resistance to all
currently available PIs but remained susceptible to TPV with a median
susceptibility of 1.7-fold WT. Tipranavir susceptibility was decreased ( > 3-fold
WT) for HIV-1 with protease enzymes containing 3 key mutations and high level
resistance ( > 10-fold WT) usually requires 4 key mutations to be
present.
Table 7.3.1: 1 Comparative
phenotype of all protease inhibitors tested in Phase II and III TPV trials
according to number of key protease mutations
|
|
|
Protease inhibitor median IC50
fold WT |
|||||||
|
Number of key mutations |
N |
TPV |
LPV |
IDV |
SQV |
APV |
NFV |
RTV |
TAZ |
|
0 |
82 |
0.7 |
1.0 |
1.1 |
0.9 |
0.6 |
2.3 |
1.1 |
1.8 |
|
1 |
232 |
1.1 |
49.7 |
12.2 |
4.4 |
4.6 |
32.4 |
43.9 |
13.4 |
|
2 |
371 |
1.7 |
90.6 |
43.5 |
33.2 |
15.1 |
41.8 |
199.1 |
76.6 |
|
3 |
112 |
3.4 |
102.8 |
53.9 |
42.2 |
30.9 |
43.1 |
361.0 |
102.9 |
|
4 |
13 |
12.0 |
100.1 |
36.7 |
46.2 |
32.3 |
41.7 |
361.0 |
95.8 |
Through a series
of multiple stepwise regression analyses of baseline and on-treatment genotypes
from all clinical studies, mutations at 16 protease codons have been associated
with reduced tipranavir susceptibility and/or reduced 2 or 24-week viral load
responses: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K,
74P, 82L/T, 83D and 84V. As shown in Figure 7.3.2: 1, a number of TPV score
mutations have not been previously associated with resistance to other PIs – at
codons 13, 35, 43, 58, 69, 74, and 83. Similarly, many IAS-USA mutations are
not associated with resistance to TPV – at codons 24, 30, 32, 48, 50, 53, 88,
and 90. This may explain the low level of cross resistance between TPV and
other currently available protease inhibitors.
Figure 7.3.2: 1 Comparison of TPV Score
Mutations with IAS-USA Mutations for Currently Available Protease Inhibitors
The accumulation of greater than 4 protease mutations among the 16
TPV-associated codons is required to predict decreased phenotypic TPV
susceptibility ( > 3-fold WT) and decreased antiviral responses
to TPV. High level resistance to TPV ( > 10
fold WT) usually requires > 7 TPV-associated mutations. The
mutation L90M does not appear to be related to decreased TPV susceptibility or
decreased antiviral responses to TPV. V82A,
the most common mutation at codon 82 selected by currently available PIs, also
does not appear related to TPV susceptibility.
L90M when combined with mutations at codons 82 or 84 may be a marker for
viruses with multiple associated protease resistance mutations.
7.3.3 FDA protease gene mutations
The FDA protease
mutation score was determined by counting any alteration at codons 30, 32, 36,
46, 47, 48, 50, 53, 54, 82, 84, 88, 90 in HIV-1 protease as defined by the FDA.
7.4 Relationship of Genotype to Phenotype
During the course of the Tipranavir Phase II/III clinical development
program genotypic resistance testing was performed at screening in all
participants. The data presented in this
section concern the results of paired genotypic and phenotypic resistance
screening sample results for 810
participants. To examine the
relationship between protease mutations detected by genotypic resistance
testing and TPV phenotypic susceptibility results, the three categories of
mutations were used (Table 7.4: 1).
Table 7.4: 1 Median
IC50 fold change from wild type for TPV by number of mutations in
the protease gene among participants in Phase II and III TPV trials
|
Number
of mutations |
N |
Median TPV Fold Change (IQR) |
|
|||
|
FDA
Protease gene mutations1 |
|||||
|
0 - 1 |
75 |
0.9 (0.5, 1.1) |
|
|||
|
2 - 3 |
179 |
1.0 (0.6, 1.9) |
|
|||
|
4 - 5 |
417 |
1.8 (0.9, 3.7) |
|
|||
|
6+ |
139 |
2.6 (1.0,
6.0) |
|
|||
|
Key
protease mutations2 |
|||||
|
0 |
82 |
0.7 (0.4,
1.0) |
|
|||
|
1 |
232 |
1.1 (0.7,
2.1) |
|
|||
|
2 |
371 |
1.7 (0.9,
3.7) |
|
|||
|
3 |
112 |
3.4 (1.9,
8.4) |
|
|||
|
4 |
13 |
12.0 (2.5,
16.6) |
|
|||
|
TPV
score mutations3 |
|||||
|
0 |
80 |
0.7 (0.4,
1.0) |
|
|||
|
1 |
105 |
0.9 (0.6,
1.4) |
|
|||
|
2 |
118 |
1.1 (0.6,
1.9) |
|
|||
|
3 |
159 |
1.4 (0.7,
2.6) |
|
|||
|
4 |
153 |
2.0 (1.0,
4.1) |
|
|||
|
5 |
114 |
3.1 (1.7,
7.0) |
|
|||
|
6 |
49 |
3.3 (1.6,
8.7) |
|
|||
|
7 |
25 |
3.9 (2.7, 12.5) |
|
|||
|
8 |
6 |
14.7 (4.9,
19.8) |
|
|||
|
9 |
1 |
52.5 (52.5, 52.5) |
|||
1 FDA
protease mutation: 30, 32, 36, 46, 47, 48, 50, 53, 54,
82, 84, 88, 90
2 Key protease mutations: 33, 82, 84, and 90.
3 TPV score mutations:
L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K,
T74P, V82L/T, N83D, and I84V.
In general, as the number of mutations in the protease gene increased, TPV
susceptibility progressively decreased.
In summary, among
the 810 screening isolates with paired genotype and phenotype resistance
testing from participants in the TPV Phase II and III programs, an increased
number of FDA protease mutations were associated with decreased TPV phenotypic
susceptibility but despite the presence of a large number of these mutations in
the protease gene, the change in TPV phenotypic susceptibility was modest. Counting TPV score mutations or key protease
mutations appeared the best predictors of changes in TPV phenotypic
susceptibility.
Table 7.4: 2 Relationship
of different protease gene scores to TPV susceptibility
|
Fold-change at baseline in
tipranavir IC50 |
FDA Mutation Score |
Key Mutation Score |
Tipranavir Score |
|
0 to < 3 |
1 to 6+ |
0 to 2 |
0 to 4 |
|
3 to <10 |
N.A. |
3 |
5 to 7 |
|
> 10 |
N.A |
4 |
8+ |
7.5 Impact of Genotype on Virologic Response
The relationship between screening genotype and VL response was examined
for 810 participants on the 500/200 mg dose of TPV/r in the TPV clinical
development program with data available at baseline. Virologic responses were
evaluated at 2 weeks (for TPV/r antiviral activity) and 24 weeks (for the
durability of TPV/r-containing regimens). A problem complicating these analyses is that
patients with viruses with higher levels of TPV resistance had very limited
options for active background drugs. Thus,
lower GSS scores were correlated with higher TPV scores.
Three mutation scores (i.e., FDA protease mutations, TPV score mutations,
and key protease mutations) are presented in this section. All
response analyses were ITT using all patients with complete data available for
the analysis.
Table 7.5: 1 Change in viral load at Weeks 2 and 24
according to baseline genotypic mutations among participants in all Phase II
and III trials using the TPV/r 500/200 mg dose
|
Mutation Category and Count |
TPV/r
Change in Viral Load from Baseline |
||||||
|
Week 2 (OT) |
|
Week 24 (LOCF d) |
|||||
|
N |
Median |
(IQR) |
|
N |
Median |
(IQR) |
|
|
FDA Protease a |
|
|
|
|
|
|
|
|
0 - 1 |
31 |
-1.09 |
(-0.58,
-1.61) |
|
24 |
-0.64 |
(-0.12, -2.34) |
|
2 - 3 |
162 |
-1.40 |
(-0.83,
-1.76) |
|
132 |
-1.65 |
(-0.47, -2.65) |
|
4 - 5 |
466 |
-1.36 |
(-0.66,
-1.86) |
|
397 |
-0.63 |
(-0.11, -2.29) |
|
6 + |
147 |
-1.37 |
(-0.43,
-1.85) |
|
135 |
-0.48 |
(-0.05, -2.28) |
|
Key proteaseb |
|
|
|
|
|
|
|
|
< 1 |
255 |
-1.35 |
(-0.77, -1.86) |
|
205 |
-1.27 |
(-0.24, -2.62) |
|
2 |
473 |
-1.39 |
(-0.67, -1.83) |
|
402 |
-0.78 |
(-0.14, -2.42) |
|
3 |
68 |
-1.25 |
(-0.26, -1.68) |
|
71 |
-0.24 |
(0.13 -1.87) |
|
4 |
10 |
-1.08 |
(-0.33, -1.54) |
|
10 |
-0.33 |
(-0.14, -0.66) |
|
TPV scorec |
|
|
|
|
|
|
|
|
< 1 |
135 |
-1.25 |
(-0.91, -1.78) |
|
114 |
-2.10 |
(-0.82, -2.77) |
|
2 |
112 |
-1.38 |
(-0.87, -1.83) |
|
91 |
-1.30 |
(-0.31, -2.54) |
|
3 |
177 |
-1.36 |
(-0.72, -1.83) |
|
151 |
-0.64 |
(-0.16, -2.29) |
|
4 |
190 |
-1.42 |
(-0.64, -1.87) |
|
156 |
-0.60 |
(-0.11, -2.39) |
|
5 |
112 |
-1.38 |
(-0.37, -1.89) |
|
104 |
-0.30 |
(0.13 -1.54) |
|
6 |
56 |
-1.35 |
(-0.23, -1.81) |
|
50 |
-0.51 |
(-0.05, -1.44) |
|
7 |
20 |
-1.06 |
(-0.18, -1.79) |
|
18 |
-0.49 |
(0, -2.84) |
|
8 |
4 |
-0.33 |
(0.11, -0.83) |
|
4 |
-0.08 |
(0.01, -0.18) |
a FDA
protease mutations: 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88, 90
b Key mutations:
33, 82, 84, and 90.
c TPV score mutations: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L,
I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, and I84V.
d LOCF: last
observation carried forward.
For
all three analyses TPV/r-containing regimens showed a median 1.1 to 1.4 log10 copies/mL response
except for mutation score cells with very few patients at 2 weeks (Table 7.5:
1). The clearest relationship with reduced
HIV RNA responses at 24 weeks was seen with increasing scores with either the
key mutations or the TPV score. None-the-less, >25% of patients had a
durable 1 log or greater response to TPV-containing regimens, even with 3 key mutations
or a TPV score of 7. These results are confirmed in the RESIST trials for viral
endpoints of < 400 copies/ml or < 50 copies/ml in Table 7.5: 2
below.
Table 7.5: 2 Summary
of TPV/r 24-week virologic response according to baseline genotypic categories in
Combined RESIST Trials
|
Mutation Category and Count |
% < 400 Copies |
% < 50 Copies |
% 1 log10 Drop from Baseline |
% 0.5 log10 Drop from Baseline |
|
Key
(33, 82, 84, 90) |
|
|
|
|
|
< 1 |
74 / 188 (39.4) |
50 / 188 (26.6) |
87 / 188 (46.3) |
97 / 144 (67.4) |
|
2 |
121 / 374 (32.4) |
86 / 374 (23.0) |
161 / 374 (43.0) |
192 / 324 (59.3) |
|
3 |
4 / 18 (22.2) |
3 / 18 (16.7) |
6 / 18 (33.3) |
5 / 15 (33.3) |
|
4 |
0 / 1 (0.0) |
0 / 1 (0.0) |
0 / 1 (0.0) |
|
|
TPV
scoreb |
|
|
|
|
|
< 1 |
59 / 104 (56.7) |
45 / 104 (43.3) |
70 / 104 (67.3) |
75 / 89 (84.3) |
|
2 |
29 / 80 (36.3) |
25 / 80 (31.3) |
34 / 80 (42.5) |
42 / 62 (67.7) |
|
3 |
38 / 127 (29.9) |
26 / 127 (20.5) |
48 / 127 (37.8) |
56 / 10 (54.4) |
|
4 |
44 / 139 (31.7) |
22 / 139 (15.8) |
58 / 139 (41.7) |
68 / 123 (55.3) |
|
5 |
17 / 83 (20.5) |
13 / 83 (15.7) |
24 / 83 (28.9) |
30 / 67 (44.8) |
|
6 |
7 / 36 (19.4) |
4 / 36 (11.1) |
13 / 36 (36.1) |
16 / 29 (55.2) |
|
7 |
5 / 12 (41.7) |
4 / 12 (33.3) |
7 / 12 (58.3) |
7 / 10 (70.0) |
a N = number within the specified genotypic category;
n = number (out of N) of patients who achieved the respective virologic
response.
b TPV score mutations: L10V, I13V, K20M/R/V, L33F, E35G,
M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, and I84V.
7.6 Impact of Phenotype on Virologic
Response
For the RESIST trials, the relationship between the change in TPV
phenotypic susceptibility at baseline and Week 2 and Week 24 virologic
responses was analyzed.
Analyses of treatment response at 24 weeks and viral load responses at 2
and 24 weeks show apparent TPV breakpoints at 3-fold and 10-fold wild type with
the clearest dose response relationship in patients who did not receive
enfuvirtide (Tables 7.6: 1 and 7.6: 2). In
all susceptibility strata, addition of enfuvirtide improved the virologic
response seen with TPV/r, especially in the patients with high level TPV resistance.
Table 7.6: 1 Treatment
Response a at Week 24 for TPV/r by Baseline Tipranavir
Susceptibility, Stratified by Enfuvirtide Use, in Combined RESIST Trials
|
Enfuvirtide
Use |
Fold-change at baseline in
TPV IC50 |
TPV/r
treatment response |
|
No |
0 to < 3 |
75/193
(38.9%) |
|
|
3 to < 10 |
10/53 (18.9%) |
|
|
> 10 |
0/12 (00.0%) |
|
Yes |
0 to < 3 |
45/61
(73.8%) |
|
|
3 to < 10 |
12/32
(37.5%) |
|
|
> 10 |
5/10
(50.0%) |
a Treatment response is the
composite endpoint of the proportion of patients with two consecutive VL
measurements >1 log10 below baseline after 24 weeks without
prior (1) evidence of a confirmed virological failure, (2) introduction of a
new ARV to the regimen for reasons other than toxicity or intolerance to a
background drug, (3) permanent discontinuation of the study drug, (4) death, or
(5) loss to follow-up.
Table 7.6: 2 HIV Viral Load Response at
Weeks 2 and 24 for TPV/r by Baseline Tipranavir Susceptibility, Stratified by
Enfuvirtide Use, in Combined RESIST trials
|
|
TPV/r |
|||||
|
|
2 weeks (OT) |
24 weeks (LOCF) |
||||
|
Fold-change at baseline in tipranavir IC50 |
N |
Median |
(IQR) |
N |
Median |
(IQR) |
|
No Enfuvirtide Use |
||||||
|
1 to < 3 |
176 |
-1.39 |
(-0.81, -1.87) |
193 |
-0.66 |
(-0.16, -2.24) |
|
3 to < 10 |
50 |
-0.67 |
(-0.21, -1.61) |
53 |
-0.32 |
(+0.03, -0.64) |
|
> 10 |
11 |
-0.52 |
(+0.21, -1.03) |
12 |
-0.15 |
(+0.10, -0.72) |
|
Enfuvirtide included in
regimen |
||||||
|
1 to < 3 |
59 |
-1.72 |
(-1.27, -2.22) |
61 |
-2.57 |
(-1.21, -3.16) |
|
3 to < 10 |
30 |
-1.85 |
(-0.15, -2.38) |
32 |
-0.85 |
(+0.02, -2.78) |
|
> 10 |
10 |
-1.70 |
(-1.07, -2.12) |
10 |
-0.94 |
(-0.27, -2.77) |
7.7 Predictors OF VIRAL Load RESPONSE at
24 Weeks
A multivariate analysis was conducted of
factors that were associated with the viral load responses seen at 24 weeks on
TPV/r-containing regimens. Factors associated with an increased viral load
reduction were TPV/r, addition of Enfuvirtide, and each additional active
NRTI/NNRTI in the regimen. Increasing TPV mutation scores were associated with
decreased antiviral responses with each mutation reducing the 24 week viral
load response by 0.2 log (Table 7.7: 1).
Table 7.7: 1 Predictors of viral load responses at 24 weeks to TPV/r-containing
regimens
|
|
24 weeks |
|
|
Parameter |
Estimate |
P-value |
|
Tipranavir/r |
-1.25 |
<0.01 |
|
Enfuvirtide use |
-0.91 |
<0.01 |
|
Per available NRTI/NNRTI in background |
-0.24 |
<0.01 |
|
Per TPV score mutation |
0.17 |
<0.01 |
·
TPV/r is
virologically active against the majority of HIV-1 with broad PI resistance.
·
There is a
high genetic barrier to resistance with TPV. It takes 3 key protease gene
mutations or > 4 TPV-associated mutations to produce decreased
susceptibility (> 3‑fold WT) in vitro or reduced antiviral responses in the clinic. High level TPV resistance (> 10-fold
WT) was seen when all 4 key mutations or > 7 TPV-associated mutations
were present.
·
Key
mutations at PI codons 33, 82, 84, 90 can produce high level resistance to
currently available PIs. Viruses with 3
or more key mutations showed > 3‑fold resistance to TPV/r.
·
In viruses
from PI-experienced patients, many of the mutations which produce resistance to
TPV are different than the mutations that produce drug resistance to currently
available PIs. This may explain the
diminished cross resistance seen between TPV and other currently available
protease inhibitors.
·
The
predominant emerging mutations with virologic failure in PI-experienced
patients receiving TPV/r are 33F/I/V, 82T/L, and 84V.
·
The drug
resistance pattern which will result from treatment of drug naïve patients is
still being evaluated.
·
The TPV
score, enfuvirtide use, and available NRTI/NNRTI in background are all strong
predictors of sustained 24 week virologic response. The associated contribution
to VL response was:
-
Tipranavir/r: 1.25
log10 copies/mL increase
-
Enfuvirtide: 0.9
log10 copies/mL increase
-
Per active NRTI/NNRTI in OBR
increase: 0.2
log10 copies/mL
-
Per TPV score mutation: 0.2 log10
copies/mL decrease
Safety data from the Safety Update utilizing
a
Overall, a total of 3,367 HIV-positive patients and 769 HIV‑negative subjects have been exposed to TPV/r in clinical trials. Adult HIV-positive patients have been treated with TPV/r in Phase II dose-finding trials (n=579), in a Phase IIb PK/Safety Trial BI 1182.51 (n=315), Phase III RESIST trials (n=748), the rollover Trial BI 1182.17 (n=772) and the Emergency Use/Expanded Access Program (n=879). Seventy-four pediatric HIV-positive patients from Trial BI 1182.14 have also been treated with TPV/r. A total of 1,411 patients have been treated with the TPV/r 500/200 mg dose, and of these 1,206 patients have been exposed for at least 24 weeks.
In the subsequent sections, safety
observations from early Phase I and II trials will be summarized, followed by comprehensive
comparative analyses of adverse events, serious adverse events, and laboratory
abnormalities for the Phase III RESIST trials.
8.2 SAFETY DATA FROM EARLY
CLINICAL TRIALS
In Phase I drug interaction studies HIV-negative
subjects who were exposed to TPV/r for between 1 to 32 days, 88.3% reported any
adverse event, 0.3% (2 subjects) reported any serious adverse event, and 11.1%
discontinued due to adverse events. The
most common adverse events reported in Phase I and II trial participants were
diarrhea, nausea, vomiting, abdominal pain, flatulence, headache, and
fatigue. This was found to be consistent
with Phase II and III trials, although the frequency of some adverse events was
higher in the Phase II trials. The
slightly higher frequency of adverse events reported in Phase I and II trials
are likely related to lower tolerability thresholds and non-induced hepatic 3A
enzyme systems in HIV-negative subjects and the use of an hard filled capsule
formulation and higher doses of TPV/r (up to TPV/r 1250/100 mg) in early trials
of HIV-positive patients.
Five TPV Phase I studies were conducted
prior to full development of QTc regulatory guidance documents. The ECG data collected in these trials were
analyzed to understand the potential for ECG abnormalities. No evidence of QTc prolongation was observed
in nearly 200 subjects administered TPV/r for up to 32 days.
In a drug interaction study of TPV/r co-administered
with ethinyl estradiol and norethindrone, female healthy volunteers experienced
rash and arthralgias that resolved upon discontinuation of these
medications. This observation of
non-serious rash occurring in women receiving ethinyl estradiol with TPV/r was
confirmed in Phase III trials of HIV‑positive women. Women using estrogens may have an increased
risk of non-serious rash.
In Phase II trials in HIV-positive
patients who received at least one dose of TPV/r, 85.1% reported any adverse
event, 10.8% reported any serious adverse event, and 7.8% discontinued
treatment due to adverse events.
The most common laboratory abnormalities noted in Phase I and II trials were elevations in serum transaminases and plasma lipids. An analysis of these trials combining TPV/r doses into groups of TPV/r <500/200 mg, 500/200 mg, and >500/200 mg revealed a dose-related increase in Grade 3 and 4 abnormalities for ALT: 0.8%, 5.7% and 11.8% respectively. Values for AST showed a similar dose dependent pattern (0.8%, 3.3%, 4.9%, respectively). The dose-finding Trial BI 1182.52 showed KM estimated probabilities of Grade 3 or 4 ALT and/or AST abnormalities through 24 weeks of TPV/r treatment for 7.5% of patients treated with TPV/r 500/100 mg, for 11.3% of patients treated with TPV/r 500/200 mg, and for 24.5% of patients treated with TPV/r 750/200 mg. At a constant dose of TPV (500 mg bid), a dose-related risk of Grade 3 or 4 ALT and/or AST abnormalities is apparent with 7.5% of patients treated with RTV 100 mg bid developing Grade 3 or 4 ALT and/or AST abnormalities as compared to 11.3% of patients treated with RTV 200 mg bid for at least 24 weeks. At a constant dose of RTV (200 mg bid), a dose-related risk of Grade 3 or 4 ALT and/or AST abnormalities is apparent with 11.3% of patients treated with TPV 500 mg bid developing Grade 3 or 4 ALT and/or AST abnormalities as compared to 24.5% of patients treated with TPV 750 mg bid for at least 24 weeks. Most of the hepatic transaminase and plasma lipid elevations were mild and not associated with clinical symptoms, and resolved spontaneously or with treatment discontinuation. No TPV dose relationship with elevated plasma lipid levels was observed in these trials.
The safety signals identified in the
Phase I and II TPV/r studies were gastrointestinal adverse events including
nausea, vomiting and diarrhea, skin rash, and abnormalities of hepatic
transaminases and elevated plasma lipids.
The findings also were observed in the Phase III trials.
8.3 CLINICAL SAFETY DATA OF PIVOTAL,
ACTIVE-CONTROLLED TRIALS (RESIST-1 AND RESIST-2)
While efficacy analyses focused on RESIST trial patients who reached the Week 24 timepoint cut-off for NDA submission for accelerated approval, safety analyses include all treated patients. For efficacy, 582 patients in the TPV/r group and 577 patients in the CPI/r group were included. Overall however, a total 748 patients received TPV/r 500/200 mg and 737 received CPI/r in the RESIST trials (mainly due to RESIST-2 patients who had reached 16 weeks for European analyses but not 24 weeks for the FDA analyses). For the CPI/r group, doses were as follows: LPV/r 400/100 mg (n=358), IDV/r 800/100 mg (n=23), SQV/r 1000/100 mg or 800/200 mg (n=162), and APV/r 600/100 mg (n=194). All doses were administered twice daily.
A number of factors in the design of the RESIST trials complicate analyses of safety including: the open-label design, the selection of comparator PI based on ARV medication history in addition to resistance data, and the differential dropout from the study arms. The design of the RESIST trials, which allowed patients with documented virological failure – but not adverse events - to leave the CPI/r arm of the study after 8 weeks, confounds comparison of safety between the treatment arms. For the NDA submission analyses at Week 24, 85.7% (639 of 746) patients remained in the TPV/r arm as compared to 48.4% (357 of 737) in the CPI/r arm. This difference continues to increase and at the cut-off for the Safety Update, 70.1% (524 of 748) patients in the TPV/r group as compared to 31.3% (231 of 737) patients in the CPI/r group remained in the study (Table 8.3: 1).
Table 8.3: 1 Disposition of RESIST trial patients
|
|
NDA Submission |
Safety Update |
||
|
Disposition: |
TPV/r |
CPI/ra |
TPV/r |
CPI/ra |
|
Total Treated |
746 (100.0) |
737 (100.0) |
748 (100.0) |
737 (100.0) |
|
Currently Continuing in Trials |
639 (85.7) |
357 (48.4) |
524 (70.1) |
231 (31.3) |
|
Prematurely Discontinued |
107 (14.3) |
380 (51.6) |
224 (29.9) |
506 (68.7) |
|
Adverse Event |
56 (7.5) |
27 (3.7) |
78 (10.4) |
35 (4.7) |
|
Non-compliant with Protocol |
8 (1.1) |
15 (2.0) |
16 (2.1) |
22 (3.0) |
|
Lost to Follow-up |
5 (0.7) |
4 (0.5) |
5 (0.7) |
5 (0.7) |
|
Consent Withdrawn |
6 (0.8) |
5 (0.7) |
8 (1.1) |
6 (0.8) |
|
Lack of Efficacy |
22 (2.9) |
248 (33.6) |
68 (9.1) |
316 (42.9) |
|
Other |
7 (0.9) |
18 (2.4) |
15 (2.0) |
29 (3.9) |
|
Missing |
3 (0.4) |
63 (8.5) |
34 (4.5) |
93 (12.6) |
a CPI/r = LPV/r 400/100, IDV/r 800/100, SQV/r
1000/100 or SQV/r 800/200, and APV/r 600/100; all doses in mg.
Of the 43% (316 of 737) of patients who left the comparator arm of the RESIST trials, 298 (94%) rolled over into Trial BI 1182.17 and received TPV/r. Patients leaving the CPI/r arm of the trial due to virological failure had lower median CD4+ counts (117 cells/mm3) and higher viral loads (4.8 log10 copies/mL) compared to patients remaining in the trial on CPI/r (median CD4+ count of 238 cells/mm3; viral load 3.7 log10 copies/mL). Thus, patients remaining in the comparator arm of the study were more immune competent, on average, than patients originally randomized into the RESIST trials, or patients remaining on TPV/r. As a result, comparisons of TPV/r and CPI/r safety data beyond the first 8 weeks of treatment should be interpreted cautiously.
The number of patients stopping trial
participation due to an adverse event was twice as frequent in the TPV/r group
(10.4%) as in the CPI/r group (4.7%). However,
these data may have been influenced by entry criteria that allowed patients
with virological failure, but not adverse events leading to CPI/r
discontinuation, to rollover to Trial BI 1182.17.
8.3.1 Exposure and disposition
In the Safety Update, exposure for the TPV/r group represents 615.0 person exposure years (PEY) while exposure for the CPI/r group represents 405.7 PEY, an exposure difference of 50%. The large difference exposure after 8 weeks between the TPV/r and CPI/r treatment groups occurred largely from patients who virologically failed the CPI/r regimen and exited the trial to receive TPV/r in the open label rollover Trial BI 1182.17 (Table 8.3: 1 and Figure 8.3.1: 1). Nearly 50% of TPV/r patients have been treated for at least 48 weeks, although not all patients have had the opportunity to achieve the 48 week milestone by the Safety Update cut-off (Table 8.3.1: 1).
Table 8.3.1: 1 Treatment
exposure to trial medication in the RESIST trials at time of NDA submission and
in Safety Update
|
Duration: |
NDA Submission |
Safety Update |
||
|
TPV/r |
CPI/ra |
TPV/r |
CPI/ra |
|
|
Total treated [N (%)] |
746 (100.0) |
737 (100.0) |
748 (100.0) |
737 (100.0) |
|
> 8 weeks |
713
(95.6) |
703
(95.4) |
715
(95.6) |
703
(95.4) |
|
> 16 weeks |
665
(89.1) |
526
(71.4) |
683
(91.3) |
536
(72.7) |
|
> 24 weeks |
385
(51.6) |
245
(33.2) |
645
(86.2) |
395
(53.6) |
|
> 32 weeks |
-- |
-- |
576
(77.0) |
285
(38.7) |
|
> 48 weeks |
-- |
-- |
354
(47.3) |
135
(18.3) |
|
Median [days] |
168.0 |
124.0 |
330.0 |
172.0 |
|
Range [days] |
1 - 274 |
1 – 313 |
1 - 523 |
1 - 511 |
|
Total person exposure yearsb |
300.3 |
264.6 |
615.0 |
405.7 |
a CPI/r = LPV/r 400/100, IDV/r 800/100, SQV/r
1000/100 or SQV/r 800/200, and APV/r 600/100; all doses in mg.
b Definition of total person exposure years
[PEY]: (sum of total duration across all patients)/365.25.
Figure 8.3.1: 1 Patients
remaining in the RESIST trials by treatment group up to 48 weeks
8.3.2 Adverse Events in RESIST trials
In the following sections, comparative frequencies of the most commonly reported adverse events as reported in the Safety Update for TPV/r and CPI/r patients in the RESIST trials are displayed. The order of presentation is: (1) adverse events of any severity considered related to study treatment, (2) serious adverse events, and (3) adverse events leading to study drug discontinuation.
Adverse events of any severity in
RESIST trials
According to BI standards, intensity of
adverse events was collected using a mild, moderate, severe scale. Investigators were provided the DAIDS grading
scale and graded adverse events as follows:
mild = DAIDS Grade 1, moderate = Grade 2, severe = Grade 3 or 4.
The TPV/r group had a higher overall
percentage of patients reporting study drug-related adverse events of any
severity: 41.7% compared with 27.8% in
the CPI/r group. In general, for study
drug-related adverse events, no major differences were observed between the 2
treatment groups. The only adverse
events with >2% differences between TPV/r and CPI/r were diarrhea, nausea,
and headache.
Table 8.3.2: 1 Study
drug-related adverse events occurring in 1% or more of RESIST trial patients in
either treatment group in the Safety Update
|
|
Unadjusted Rate |
Crude adjusted rate per 100 PEY |
||
|
SOC / Preferred
Term |
TPV/r
a |
CPI/r
a |
TPV/r |
CPI/r |
|
Total Treated or
Total Exposure |
748 (100.0) |
737 (100.0) |
615 PEY |
405.7 PEY |
|
Total with Any AE |
361 (48.3) |
220 (29.9) |
361 (58.7) |
220 (54.2) |
|
Gastrointestinal Disorders |
233 (31.1) |
161 (21.8) |
233 (37.9) |
161 (39.7) |
|
Diarrhea |
109 (14.6) |
84 (11.4) |
109 (17.7) |
84 (20.7) |
|
Nausea |
93 (12.4) |
62 (8.4) |
93 (15.1) |
62 (15.3) |
|
Vomiting |
32 (4.3) |
23 (3.1) |
32 (5.2) |
23 (5.7) |
|
Abdominal
Pain |
19 (2.5) |
20 (2.7) |
19 (3.1) |
20 (4.9) |
|
Flatulence |
23 (3.1) |
15 (2.0) |
23 (3.7) |
15 (3.7) |
|
Abdominal Distension |
20 (2.7) |
13 (1.8) |
20 (3.3) |
13 (3.2) |
|
Abdominal Pain Upper |
8 (1.1) |
8 (1.1) |
8 (1.3) |
8 (2.0) |
|
Loose Stools |
12 (1.6) |
9 (1.2) |
12 (2.0) |
9 (2.2) |
|
Dyspepsia |
8 (1.1) |
6 (0.8) |
8 (1.3) |
6 (1.5) |
|
Nervous System Disorders |
53 (7.1) |
39 (5.3) |
53 (8.6) |
39 (9.6) |
|
Headache |
28 (3.7) |
9 (1.2) |
28 (4.6) |
9 (2.2) |
|
Dizziness |
11 (1.5) |
7 (0.9) |
11 (1.8) |
7 (1.7) |
|
General Disorders |
49 (6.6) |
32 (4.3) |
49 (8.0) |
32 (7.9) |
|
Fatigue |
34 (4.5) |
19 (2.6) |
34 (5.5) |
19 (4.7) |
|
Metabolism and Nutrition |
61 (8.2) |
30 (4.1) |
61 (9.9) |
30 (7.4) |
|
Anorexia |
8 (1.1) |
7 (0.9) |
8 (1.3) |
7 (1.7) |
|
Hypertriglyceridemia |
24 (3.2) |
6 (0.8) |
24 (3.9) |
6 (1.5) |
|
Hyperlipidemia |
17 (2.3) |
4 (0.5) |
17 (2.8) |
4 (1.0) |
|
Skin |
46 (6.1) |
27 (3.7) |
46 (7.5) |
27 (6.7) |
|
Rash |
13 (1.7) |
7 (0.9) |
13 (2.1) |
7 (1.7) |
|
Pruritus |
11 (1.5) |
3 (0.4) |
11 (1.8) |
3 (0.7) |
|
Investigations |
48 (6.4) |
10 (1.4) |
48 (7.8) |
10 (2.5) |
|
ALT
increased |
17 (2.3) |
1 (0.1) |
17 (2.8) |
1 (0.2) |
|
AST
increased |
12 (1.6) |
1 (0.1) |
12 (2.0) |
1 (1.2) |
|
GGT
increased |
13 (1.7) |
1 (0.1) |
13 (2.1) |
1 (0.2) |
|
Triglycerides
increased |
9 (1.2) |
4 (0.5) |
9 (1.5) |
4 (1.0) |
a BID Doses:
TPV/r 500/200; CPI/r: LPV/r 400/100, IDV/r 800/100, SQV/r 1000/100 or
800/200, APV/r 600/100.
The frequency of adverse events for
each of the individual protease inhibitors in the CPI/r group was examined and
the highest percentage of patients with study drug-related adverse events was 34.6%
in the SQV/r group compared with 25.3% in the APV/r group and 25.1% in the
LPV/r groups. There were only 23
patients in the IDV/r group, thus no comparisons for this group were made. The SQV/r group had the highest percentage of
patients with study drug-related gastrointestinal adverse events: 26.5% compared with 19.1% and 19.0% in the
APV/r and LPV/r groups, respectively. In
addition, the SQV/r group had the highest percentage of patients with study
drug-related nervous system disorder adverse events: 7.4% compared with 6.2% and 3.6% in the APV/r
and LPV/r groups, respectively. The
APV/r group had the highest percentage of patients (4.6%) with study
drug-related skin and subcutaneous disorder adverse events (1.1% in the LPV/r
group and 2.5% in the SQV/r group).
Diarrhea was self-limiting, manageable,
and similar across both treatment arms in the RESIST studies. Frequencies of patients with diarrhea were
higher in the Phase II trials likely due to the higher doses of TPV used in
early Phase II trials.
Although
individual variability in the type and frequency of adverse events was observed
in evaluation of adverse events by age, gender, race and geographic location,
clinically, no unusual adverse event patterns or other safety concerns were
identified in the RESIST trials that would suggest that TPV/r should be restricted
or have the dose adjusted based on these factors.
Severe adverse events in RESIST
trials
Severe adverse events (DAIDS
Grade 3 to 4) were reported in 16.1% of the 1483 patients; the most frequently
reported severe adverse event was diarrhea (TPV/r, 1.3%; CPI/r, 1.8%).
SAEs in the
RESIST trials
In the Safety Update of RESIST
trials, 18.9% of patients in the TPV/r arm as compared to 14.7% of patients in
the CPI/r arm experienced SAEs, regardless of causality. The most frequently observed SAEs were in the
infections and infestations system organ class (SOC). Most events were associated with advanced HIV
disease and were comparable between the two treatment groups. Many of the excess SAEs seen with TPV/r are
no longer present after exposure adjustment.
The SAEs which remain more prevalent with TPV/r are in the general
disorders, metabolism and investigations SOC (Table 8.3.3: 1).
Table 8.3.3: 1 Any Serious Adverse Events
occurring in 0.5% or more of RESIST trial patients in the Safety Update
|
SOC / Preferred Term |
Unadjusted Rate |
Crude adjusted rate per 100
PEY |
||
|
TPV/ra |
CPI/ra |
TPV/r |
CPI/r |
|
|
Total Treated or Total Exposure |
748 (100.0) |
737 (100.0) |
615 PY |
405.7 PY |
|
Total with Any
SAE |
141 (18.9) |
108 (14.7) |
141 (22.9) |
108 (26.6) |
|
Infections and
Infestations |
53 (7.1) |
49 (6.6) |
53 (8.6) |
49 (12.1) |
|
Pneumonia |
10 (1.3) |
5 (0.7) |
10 (1.6) |
5 (1.2) |
|
Gastroenteritis |
4 (0.5) |
1 (0.1) |
4 (0.7) |
1 (0.2) |
|
CMV Chorioretinitis |
4 (0.5) |
2 (0.3) |
4 (0.7) |
2 (0.5) |
|
Esophageal Candidiasis |
4 (0.5) |
5 (0.7) |
4 (0.7) |
5 (1.2) |
|
PCP Pneumonia |
4 (0.5) |
3 (0.4) |
4 (0.7) |
3 (0.7) |
|
PML |
1 (0.1) |
4 (0.5) |
1 (0.2) |
4 (1.0) |
|
General
Disorders |
30 (4.0) |
18 (2.4) |
30 (4.9) |
18 (4.4) |
|
Pyrexia |
17 (2.3) |
11 (1.5) |
17 (2.8) |
11 (2.7) |
|
Rigors |
4 (0.5) |
0 (0.0) |
4 (0.7) |
0 (0.0) |
|
Gastrointestinal
Disorders |
27 (3.6) |
18 (2.4) |
27 (4.4) |
18 (4.4) |
|
Diarrhea |
9 (1.2) |
5 (0.7) |
9 (1.5) |
5 (1.2) |
|
Pancreatitis |
4 (0.5) |
0 (0.0) |
4 (0.7) |
0 (0.0) |
|
Abdominal Pain |
4 (0.5) |
1 (0.1) |
4 (0.7) |
1 (0.2) |
|
Vomiting |
4 (0.5) |
3 (0.4) |
4 (0.7) |
3 (0.7) |
|
Metabolism and
Nutrition |
14 (1.9) |
7 (0.9) |
14 (2.3) |
7 (1.7) |
|
Dehydration |
8 (1.1) |
3 (0.4) |
8 (1.3) |
3 (0.7) |
|
Respiratory
Disorders |
14 (1.9) |
10 (1.4) |
14 (2.3) |
10 (2.5) |
|
Dyspnea |
3 (0.4) |
4 (0.5) |
3 (0.5) |
4 (1.0) |
|
Nervous System
Disorders |
13 (1.7) |
14 (1.9) |
13 (2.1) |
14 (3.5) |
|
Headache |
5 (0.7) |
2 (0.3) |
5 (0.8) |
2 (0.5) |
|
Investigations |
11 (1.5) |
5 (0.7) |
11 (1.8) |
5 (1.2) |
|
ALT Increased |
5 (0.7) |
0 (0.0) |
5 (0.8) |
0 (0.0) |
|
Renal and
Urinary Disorders |
11 (1.5) |
5 (0.7) |
11 (1.8) |
5 (1.2) |
|
Renal Failure Acute |
5 (0.7) |
2 (0.3) |
5 (0.8) |
2 (0.5) |
|
Psychiatric Disorders |
4 (0.5) |
8 (1.1) |
4 (0.7) |
8 (2.0) |
|
Depression |
1 (0.1) |
5 (0.7) |
1 (0.2) |
5 (1.2) |
|
Blood and
Lymphatic System |
8 (1.1) |
10 (1.4) |
8 (1.3) |
10 (2.5) |
|
Anemia |
4 (0.5) |
7 (0.9) |
4 (0.7) |
7 (1.7) |
a BID Doses:
TPV/r 500/200; CPI/r: LPV/r 400/100, IDV/r 800/100, SQV/r 1000/100 or
800/200, APV/r 600/100.
Based on the data in the comparative
RESIST trials, there are no indications that TPV/r therapy contributes to more
SAEs or has a unique safety profile compared with other ritonavir-boosted PIs.
8.3.4 Adverse events leading to discontinuation of treatment
In the RESIST trials, 12.3% of patients in the TPV/r group and 4.9% of patients in the CPI/r group experienced adverse events which led to study drug discontinuation (Table 8.3.4: 1).
The SOC with the highest percentage of patients with adverse events leading to discontinuation of study medication was the gastrointestinal disorders SOC (4.5% TPV/r and 3.0% CPI/r).
The percentages of patients with adverse
events leading to discontinuation of study medication were consistently higher
in the TPV/r group. While numbers were
small, it should be noted that the TPV/r group had many more patients
discontinuing with events in the SOC of investigations (TPV/r 2.7%, CPI/r 0.1%),
and this difference between treatment groups remained with crude adjustment for
exposure. The investigations SOC includes
laboratory test abnormality events which are discussed in detail in the
laboratory data section.
The most frequently reported adverse
events leading to discontinuation of study medication in the RESIST trials
consisted of the following: nausea (1.7%
TPV/r, 1.1% CPI/r), diarrhea (1.7% TPV/r, 1.1% CPI/r), vomiting (1.1% in both TPV/r
and CPI/r groups), and increased ALT (0.9% TPV/r, 0.0% CPI/r). All other adverse events leading to
discontinuation of study medication occurred in £0.5% of all patients (< 4 patients).
Table 8.3.4: 1 Adverse
events leading to discontinuation of study medication in 3 or more RESIST trial
patients in the Safety Update
|
|
Unadjusted rate |
Crude adjusted rate per 100
PEY |
||
|
TPV/ra |
CPI/ra |
TPV/r |
CPI/r |
|
|
Total Treated
or Total Exposure |
748 (100.0) |
737 (100.0) |
615 PY |
405.7 PY |
|
Total with Any AE Leading to Discontinuation |
92 (12.3) |
47 (6.4) |
92 (15.0) |
47 (11.6) |
|
Gastrointestinal
Disorders |
34 (4.5) |
22 (3.0) |
34 (5.5) |
22 (5.4) |
|
Nausea |
13 (1.7) |
8 (1.1) |
13 (2.1) |
8 (2.0) |
|
Vomiting |
8 (1.1) |
8 (1.1) |
8 (1.3) |
8 (2.0) |
|
Diarrhea |
13 (1.7) |
8 (1.1) |
13 (2.1) |
8 (2.0) |
|
Abdominal Pain |
2 (0.3) |
4 (0.5) |
2 (0.3) |
4 (1.0) |
|
Investigations |
20 (2.7) |
1 (0.1) |
20 (3.3) |
1 (0.2) |
|
ALT
Increased |
7 (0.9) |
0 (0.0) |
7 (1.1) |
0 (0.0) |
|
AST
Increased |
3 (0.4) |
0 (0.0) |
3 (0.5) |
0 (0.0) |
|
GGT
Increased |
4 (0.5) |
0 (0.0) |
4 (0.7) |
0 (0.0) |
|
Hepatic
Enzyme Increased |
3 (0.4) |
0 (0.0) |
3 (0.5) |
0 (0.0) |
|
Triglycerides
Increased |
3 (0.4) |
0 (0.0) |
3 (0.5) |
0 (0.0) |
|
General Disorders |
15 (2.0) |
7 (0.9) |
15 (2.4) |
7 (1.7) |
|
Fatigue |
4 (0.5) |
1 (0.1) |
4 (0.7) |
1 (0.2) |
|
Pyrexia |
4 (0.5) |
3 (0.4) |
4 (0.7) |
3 (0.7) |
|
Metabolism and Nutrition |
11 (1.5) |
6 (0.8) |
11 (1.8) |
6 (1.5) |
|
Anorexia |
4 (0.5) |
1 (0.1) |
4 (0.7) |
1 (0.2) |
|
Hepatobiliary Disorders |
9 (1.2) |
1 (0.1) |
9 (1.5) |
1 (0.2) |
|
Cytolytic Hepatitis |
2 (0.3)b |
0 (0.0) |
2 (0.3) |
0 (0.0) |
|
Skin Disorders |
7 (0.9) |
5 (0.7) |
7 (1.1) |
5 (1.2) |
|
Rash |
4 (0.5) |
1 (0.1) |
4 (0.7) |
1 (0.2) |
a BID Doses:
TPV/r 500/200; CPI/r: LPV/r 400/100, IDV/r 800/100, SQV/r 1000/100 or
800/200, APV/r 600/100.
The rate of discontinuation from the
trial is slightly higher in the TPV/r group than the CPI/r group, but this rate
is offset by the high rate of discontinuations due to virologic failure in the
CPI/r group, leaving a disproportionately higher number of patients on TPV/r
treatment in the RESIST trials.
There were no new or unexpected events
identified that lead to discontinuation of study medication in the RESIST
trials; data are consistent to early Phase II findings.
8.3.5 Exploratory analyses of medically selected terms
An exploratory analysis of adverse
events was conducted to evaluate PI-specific class effects (e.g., fat
redistribution), events warranting evaluation because of preclinical or early
clinical experience with TPV/r (e.g., hepatitis, bleeding, rash), or identified
as issues of concern for the development of any drug product or effects of
concern for the development of any drug product (e.g., QTc prolongation). For this analysis, a broad range of preferred
terms were included to comprise each medically selected term (MST); the MST
name is a descriptor of the preferred terms and only one of the collection of
preferred terms, thus the MST name is used with quotes (“ “) around the term.
Figure 8.3.5: 1 summarizes the relative
risk of individual Medically Selected Terms observed with TPV/r as compared to
CPI/r in the NDA Summary of Clinical Safety (SCS) and in the Safety Update. In the Safety Update population there was no
overall increased risk for TPV/r compared to the CPI/r of “hyperglycemia,”
“ischemic heart disease,” “pancreatitis”, “rash”, “renal failure” and “QTc
prolongation” events. The relative risk (RR) of these MSTs ranged from 0.44 to
1.00, however, these measures were moderately precise.
Figure 8.3.5: 1 Relative
risk of medically selected term adverse events between treatment groups in
RESIST trials: Comparison of NDA Summary
of Clinical Safety and Safety Update populations
a Relative
risk = TPV/r to CPI/r.
The overall relative risk of “bleeding”
events decreased from 1.98 (95% CI = 1.03, 3.80) in the Summary of Clinical
Safety population to 1.19 (95% CI = 0.67, 2.12) in the Safety Update
population. There appears to be no
consistent pattern of “bleeding” events.
There are no notable differences between treatment groups in Grade 3 or
4 laboratory parameters for decreased hemoglobin, decreased platelets, or
prolonged PT (see laboratory section). Overall,
there seems to be normalization of the relative risk of bleeding between the
TPV/r and CPI/r arm with the Safety Update.
The RESIST trials
evaluated a highly PI-experienced patient population, with many patients
entering the trials with significant lipodystrophy. In the Safety Update, TPV/r patients continue
to have a greater risk of “fat redistribution” than CPI/r patients. The ultimate impact of TPV/r on “fat
redistribution” will need to be assessed with longer term data from the RESIST
trials and a metabolic substudy including DEXA exams in Trial BI 1182.33 of
treatment naïve HIV-positive patients.
Elevated liver
enzymes (ALT/AST) and clinical “hepatitis” were more common in patients receiving
TPV/r than patients receiving CPI/r. This
will be described in the laboratory section below.
“Hyperlipidemia”
was more common in TPV/r patients than CPI/r patients. These lipid elevations were not associated
with increased rates of “pancreatitis” or “ischemic heart disease”. Given the short duration of follow-up, it is
not possible to draw definitive conclusions regarding risk of potential long
term sequelae of elevated plasma lipids, e.g. ischemic heart disease. Long term follow-up data will be needed to
adequately assess this potential risk.
Treatment with
TPV/r does not appear to increase the risk of “rash” compared to other
ritonavir-boosted PIs. However, based on
the signal from the Phase I drug interaction study of oral contraceptive use in
women and analyses conducted on the Phase III RESIST data, patients with lower
CD4+ counts and women using estrogens appear to be at greater risk of
developing non-serious rashes.
8.4 LABORATORY EVALUATIONS OF PIVOTAL,
ACTIVE-CONTROLLED TRIALS (RESIST-1 AND RESIST-2)
An evaluation of DAIDS
Grade 3 and 4 laboratory abnormalities, including assessments of risk factors
and patterns of elevations, is presented in this section.
8.4.1 Overview of DAIDS Grade 3 and 4 Laboratory Abnormalities in
the Safety Update
For the
hematology parameters, with the exception of Grade 3 or 4 decreased WBC in 4.9%
of TPV/r patients and 5.5% of CPI/r patients, few patients had hematology
abnormalities (Table 8.4.1: 1). For
most chemistry analytes, Grade 3 or 4 abnormalities were relatively few and
similar between treatment groups, with the exception of ALT, AST, total
cholesterol and triglycerides.
|
|
TPV/r N=733 |
CPI/r N=737 |
||||
|
Laboratory Test |
Grade 3 |
Grade 4 |
Total |
Grade 3 |
Grade 4 |
Total |
|
Hematology |
|
|
|
|
|
|
|
Haemoglobin |
2 (0.3) |
1 (0.1) |
3 (0.4) |
2 (0.3) |
0 (0.0) |
2 (0.3) |
|
WBC Count
(decrease) |
34 (4.6) |
2 (0.3) |
36 (4.9) |
32 (4.4) |
8 (1.1) |
40 (5.5) |
|
Platelets |
5 (0.7) |
3 (0.4) |
8 (1.1) |
6 (0.8) |
1 (0.1) |
7 (1.0) |
|
Prothrombin
Time |
6 (0.8) |
2 (0.3) |
8 (1.1) |
6 (0.8) |
2 (0.3) |
8 (1.1) |
|
Chemistry |
|
|
|
|
|
|
|
ALT |
38 (5.2) |
28 (3.8) |
66 (9.0) |
12 (1.7) |
4 (0.6) |
16 (2.2) |
|
AST |
34 (4.6) |
10 (1.4) |
44 (6.0) |
11 (1.5) |
3 (0.4) |
14 (1.9) |
|
ALT and/or
AST |
44 (6.0) |
28 (3.8) |
72 (9.8) |
17 (2.3) |
5 (0.7) |
22 (3.0) |
|
Bilirubin,
Total |
3 (0.4) |
2 (0.3) |
5 (0.7) |
3 (0.4) |
1 (0.1) |
4 (0.6) |
|
Alkaline phosphatase |
3 (0.4) |
0 (0.0) |
3 (0.4) |
1 (0.1) |
1 (0.1) |
2 (0.3) |
|
Amylase |
40 (5.5) |
2 (0.3) |
42 (5.7) |
45 (6.2) |
5 (0.7) |
50 (6.9) |
|
Lipase |
17 (2.3) |
2 (0.3) |
19 (2.6) |
15 (2.1) |
3 (0.4) |
18 (2.5) |
|
Total
Cholesterol |
22 (3.0) |
7 (1.0) |
29 (4.0) |
2 (0.3) |
1 (0.1) |
3 (0.4) |
|
Triglycerides |
117 (16.0) |
53 (7.2) |
170 (23.2) |
59 (8.1) |
30 (4.1) |
89 (12.2) |
|
Glucose
(increase) |
11 (1.5) |
2 (0.3) |
13 (1.8) |
7 (1.0) |
1 (0.1) |
8 (1.1) |
|
Glucose
(decrease) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
3 (0.4) |
3 (0.4) |
|
Creatinine |
2 (0.3) |
0 (0.0) |
2 (0.3) |
1 (0.1) |
0 (0.0) |
1 (0.1) |
a Total number of patients with Grade 3 or 4 elevations
as worst intensity during 24 weeks. For
inclusion in this analysis both a baseline and at least one on-treatment lab
value had to be present.
b Grade (DAIDS or BI) and lab value units: ALT or AST
Grade 3 = >5.0 - 10.0 x ULN or 201 – 400 U/L; Grade 4 = >10.0 x ULN or
>400 U/L; Total bilirubin Grade 3 = >2.5 – 5.0 x ULN or >3.0 – 6.0
mg/dl; Grade 4 = >5.0 x ULN or >6.0 mg/dl; Total cholesterol Grade 3 =
400 – 500 mg/dl; Grade 4 - >500 mg/dl; Fasting triglycerides Grade 3 = 751‑1200
mg/dl; Grade 4 = >1200 mg/dl.
8.4.2 Hepatic
transaminase elevations in the Safety Update
8.4.2.1 Evaluation of ALT and/or AST
abnormalities
In the Safety Update, Grade 3 or 4 ALT and/or AST
combined (ALT/AST) abnormalities were found in 72 (9.8%) of 733 patients in the
TPV/r group compared to 26 (3.6%) of 727 patients in the CPI/r group. Two additional patients in the TPV/r group were
found to have Grade 3 total bilirubin.
Grade 4 ALT/AST abnormalities were found in 28 (3.8%) of 733 patients in
the TPV/r group compared to 5 (0.7%) of 727 patients in the CPI/r group.
The relative risk of Grade 3 or 4 ALT/AST
abnormalities (Table 8.4.2.1: 1), adjusted for patient exposure years to
study medication, was higher in the TPV/r group compared to CPI/r group
(RR=2.41, 95% CI 1.49, 3.88).
The Kaplan-Meier (K-M) estimates of the time to first
Grade 3 or 4 ALT/AST laboratory abnormalities up to 48 weeks are shown in
Figure 8.4.2.1: 1. The K‑M
cumulative probability for Grade 3 or 4 ALT/AST in the TPV/r group was 10.3% at
48 weeks; while the cumulative probability for Grade 3 or 4 ALT/AST in the
CPI/r group was 3.9% at 48 weeks (p
= 0.0002, log rank test).
The K-M cumulative probability of developing Grade 4
ALT/AST abnormalities at 48 weeks was 4.2% in the TPV/r group compared to 0.9%
in the CPI/r group (p = 0.0014, log rank test).
Table 8.4.2.1: 1 Number and cumulative probability of
DAIDS Grade 3 or 4 ALT or AST abnormalities in RESIST trials
|
Weeks in Trial |
TPV/r |
CPI/r |
||
|
|
No. (%) Patients with Grade 3 or 4 |
No. Patients Entering Interval |
No. (%) Patients with Grade 3 or 4 |
No. Patients Entering Interval |
|
<
0 - 2 |
7 (0.9) |
748 |
0 (0.0) |
737 |
|
>
2 - 4 |
9 (2.2) |
733 |
6 (0.8) |
729 |
|
>
4 - 8 |
6 (3.0) |
714 |
4 (1.4) |
711 |
|
>
8 - 16 |
7 (4.0) |
696 |
5 (2.1) |
693 |
|
>
16 - 24 |
13 (5.9) |
659 |
2 (2.6) |
524 |
|
>
24 - 32 |
11 (7.7) |
613 |
3 (3.4) |
384 |
|
>
32 - 40 |
9 (9.4) |
539 |
0 (3.4) |
276 |
|
>
40 - 48 |
4 (10.3) |
445 |
1 (3.9) |
201 |
Figure 8.4.2.1: 1 Kaplan-Meier estimates for time to onset of DAIDS Grade 3 or 4
ALT or AST abnormalities up to 48 weeks in RESIST trials
8.4.2.2 Multivariable
analysis for risk of LFT elevations
A Cox regression
multivariable analysis was performed to identify factors predicting the risk of
liver laboratory test abnormality for TPV/r and CPI/r patients (Table
8.4.2.2: 1). Liver laboratory test
abnormalities were defined as any Grade 3 or 4 ALT, AST, or total bilirubin elevation
during treatment as these three parameters are deemed to be reflective of
potential liver injury.
The analysis
considered treatment group, age, gender, race, CD4+ cell count at baseline, HIV
RNA count at baseline, Center for Disease Control (CDC) HIV infection
classification category, time since first diagnosis of HIV infection, use of
NRTIs with the potential for hepatotoxicity (ddI, d4T, or ddC), HBV or HCV
co-infection, number of prior ARV medications, NNRTI usage, the maximum
baseline Grade for ALT, AST and total bilirubin, and elevated baseline
triglycerides.
The model
identified TPV/r treatment as a significant risk factor associated with the
development of liver test abnormalities (RR=2.4, 95% CI =1.5-3.8). Other risk factors were elevated baseline
liver tests, co-infection with HBV and/or HCV, and CD4+ cell count >200
cell/mm3. The risk posed by
TPV/r treatment is similar to that of elevated baseline liver function tests.
Table 8.4.2.2: 1 Cox
regression assessing risk a for Grade 3 or 4 ALT, AST
or total bilirubin abnormalities
|
Factor/Comparison |
Risk Ratio |
95% CI |
|
Baseline ALT, AST total bilirubin: Grade 2 or 3 vs Grade 0 to 1: |
2.5 |
1.3-4.8 |
|
Treatment
Group: TPV/r vs CPI/r |
2.4 |
1.5-3.8 |
|
CD4+ Cell Count at Baseline (cells/mm3): ≥200 vs <200 |
2.0 |
1.3-2.5 |
|
HBV or HCV Co-infection: Co-infected vs not co-infected |
2.3 |
1.4-3.7 |
a Risk factors for Grade 3-4 ALT/AST are similar in TPV/r and CPI/r
8.4.2.3 Actions
taken with LFT abnormalities
Following the onset of Grade 3 or 4 ALT, AST or total bilirubin liver test abnormalities, investigators in the RESIST trials had protocol management guidelines, but were able to continue, interrupt or discontinue a patient's study medication. Most patients who developed Grade 3 or 4 liver test abnormalities remained on treatment or temporarily interrupted treatment without permanent discontinuation as detailed below:
Among patients treated with TPV/r, 74 who had Grade
3/4 liver test abnormalities:
·
57 (77.0%) of the 74 TPV/r patients
with Grade 3 or 4 liver test abnormalities continued TPV/r treatment:
o
46
(62.2%) patients continued treatment without interruption:
§
7
(9.5%) patients had Grade 3 or 4 liver test abnormalities at their last
observed visit and were not discontinued;
§
30
(40.5%) patients continued study treatment, and the liver test abnormalities
returned to values of Grade 2 or less;
§
8
(10.8%) patients continued study treatment, and the liver test abnormalities
remained stable (Grade 3 or higher);
§
1
(1.4%) patient continued study treatment, and a Grade 3 elevated
ALT/AST/bilirubin level increased to Grade 4.
o
11
(14.8%) of the 74 TPV/r patients had a treatment interruption associated with
Grade 3 or 4 liver test abnormalities that subsequently returned to Grade 2 or
less
·
17
(23.0%) of the 74 TPV/r patients had study medication discontinued due to a
liver test abnormalities. The reason for
discontinuation was directly related to transaminase elevation and/or a
liver-related AE preferred term.
Among patients treated with CPI/r, 26 who had Grade 3/4 liver test
abnormalities:
· 26 (100.0%) of the 26 CPI/r patients with Grade 3 or 4 liver test abnormalities continued CPI/r treatment without permanent discontinuation.
o 23 (88.5%) of the 26 CPI/r patients with Grade 3 or 4 liver test abnormalities continued treatment without interruption:
§ 5 (19.2%) patients had Grade 3 or 4 liver test abnormalities at their last observed visit and were not discontinued;
§ 18 (69.2%) patients continued study treatment, and the Grade 3 or 4 liver test abnormalities returned to values of Grade 2 or less;
o
3 (11.5%) of the 26 CPI/r
patients had a treatment interruption associated with a Grade 3 or 4 liver test
abnormalities that subsequently returned to Grade 2 or less;
·
There
were no patients in the CPI/r group who had study medication discontinued due
to a Grade 3 or 4 liver test abnormalities.
8.4.2.4 Clinical hepatic adverse events
In an evaluation
of clinical hepatic adverse events associated with Grade 3 or 4 LFT abnormalities
(ALT, AST, or total bilirubin), each of the 74 patients treated with TPV/r and
26 patients treated with CPI/r were reviewed and categorized as having (1) adverse events potentially related to
liver injury, i.e., hepatobiliary disorders, investigations indicative of an
elevation in a liver test reported as an adverse event, or infection associated
with HBV or HCV; or (2) other adverse events not attributable to liver injury (Table
8.4.2.4: 1).
Of the 74 TPV/r
patients with Grade 3 or 4 LFT elevations, 39 (52.7%) patients had
liver-related adverse events compared with 5 (19.2%) of the 26 patients in the
CPI/r group. Serious adverse events in
any SOC were reported in 22 (29.7%) of the 74 TPV/r patients with Grade 3 or 4
liver test elevations as compared with 5 (19.2%) of the 26 patients in the
CPI/r group. There were 8 (10.8%)
liver-related SAEs in the TPV/r group and no liver-related SAEs in the CPI/r
group.
Thirty (40.5%) of
74 TPV/r patients and 18 (69.2%) of 26 CPI/r patients discontinued treatment
for any reason. Of all patients with
Grade 3 or 4 test abnormalities who discontinued study drug, 17 (23.0%) of the
30 patients in the TPV/r group and none of the 18 patients in the CPI/r
group were discontinued due to a liver-related adverse event.
Three TPV/r
treated patients in the RESIST trials who died had a hepatic event reported as
part of the clinical course prior to their death. These patients are discussed in the context
of mortality observed in the entire TPV development program in Section 8.5.
Table 8.4.2.4: 1 Potential liver-related clinical
events associated with Grade 3 or 4 liver test abnormalities in the RESIST
trials
|
|
TPV/r |
CPI/r |
|
Total Treated |
748
(100.0) |
737
(100.0) |
|
Total with Laboratory
Informationa |
735
(98.3) |
728
(98.8) |
|
Total with Grade 3 or 4 ALT, AST, or Total Bilirubin
Event |
74
(10.1) |
26
(3.6) |
|
Total
with Any SAE |
22
(29.7) |
5
(19.2) |
|
Total
with Liver-related SAE |
8
(10.8) |
0 |
|
Total
Discontinued for Any Reason |
30
(40.5) |
18
(69.2) |
|
Total
Discontinued for Liver-related Event |
17
(23.0) |
0 |
|
Clinical
Events |
72
(97.39) |
23
(88.5) |
|
Hepatobiliary
Disordersb |
17
(23.0) |
0 |
|
Investigationsc |
26
(35.1) |
5
(19.2) |
|
Infections
and Infestationsd |
1
(1.4) |
1
(3.8) |
|
Other
System Organ Classes |
66
(89.2) |
23
(88.5) |
|
Total
of Hepatobiliary, Investigations, and Infections and Infestations |
39
(52.7) |
5
(19.2) |
a All
on-treatment laboratory test values used, regardless of whether baseline value
was available.
b Preferred
terms: cholestasis, cytolytic hepatitis, hepatitis toxic, hyperbilirubinemia,
jaundice, and liver disorder.
c Preferred
terms: alanine aminotransferase (ALT) increased, aspartate aminotransferase
(AST) increased, hepatic enzyme increased, liver function test abnormal, and
transaminase increased.
d Preferred
terms: Hepatitis B and Hepatitis C.
8.4.2.5 Summary of Hepatic Findings
During the Phase
I and II trials, a dose related increase in Grade 3/4 elevations in ALT or AST
was observed. Most of the hepatic
transaminase elevations were mild; not associated with clinical symptoms; and
resolved spontaneously or with treatment discontinuation. These findings were confirmed in the Phase
III RESIST trials. The majority of TPV/r
patients with Grade 3/4 elevated ALT or AST continued TPV/r treatment without
permanent discontinuation.
A Cox regression model
identified treatment with TPV/r, elevated baseline LFTs (Grade 2/3), CD4+ cell
count > 200 and
co-infection with Hepatitis B or C as risk factors for developing Grade 3/4
elevations in hepatic transaminases.
An exploratory
analysis of medically selected hepatic terms from the RESIST trials, laboratory
and clinical outcomes, suggested that TPV/r treated patients were at greater
risk of developing laboratory or clinical hepatic events compared to
CPI/r.
8.4.3 Fasting lipid elevations
8.4.3.1 Triglyceride elevations
Grade 3 or Grade 4 triglyceride elevations occurred in
23.2% patients in the TPV/r group and 12.2% patients in the CPI/r group. These abnormalities continued to develop in
both treatment groups through 48 weeks.
The Kaplan-Meier estimates of time to first Grade 3 or 4 triglyceride
abnormality are shown in Figure 8.4.3.1: 1. The estimated probability of a Grade 3 or 4
triglyceride elevation was higher in the TPV/r group (7.7%) than in the CPI/r
group (5.4%) at 4 weeks and increased with time (p <0.0001, log rank
test). At 48 weeks the probability was
25.2% in the TPV/r group compared with 15.6% in the CPI/r group.
Patients have had longer median duration of exposure
to TPV/r than with CPI/r study medication (330.0 days and 172.0 days, respectively). Adjusting for patient exposure, the relative
risk of Grade 3 or 4 triglyceride elevations with TPV/r is higher than with
CPI/r (RR=1.53, 95% CI 1.19, 1.97).
Figure 8.4.3.1: 1 Kaplan-Meier estimates for time to onset
of Grade 3 or 4 triglyceride abnormalities in RESIST trial patients
Adverse events related to ischemic heart disease (IHD)
were reported in 38 (5.1%) of 748 patients treated with TPV/r and 35 (4.7%) of
737 patients treated with CPI/r. Eight
(21.1%) of the 38 TPV/r patients, and 8 (22.9%) of the 35 CPI/r patients with
IHD adverse events, had Grade 3 or 4 triglyceride abnormalities.
In the TPV/r group, 27.3% of patients with Grade 3 or
4 triglycerides abnormalities had study medication discontinued, compared to
49.5% patients in the CPI/r group.
Discontinuation of study medication due to IHD adverse events was
observed in 3 (7.9%) of the 38 TPV/r group patients and 0 (0.0%) of the 35
CPI/r group patients.
The most clinically relevant potential risk factors
for the occurrence of Grade 3 or 4 triglyceride abnormalities are elevated
triglyceride levels at baseline, male gender, and age.
8.4.3.2 Cholesterol elevations
Grade 3 or Grade 4 total cholesterol elevations
occurred in 4.0% patients in the TPV/r group and 0.4% patients in the CPI/r
group.
In the TPV/r group, the risk of Grade 3 or 4 total
cholesterol elevations continued through 48 weeks, while it remained flat
in the CPI/r group. The Kaplan-Meier
estimates of time to first Grade 3 or 4 total cholesterol elevation are shown
in Figure 8.4.3.2: 1. The estimated
probability of a Grade 3 or 4 total cholesterol elevation was higher in the
TPV/r group (1.5%) than in the CPI/r group (0.0%) at 8 weeks and increased with
time (p <0.0001, log rank test). At
48 weeks the probability was 4.4% in the TPV/r group compared with 0.5% in the
CPI/r group.
Patients have had longer median duration of exposure
to TPV/r than with CPI/r study medication (330.0 days and 172.0 days,
respectively). Adjusting for patient
exposure, the relative risk of Grade 3 or 4 total cholesterol elevations with
TPV/r is significantly higher than with CPI/r (RR=7.07, 95% CI 2.15, 23.2),
although associated with a low frequency.
Adverse events related to ischemic heart disease (IHD)
were reported in 38 (5.1%) of 748 patients treated with TPV/r and 35 (4.7%) of
737 patients treated with CPI/r. Four
(10.5%) of the 38 TPV/r patients, and 0 (0.0%) of the 35 CPI/r patients with
IHD adverse events, had Grade 3 or 4 total cholesterol abnormalities.
In the TPV/r group, 44.8% of patients with Grade 3 or
4 total cholesterol abnormalities had study medication discontinued, compared
to none of the patients in the CPI/r group. Discontinuation of study medication due to IHD
adverse events was observed in 3 (7.9%) of the 38 TPV/r group patients and 0
(0.0%) of the 35 CPI/r group patients. 
Figure 8.4.3.2: 1 Kaplan-Meier estimates for time to onset
of Grade 3 or 4 total cholesterol abnormalities in RESIST trials
8.5 MORTALITY AND AIDS PROGRESSION
8.5.1 Deaths
in all TPV trials
From the beginning of the TPV program through
Table 8.5.2: 1 Classification of fatal cases as attributable
to Opportunistic Infections, an AIDS-related illness, or both in all
HIV-positive patients
|
Trial Number |
Pre-exposure |
Post-exposure TPV/r |
Post-exposure CPI/r |
Total (%) |
|
Patient deaths |
13 |
104 |
14 |
131 (100.0) |
|
AIDS-defining OI |
3 |
40 |
7 |
50 (38.2) |
|
AIDS-related illness |
5 |
29 |
1 |
35 (26.7) |
|
Both |
0 |
19 |
3 |
22 (16.8) |
|
Neither |
5 |
16 |
3 |
24 (18.3) |
8.5.2 AIDS progression events in RESIST Trials
Using the
methodology established to classify fatal outcomes, BI Medical Officers
retrospectively reviewed treatment emergent outcomes in both treatment arms in
order to assess AIDS progression events occurring in the RESIST trials. Outcomes were classified as treatment
emergent AIDS progression events if they met the following criteria: AIDS-defining opportunistic illness (OI) as
defined by the Center for Disease Control, or an AIDS-related illness (an
illness clearly attributable to immunosuppression or that is known to occur in
excess among HIV-positive patients). In
the RESIST trials, the proportion of patients who developed a new
AIDS-progression event was less in the TPV/r group (3.4%) than in the CPI/r
group (4.6%). This finding did not
reach statistical significance; the RESIST trials were not powered to detect
differences in AIDS progression events.
As of
Table 8.5.3: 1 Summary
of duration of therapy in days for patients that died in RESIST trials
|
Treatment |
Median (days) |
0-30 days |
31-90 days |
91-180 days |
>180 days |
|
Patient
deaths |
134.5 |
4 |
10 |
12 |
13 |
|
CPI/r (n=14) |
95.0 |
1 (7.1%) |
6 (42.9%) |
5 (35.7%) |
2 (14.3%) |
|
TPV/r (n=25) |
156.0 |
3 (12.0%) |
4 (16.0%) |
6 (24.0%) |
12 (48.0%) |
Table 8.5.3: 2
summarizes the number of days after study medication was discontinued until the
patient died. The majority of deaths
(87.2%, 34 of 39 deaths) occurred within 30 days of stopping study
medication. However, in all
presentations of fatalities, the deaths occurring >30 days beyond stopping
study therapy have been included.
Greater than 50% of TPV/r patients and >70% of CPI/r patients died
within 7 days after stopping their study medication.
Table 8.5.3: 2 Summary
of days off of study medication until death in RESIST Trials
|
Treatment |
0-7 days |
8-30 days |
>30 days |
Total |
|
Patient
deaths |
24 |
10 |
5 |
39 |
|
CPI/r |
10 (71.4%) |
2 (14.3%) |
2 (14.3%) |
14 |
|
TPV/r |
14 (56.0%) |
8 (32.0%) |
3 (12.0%) |
25 |
8.5.4 Adjustment
for exposure in RESIST trials
As of
Figure 8.5.4:
1 Mortality in RESIST trials
A comparison of
the causes of death, as identified by investigators, for patients in the RESIST
trials revealed the majority, in either treatment arm, were attributable to
progression of underlying HIV disease or HIV related opportunistic
complications (Table 8.5.4: 1).
Table 8.5.4: 1 Comparison of mortality in the RESIST
clinical program
|
TPV/r (n=25) |
CPI/r (n=14) |
|
AIDS / Infections (9) Lymphoma (4) Neoplasm (2) General medical:
Respiratory (4) Cardiac
(1)
Hepatorenal (1) Sepsis
(2) Unknown (2) |
AIDS / Infections (4) Lymphoma (4) Neoplasm (2) General medical: Cardiac
(2)
Multi-organ failure (1) Unknown (1) |
This finding is
consistent with the fact that the median CD4+ cell count of the
patients who died in the RESIST trials was 17 cells/mm3 for TPV/r patients and 53 cells/mm3 for CPI/r patients.
8.5.5 Analysis
of patients who rolled over to Trial BI 1182.17 from the CPI/r arm of RESIST
trials and died
As noted in Section
8.3, at the cut-off for the Safety Update, 43% of patients (316 out of 737)
left the comparator arm of the RESIST trials due to virologic failure Of the 316 patients, 298 (94%) rolled over
into the BI 1182.17 study and received TPV/r.
Patients leaving the CPI/r arm of the trial due to virologic failure had
lower CD4+ counts (117 cells/mm3) and higher viral loads (4.8 log10
copies/mL) compared to patients remaining in the trial on CPI/r (CD4+ counts of
238 cells/mm3 and viral load of 3.7 log10
copies/mL). Of the patients who rolled
over into BI 1182.17 from the CPI/r arm of the RESIST trials, 14 patients
died. This finding is consistent with
the fact that the median CD4+ cell count of the CPI/r RESIST trial
rollover patients who died in BI 1182.17 after receiving TPV/r was 10 cells/mm3. An overview of the cause of death for these patients
is shown in Table 8.5.5: 1; details of each case are listed in
Appendix 4.
Table 8.5.5: 1 Mortality
in the CPI/r rollover patients from the RESIST trials
|
RESIST trials CPI/r (n=14) |
Rollover Trial 1182.17 CPI/r to TPV/r (n=14) |
|
AIDS / Infections (4) Lymphoma (4) Neoplasm (2) General medical: Cardiac (2) Multi-organ failure (1) Unknown (1) |
AIDS / Infections (9) Neoplasm (1) General medical: Cardiopulmonary (2) Hepatic failure (1) Renal failure (1) |
Additional
support of the advanced disease status of CPI/r patients with virologic failure
who rolled into Trial BI 1182.17 is evidenced by comparing these patients
to those who entered the rollover study from other trials. As of
The difference in
the duration of TPV/r therapy that patients received prior to their death in BI
1182.17 was notable, comparing those CPI/r patients who rolled over from RESIST
studies and the remaining patients who have died in BI 1182.17
(Table 8.5.6: 1). 50% of the
mortality in the CPI/r rollover patients occurred within 90 days of starting
TPV/r therapy compared with no patients who had been receiving TPV/r in a
previous study. The median days of
therapy was 100 days for those patients who were CPI/r virologic failures
receiving TPV/r in Trial BI 1182.17 compared with 335 days for patients who
were receiving TPV/r in a previous study and are now in Trial BI 1182.17.
Table 8.5.6: 1 Summary
of duration of therapy in days for patients that died in Trial BI 1182.17
|
Treatment |
Median (days) |
0-30 days |
31-90 days |
91-180 days |
>180 days |
|
Patient
deaths (n=27) |
205 |
2 |
5 |
6 |
14 |
|
CPI/r
virologic failures from RESIST that have died in 1182.17 (n=14) |
100 |
2 (14.3%) |
5 (35.7%) |
5 (35.7%) |
2 (14.3%) |
|
TPV/r
patients that have died in 1182.17 that were previously on TPV/r in trials
1182.4, 1182.51 or 1182.52 (n=13) |
335 |
0 |
0 |
1 (7.7%) |
12 (92.3%) |
8.5.7 Review of hepatic deaths
In the TPV
clinical development program there have been a limited number of cases of
clinical hepatitis or death due to hepatic failure; these have generally
occurred in patients with advanced HIV disease taking multiple concomitant
medications, often in the setting of underlying chronic hepatitis or
cirrhosis. Through
During the three
month period from