NDA 21-686
Ximelagatran (H376/95)
Indication: Prevention of
stroke and thromboembolic complications associated with atrial fibrillation
Mehul
Desai, M.D.
Medical
Officer
Division
of Cardiovascular and Renal Drug Products
NOTE: This is a
preliminary/draft review that is not intended to provide any recommendations on
the approvability of NDA 21,686. Any
opinions expressed in the review do not necessarily reflect those of the
Division/Office.
Table of Contents
I. Recommendations............................................................................................................... 10
A. Recommendation on Approvability................................................................................ 10
B. Recommendation on Phase 4 Studies
and/or Risk Management Steps............................ 11
II. Summary
of Clinical Findings............................................................................................... 11
A. Brief Overview of Clinical Program............................................................................... 11
B. Efficacy........................................................................................................................ 12
C. Safety........................................................................................................................... 12
D. Dosing.......................................................................................................................... 13
E. Special Population........................................................................................................ 14
Clinical
Review................................................................................................................................ 15
III. Introduction
and Background............................................................................................... 15
A. Drug Established and Proposed
Trade Name, Drug Class, Sponsor’s Proposed Indication(s), Dose Regimens, Age
Groups............................................................................................................................ 15
B. State of Armamentarium for
Indication(s)...................................................................... 15
C. Important Milestones in Product
Development............................................................... 15
IV. Clinically
Relevant Findings from From Chemistry, Animal Pharmacology and Toxicology, Microbiology,
Biopharmaceutics, Statistics and/or Other Consultant Reviews...................................................... 16
V. Human
Pharmacokinetics and Pharmacodynamics................................................................ 16
A. Pharmacokinetics.......................................................................................................... 16
B. Pharmacodynamics....................................................................................................... 19
VI. Description
of Clinical Data and Sources.............................................................................. 22
A. Overall Data................................................................................................................. 22
B. Tables Listing the Clinical Trials..................................................................................... 23
C. Postmarketing Experience............................................................................................. 23
D. Literature Review......................................................................................................... 24
VII. Clinical
Review Methods..................................................................................................... 31
A. How the Review was Conducted.................................................................................. 31
B. Overview of Materials Consulted in
Review.................................................................. 31
C. Overview of Methods Used to
Evaluate Data Quality and Integrity................................ 31
D. Were Trials Conducted in
Accordance with Accepted Ethical Standards....................... 31
E. Evaluation of Financial
Disclosure.................................................................................. 32
VIII. Integrated
Review of Efficacy.............................................................................................. 32
A. Brief Statement of Conclusions...................................................................................... 32
B. General Approach to Review of the
Efficacy of the Drug............................................... 33
C. Detailed Review of Trials by
Indication.......................................................................... 33
1. SPORTIF V........................................................................................................... 33
a. Study dates......................................................................................................... 33
b. Protocol amendments:......................................................................................... 33
c. Study Design:...................................................................................................... 35
d. Rationale for doses selected................................................................................. 38
e. Blinding/Randomization........................................................................................ 38
f. Pre-specified Study Objectives............................................................................ 39
g. Definitions of study endpoints............................................................................... 39
h. Inclusion/Exclusion Criteria.................................................................................. 41
i. Statistical considerations
(please refer to statistical review for details).................... 42
j. Study patient disposition...................................................................................... 45
k. Protocol deviations.............................................................................................. 47
l. Demographics and other patient
characteristics..................................................... 48
m. Primary endpoint results....................................................................................... 52
n. Secondary and Tertiary endpoint
results............................................................... 54
o. Adequacy of anticoagulation in the
warfarin arm................................................... 56
2. SPORTIF III.......................................................................................................... 57
a. Study dates......................................................................................................... 57
b. Protocol Amendments......................................................................................... 57
c. Study Design:...................................................................................................... 59
d. Rationale for doses selected................................................................................. 60
e. Blinding/Randomization:....................................................................................... 60
f. Pre-specified study objectives.............................................................................. 60
g. Definitions of study endpoints............................................................................... 60
h. Inclusion/Exclusion Criteria:................................................................................. 60
i. Statistical Considerations
(please refer to the statistical review for details):............. 60
j. Study patient disposition...................................................................................... 60
k. Protocol deviations.............................................................................................. 62
l. Demographics and other patient
characteristics..................................................... 63
m. Primary endpoint results....................................................................................... 67
n. Secondary and Tertiary endpoint
results............................................................... 69
o. Adequacy of anticoagulation in the
warfarin arm................................................... 70
D. Efficacy Conclusions..................................................................................................... 71
IX. Integrated
Review of Safety................................................................................................. 72
A. Brief Statement of Conclusions...................................................................................... 72
B. Description of Patient Exposure.................................................................................... 73
C. Methods and Specific Findings of
Safety Review........................................................... 74
1. Study population definitions..................................................................................... 74
2. Deaths.................................................................................................................... 75
3. Serious Adverse Events other than
death.................................................................. 76
4. Discontinuations due to Adverse
Events................................................................... 78
5. Adverse Bleeding Events......................................................................................... 79
6. Hepatobiliary Adverse Events.................................................................................. 84
7. Most commonly reported adverse
events (AE’s)...................................................... 90
8. Pancreatic Adverse Events...................................................................................... 91
9. Other Laboratory Test Adverse
events.................................................................... 92
10. Adverse events related to vital
signs, ECG, physical findings..................................... 93
D. Adequacy of Safety Testing.......................................................................................... 93
E. Summary of Critical Safety
Findings and Limitations of Data.......................................... 93
X. Dosing,
Regimen, and Administration Issues......................................................................... 93
XI. Use in
Special Populations................................................................................................... 94
A. Evaluation of Sponsor’s Gender
Effects Analyses and Adequacy of Investigation........... 94
B. Evaluation of Evidence for Age,
Race, or Ethnicity Effects on Safety or Efficacy............. 94
C. Evaluation of Pediatric Program.................................................................................... 94
D. Comments on Data Available or
Needed in Other Populations....................................... 94
XII. Conclusions
and Recommendations..................................................................................... 94
A. Conclusions.................................................................................................................. 94
B. Recommendations........................................................................................................ 95
XIII. Appendix............................................................................................................................ 95
A. Other Relevant Materials.............................................................................................. 95
1. SPORTIF II............................................................................................................ 95
2. SPORTIF IV.......................................................................................................... 96
B. Individual More Detailed Study
Reviews (if performed)................................................. 97
List of
Tables
Table I: Cumulative risk of major bleeding with
increasing exposure of study drug in SPORTIF III/V. 13
Table II: Cumulative risk of ALAT >3x ULN with
increasing exposure of study drug in SPORTIF III/V 14
Table III: Important milestones in Product development.................................................................... 15
Table IV: Effects of renal impairment on the
pharmacokinetics of melagatran, the active metabolite of ximelagatran. Values represent the ratio of subjects with
renal impairment to patients with normal renal function......... 18
Table V: Summary of the clinical trials submitted in
support of the atrial fibrillation indication.............. 23
Table VI: Summary of randomized controlled trials of
warfarin in patients with atrial fibrillation........... 26
Table VII: Summary of the issue dates of the original
protocol and protocol amendments to Study 0005 34
Table VIII: Table summarizing the primary reason for
discontinuing study drug (ITT population)a....... 46
Table IX: Comparison of total study drug discontinuation
rates including and excluding patients with ALAT > 3x ULNa 46
Table X: Summary of inclusion/exclusion criteria
violations by treatment groups (Please refer to inclusion/exclusion criteria
section of this review to match the number with the description of the
criteria)a.......................... 47
Table XI: Number (%) of patients by total days of
treatment interruption, and treatment groupa......... 48
Table XII: INR measurements for warfarin patients in
SPORTIF V.................................................. 48
Table XIII: Patient characteristics at screening: number
(%) of patients by treatment group (ITT population)a 49
Table XIV: Mean (+SD) of patient characteristics at
screening (ITT population)a.............................. 50
Table XV: Number (%) of patients with the presence of the
listed risk factor at study entry............... 50
Table XVI: Number (%) of patients with concomitant
medication use at study entry by treatment group (ITT population)a............................................................................................................................................... 51
Table XVII: Proportion of time patients took concomitant
ASA between the first and last dose of study drug (ITT population)a............................................................................................................................. 51
Table XVIII: Number (%) of patients using other
cardiovascular medications between the first and last dose of study drug, by
treatment group (ITT population)a....................................................................................... 52
Table XIX: Number of patients with stroke and/or SEE by
treatment group (primary prespecified endpoint)a 52
Table XX: Breakdown of primary endpoint by type of event
and whether fatal or non-fatala.............. 53
Table XXI: Number of patients with all cause
mortality/stroke/ SEE/AMI by treatment group (secondary prespecified endpoint
based on OT analysis)a.............................................................................................. 55
Table XXII: Number of patients with ischemic
stroke/TIA/SEE by treatment group (secondary prespecified endpoint based on OT
analysis)a...................................................................................................................... 55
Table XXIII: Number of patients with strokes with a poor
outcome by treatment group (tertiary prespecified endpoint based on ITT
analysis)a...................................................................................................................... 55
Table XXIV: Number of patients with stroke or SEE as a
function of age (<, > 75 years of age) (tertiary prespecified endpoint
based on ITT analysis)a.............................................................................................. 56
Table XXV: Original
Protocol and Protocol Amendment Issue dates for SPORTIF III.................... 57
Table XXVI: Summary of the reasons for discontinuing study
drug (ITT population)a......................... 62
Table XXVII:
Comparison of total study drug discontinuation rates including and
excluding patients with ALAT > 3x ULNa............................................................................................................................................... 62
Table XXVIII: Number of patients that discontinued the
study and had missing vital status or primary event data at time of study
closure procedures but were asked to re-consent to provide follow-up
information.......... 62
Table XXIX: Inclusion/exclusion criteria violations by
treatment group.............................................. 63
Table XXX: Number (%) of patients by total days of
treatment interruption, and treatment groupa..... 63
Table XXXI: Patient characteristics at screening: number
(%) of patients by treatment group (ITT population)a 64
Table XXXII: Mean (+SD) of patient characteristics at
screening (ITT population)a.......................... 65
Table XXXIII: Number (%) of patients with presence of the
listed risk factor at study entrya............. 65
Table XXXIV: Number (%) of patients with concomitant
medication use at study entry by treatment group (ITT population)a............................................................................................................................................... 66
Table XXXV: Proportion of time patients took concomitant
ASA between the first and last dose of study drug (ITT population)a............................................................................................................................. 66
Table XXXVI: Number (%) of patients using other
cardiovascular medications between the first and last dose of study drug, by
treatment group (ITT population)a....................................................................................... 67
Table XXXVII: Number of patients with stroke and/or SEE by
treatment group (primary prespecified endpoint)a 67
Table XXXVIII: Listing of the individual components of the
primary endpoint in SPORTIF IIIa......... 67
Table XXXIX: Number of patients with all cause
mortality/stroke/ SEE/AMI by treatment group (secondary prespecified endpoint
based on OT analysis)a.............................................................................................. 69
Table XL: Number of patients with ischemic stroke/TIA/SEE
by treatment group (secondary prespecified endpoint based on OT analysis)a........................................................................................................................... 70
Table XLI: Number of patients with strokes with a poor
outcome by treatment group (tertiary prespecified endpoint based on ITT
analysis)a...................................................................................................................... 70
Table XLII: Number of patients with stroke or SEE as a
function of age (<, > 75 years of age) (tertiary prespecified endpoint
based on ITT analysis)a.............................................................................................. 70
Table XLIII:
Demographic description of Safety population............................................................. 73
Table XLIV: Summary of Exposure Data......................................................................................... 74
Table XLV: Listing of the most common adverse events
leading to deatha(PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED)......................................................... 75
Table XLVI: Listing of serious adverse events not leading
to deatha, b, c, d, e (PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN
PERCENTAGES ARE REPORTED).......................................... 76
Table XLVII: Listing of study drug discontinuations due to
adverse events. Listed are the total
number of AE’s occurring at a frequency of > 1% in the ximelagatran group or
were > 2x fold higher in the ximelagatran arm relative to the warfarin arma
(PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED) 78
Table XLVIII: Summary Table of Major bleeding events
(Based on On Treatment – OT Analysis)a.. 79
Table XLIX: Number of patients with major bleeding events
according to the CEAC, by criteria for judgment according to local criteria
assessed and by treatment group (OT analysis)a.................................................... 82
Table L: Locations/subtypes of major bleedsa................................................................................... 82
Table LI: Frequency of patients with elevated ALAT, ASAT,
ALP, and Bilirubin (ITT population)a (PLEASE NOTE THAT NUMBER OF
EVENTS RATHER THAN PERCENTAGES ARE
REPORTED)................. 84
Table LII: Number of Patients with ALAT > 3x ULN
followed by a bilirubin level > 2x ULN within one month of the elevated ALAT
(PLEASE NOTE THAT NUMBER OF EVENTS
RATHER THAN PERCENTAGES ARE REPORTED) ......................................................................................................................... 85
Table LIII: Pattern of liver enzyme progression for
Patient 7259....................................................... 88
Table LIV: Pattern of liver enzyme progression for patient
7859....................................................... 89
Table LV: Most common AE’s with an absolute frequency >
5% (based on the ximelagatran arm) or were > 2 fold higher than on the
control group (warfarin)a........................................................................................ 90
Table LVI: Summary of pancreatic adverse events in SPORTIF
III and SPORTIF V....................... 91
Table LVII: Comparison of cholecystokinin plasma
concentrations at month 3 in a subset of patients in the SPORTIF V studya...................................................................................................................................... 91
Table LVIII: Pancreatic volume obtained via CT scan: mean
change from screening to last available value.
(SPORTIF V study)a..................................................................................................................................... 92
Table LIX: Summary of safety findings from SPORTIF II
study (shown are the numbers of patients with events) 96
Table LX: Summary of findings from the SPORTIF IV study............................................................ 97
Table LXI: Pattern of liver enzyme progression in patient
3174......................................................... 98
Table LXII: Pattern of liver enzyme progression for
patient 1967...................................................... 99
Table LXIII: Pattern of liver enzyme progression for
patient 7986................................................... 100
Table LXIV: Pattern of liver enzyme progression for
patient 5402................................................... 101
Table LXV: Pattern of liver enzyme progression for patient
8387.................................................... 101
List of
Figures
Figure 1: The metabolic pathways of ximelagatran
for the formation of melagatran (Figure taken from Figure 1 of Summary of
Clinical Pharmacology Studies)............................................................................................ 17
Figure 2: Mean CrCL (ml/min) versus CL/F (l/h) after oral
ximelagatran administration (This figure taken from Figure 11:9 of Sponsor’s
Clinical Pharmacology Study Report for study SH-TP1-0026)................................. 19
Figure 3: Relationship between aPTT levels and plasma
concentrations of melagatran (obtained from Figure 18 of the Sponsor’s Summary
of Clinical Pharmacology Studies)............................................................ 20
Figure 4: Relationship between the PK time course of
melagatran and the PD time course of aPTT (obtained from Figure 19 of the
Sponsor’s Summary of Clinical Pharmacology Studies)................................................... 21
Figure 5: INR
values plotted versus plasma melagatran concentration (Figure obtained from
Figure 27 of Summary of Clinical Pharmacology Studies)................................................................................................ 22
Figure 6: Study Schema for SPORTIF V (Figure taken from
Figure 1 of SPORTIF V CSR)............ 36
Figure 7: Patient disposition in SPORTIF V (Figure taken
from Figure 4 of SPORTIF V CSR)......... 45
Figure 8: Cumulative proportion of patients with stroke
and/or SEE over time-estimated Kaplan-Meier curves (Figure taken from Figure 12
of SPORTIF V CSR)...................................................................................... 53
Figure 9: Event rate difference (ximelagatran – warfarin)
for the primary endpoint (stroke and/or SEE) according to prognostic factors
(Figure taken from Figure 16 of SPORTIF V CSR)..................................... 54
Figure 10: Adequacy of anticoagulation as assessed by INR
in patients assigned to warfarin (OT population); (Figure taken from Figure 23
of SPORTIF V CSR)...................................................................................... 56
Figure 11: Study Schema for SPORTIF III (Figure obtained
from Figure 1 of SPORTIF III CSR).... 59
Figure 12: Patient disposition in SPORTIF III (Figure
obtained from Figure 4 of SPORTIF III CSR) 61
Figure 13: Cumulative proportion of patients with stroke
and/or SEE (primary endpoint) over time – estimated Kaplan-Meier curves (This
figure obtained from Figure 12 of SPORTIF III CSR)................................. 68
Figure 14: Event rate difference (ximelagatran – warfarin)
for the primary endpoint (stroke and/or SEE) according to prognostic factors
(This figure obtained from Figure 13 of SPORTIF III CSR)......................... 69
Figure 15: Adequacy of anticoagulation as assessed by INR
in patients assigned to warfarin (OT population) (This figure was obtained from Figure 25 of
SPORTIF III CSR)................................................................ 71
Figure 16: Cumulative percentage of patients with major
bleeding events over time – Estimated Kaplan-Meir Curves (OT analysis) for
SPORTIF III study (Obtained from Figure 32 of Sponsor’s SPORTIF III Clinical
Study report) 81
Figure 17: Cumulative percentage of patients with major
bleeding events over time; estimated Kaplan-Meier curves (OT Analysis).
(Obtained from Figure 25 of Sponsor’s SPORTIF V Clinical Study report).............. 81
Figure 18: Summary of safety comparison: ximelagatran vs.
warfarin (difference in percent events, with 95% CI) for major bleed events,
according to prognostic factors (OT analysis) (SPORTIF III) (Obtained from
Figure 33 of SPORTIF III CSR)...................................................................................................................................... 83
Figure 19: Summary of safety comparison: ximelagatran vs.
warfarin (difference in percent events, with 95% CI) for major bleed events,
according to prognostic factors (OT analysis) (SPORTIF V) (Obtained from Figure
26 of SPORTIF V CSR)...................................................................................................................................... 84
Figure 20: Cumulative risk of ALAT > 3x ULN versus time
after randomization (ITT population) (Figure obtained from Figure 36 of SPORTIF
III CSR)............................................................................................. 86
Figure 21: Cumulative risk of ALAT > 3x ULN versus time
after randomization (ITT population) (Figure obtained from Figure 33 of SPORTIF
V CSR).............................................................................................. 86
Figure 22: Summary of patients on ximelagatran with an
ALAT > 3x ULN in SPORTIF III............... 87
Figure 23: Estimated within-group ratios relative to
baseline (each patient’s mean of all measurements post-randomization divided by
baseline) with 95% CI. Between-group comparisons for those ratios made with
unpaired t-test (OT analysis) (Figure taken from Figure 41 of SPORTIF V CSR)................................................... 92
Executive Summary
The sponsor of NDA 21-686 is currently seeking approval of ximelagatran
(H376/95) for 3 different indications.
The indication that is the focus of this review is the prevention of
stroke and other thromboembolic complications associated with atrial
fibrillation. Two pivotal phase 3
studies (SPORTIF III and SPORTIF V) have been submitted in support of the
stated indication. The two studies are
active controlled studies designed to show that ximelagatran is non-inferior or
“as efficacious as” treatment with warfarin, the current standard of care. The active controlled, non-inferiority design
of the SPORTIF studies makes interpretation of efficacy relatively more
complicated compared to a design involving a placebo control. An important step in interpreting the
effectiveness of ximelagatran in the SPORTIF studies is to understand the
benefit of warfarin relative to placebo.
The benefit of warfarin relative to placebo was derived from several placebo
controlled trials conducted approximately 10 to 15 years ago and published in
the peer reviewed medical literature. A
summary of these studies is discussed in detail elsewhere in this review. Based on these studies, the relative risk
reduction for stroke appears to be approximately 64% (95% CI à 47%, 75%).
The 2 SPORTIF studies compared the effectiveness of a fixed dose of
ximelagatran, 36 mg administered twice a day, to warfarin, targeting an INR of
2 – 3 in patients with nonvalvular atrial fibrillation and at least one
additional risk factor for stroke.
SPORTIF III and SPORTIF V were similar in design except that the former
was open-label while the latter was blinded.
The primary endpoint was a composite of all strokes (ischemic and
hemorrhagic) and systemic embolic events.
The sponsor pre-specified a non-inferiority margin of 2% in the event
rate. Ximelagatran would be called
non-inferior if an excess of 2% per year in the event rate relative to warfarin
could be confidently excluded. A margin
of this magnitude could leave open the possibility that ximelagatran was only
half as effective as warfarin and still be considered non-inferior to
warfarin. The magnitude of this
non-inferiority margin was not formally agreed upon by the reviewing division
within the Agency and marked as a point of future review/discussion.
The two SPORTIF studies produced divergent results despite similar
designs. In SPORTIF III, the primary
event rate was numerically higher in the warfarin arm compared to the ximelagatran
arm. In SPORTIF V, the primary event
rate was numerically higher in the ximelagatran arm compared to the warfarin
arm. Comparing the event rates in the
common arm of both SPORTIF studies, the
rate in the ximelagatran arm was practically the same in both studies while the
event rate in the warfarin arm varied by nearly two-fold. The variable event rate on warfarin in the
two studies could potentially be attributed to the fact that patients in the
two studies were slightly different at baseline. Patients in SPORTIF V were slightly older, had
lower blood pressures on average, had fewer patients with histories of
transient ischemic attacks (TIA’s) or strokes, and had greater consumption of
HMG CoA reductase inhibitors than did patients enrolled in SPORTIF III. It is puzzling why differences in patient
populations of both studies would lead to differences in event rates in the
warfarin arms while leaving the event rate in the ximelagatran arms unaffected. In such a setting where two similarly designed
studies produce divergent results, I would favor the results from a
double-blind study.
In terms of safety, liver toxicity as assessed by serum aminotransferase
abnormalities occurred approximately 6 times more often on ximelagatran
compared to warfarin and was consistent across both trials. There was one well documented case (and most
probably a second case) of drug induced liver failure leading to coagulopathy
and death among the approximately 3700 patients randomized to
ximelagatran. Intense protocol mandated
liver enzyme monitoring did not prevent serious liver toxicity in these two
cases although in some other cases it did prevent serious adverse
outcomes. These two cases highlight the
possibility that liver enzyme monitoring as a risk management strategy may not
be entirely fool proof. In terms of
major bleeding events, the total number of bleeds was numerically lower in the
ximelagatran arm of both studies. In
neither of the studies did the difference achieve statistical significance. The majority of major bleeds in both studies
were due to bleeding with a fall in the hemoglobin level of > 2g/dL
or due to overt bleeding requiring > 2 units of whole blood. Bleeding events leading to death were
relatively few in both studies and similar in the two treatment arms.
With respect to dosing, there is a strong correlation between the oral
clearance of melagatran (the active metabolite of ximelagatran) and creatinine
clearance. Thus exposure to melagatran
will be affected by renal impairment.
Varying degrees of renal impairment are expected in the patient
population for which this therapy is targeted and will potentially be a
significant factor affecting exposure to melagatran. There is a clear relationship between higher
exposures to melagatran and increased risk of major bleeds and elevations in
aminotransferases. A strategy of fixed
dosing as is being proposed for ximelagatran is concerning.
The sponsor has proposed a risk
management program that is intended to minimize the risk of severe hepatic
injury that could occur in the setting ximelagatran use. One of the key features of this program
involves liver enzyme (ALAT) monitoring.
The method of monitoring proposed in the risk management plan is similar
in intensity to the monitoring that was conducted in the pivotal clinical
trials. Unfortunately, the relatively
intense liver enzyme monitoring in the clinical trials did not prevent two
cases of drug induced liver failure/death in the SPORTIF V study.
The experience of the FDA in
using liver enzyme monitoring as a risk management tool has been disappointing
particularly in the case of troglitazone.
Troglitazone was an antidiabetic agent that was approved in 1997 but
taken off the market in 2000 because of numerous cases of liver failure
reported post marketing. Despite
labeling changes, Dear doctor letters and other risk management strategies,
baseline testing of liver enzymes was conducted in less than one-half of the
patients that were started on troglitazone (Graham et al JAMA
2001;286:831-833).
One of the indications that
ximelagatran is being developed for is the prevention of stroke and other
thromboembolic complications associated with atrial fibrillation. Two pivotal phase 3 studies have been
submitted in support of the stated indication.
In the atrial fibrillation development program a total of approximately
7,300 patients were followed for an average of 1.4 years. The two studies were active controlled
studies designed to show that ximelagatran is “non-inferior” to treatment with
warfarin, the current standard of care.
The 2 SPORTIF studies compared the effectiveness of fixed doses of
ximelagatran 36 mg administered twice a day versus warfarin, targeting an INR
of 2 – 3 in patients with nonvalvular atrial fibrillation and at least one
additional risk factor for stroke.
SPORTIF III and SPORTIF V are two Phase III, active control,
non-inferiority studies that were provided in support of NDA21-686. Both studies compared the effectiveness of a
fixed dose of ximelagatran, 36 mg administered twice a day to warfarin
targeting an INR of 2 to 3 in patients with nonvalvular atrial fibrillation and
at least one additional risk factor for stroke.
The studies were very similar in design except that SPORTIF III was open
label while SPORTIF V was double-blind.
The primary endpoint was the composite of all strokes (fatal and
non-fatal) and systemic embolic events.
The sponsor pre-specified a non-inferiority margin of 2% points in the
event rate in both studies. A margin of
that size could leave open the possibility that ximelagatran is only half as
effective as warfarin and still be considered “non-inferior.”
In both studies, the efficacy of ximelagatran was within the
sponsor’s pre-specified non-inferiority margin of 2% and it was concluded by
the sponsor that ximelagatran was as efficacious as warfarin. While the two studies could be considered
“successes” based on the sponsor’s pre-specified margin, the margin chosen was
too liberal.
The two SPORTIF studies produced
divergent results despite their similar designs and patient populations studied. In SPORTIF V, the event rate was higher in
the ximelagatran arm compared to the warfarin arm while in SPORTIF III, the
event rate was higher in the warfarin arm compared to the ximelagatran arm. Comparing the event rates in common arm of
both studies, the event rate in the ximelagatran arm of both SPORTIF studies
were similar at approximately 1.6%.
However, the event rate in the warfarin arm varied by almost two-fold:
1.2% in SPORTIF V versus 2.3% in SPORTIF III.
Differences in the patient populations in the two studies at baseline
could be a possible explanation of the differences in the event rate in the
treatment arms. However, it is difficult
to explain why such differences would lead to differences in event rates in the
warfarin arm while leaving the event rate in the ximelagatran arm
unaffected. In a setting where two
similarly designed studies produce divergent results, I would favor the results
from a double-blind study. It is
important to note that the event rate in both studies was primarily driven by
the occurrence of ischemic strokes. More
than 80% of the events in both studies were ischemic strokes.
In SPORTIF III, there were a total of 145 deaths that occurred on drug or
during the follow-up period: 75 Ximelagatran, 70 Warfarin. In SPORTIF V, there were a total of 237
deaths occurring on drug or during the follow-up period: 116 Ximelagatran, 121
Warfarin. The etiologies of deaths were
consistent with what is to be expected from an elderly population with
co-morbidities. The most common
etiologies of death included sudden death, heart rate and rhythm disorders,
myocardial infarctions, and congestive heart failure.
In terms of serious adverse events (SAE’s) not leading to death, the
reporting rate was lower in SPORTIF III compared to SPORTIF V. The etiologies of the SAE’s not leading to
death were also consistent with what would be expected in an elderly
population. The most common etiologies
of SAE’s included congestive heart failure, cerebrovascular disorders, myocardial
infarctions, GI hemorrhage, pneumonia, and angina pectoris.
Discontinuations due to adverse events were numerically greater in the
ximelagatran arms of both SPORTIF studies.
The most common reason for study drug discontinuation from ximelagatran
was liver and biliary system disorders.
The frequency of aminotransferase abnormalities was significantly higher
on ximelagatran compared to warfarin regardless of the criteria used to define
abnormal (e.g. ALAT or ASAT > 3x ULN, > 5x ULN, or > 10 x ULN). The majority of patients that developed liver
enzyme abnormalities did so beginning 2 to 4 months after starting ximelagatran
therapy. There was one case of a biopsy
documented drug induced liver failure leading to death. There was a second probable case of drug
induced liver failure leading to coagulopathy and subsequently death. In addition there were multiple cases of
aminotransferase abnormalities greater than 3 times the upper limit of normal
temporally associated with a bilirubin increase of greater than 2 times the
upper limit of normal. The cases fitting
the description of “Hy’s Law” and their associated narratives are listed in the
Appendix of this review. In most of
these cases the patients were asymptomatic.
Liver enzyme abnormalities returned to normal after drug discontinuation
in these patients.
In terms of major bleeding
events, the total number of bleeds was numerically lower in the ximelagatran
arm of both SPORTIF studies. In neither
of the studies did this difference achieve statistical significance. The majority of major bleeds in both studies
was due to bleeding with a fall in the hemoglobin level of greater than or
equal to 2 g/dL or due to overt bleeding requiring > 2 units of whole
blood.
A fixed dose of ximelagatran 36mg bid was studied in the
SPORTIF trials. The sponsor’s
preliminary labeling proposes for the use of fixed doses of ximelagatran
without recommending dose adjustment.
There is a strong correlation between creatinine clearance
and the apparent oral clearance of melagatran, the active metabolite of
ximelagatran. As creatinine clearance
decreases, there is a proportional decrease in melagatran clearance. In the sponsor’s proposed labeling there are
no provisions for dose adjustment in patients with varying degrees of renal
impairment. The proposed labeling would
only contradict the use of ximelagatran in patients with a creatinine clearance
less than 30 ml/min. Not allowing for
dose adjustment in renal impairment may compromise safety because the risk of
serious adverse events increases as the exposure to drug increases as shown in Table I and Table
II below.
Table
I below shows that as the exposure to melagatran increases
as measured by the area under the plasma concentration time curve increases,
the cumulative risk of major bleeding increases by a factor of about 4
fold.
Table I: Cumulative risk of major bleeding with
increasing exposure of study drug in SPORTIF III/V
|
Study
(SPORTIF III/V)
|
|
AUC value
|
Cumulative Risk (%)
|
95%CI
|
|
|
Lower (%)
|
Upper (%)
|
|
|
Lowest 5%
|
2.06
|
1.00
|
.64
|
1.37
|
|
|
Lowest 25%
|
2.77
|
1.29
|
0.89
|
1.70
|
|
|
Median
|
3.46
|
1.65
|
1.21
|
2.10
|
|
|
Highest 75%
|
4.38
|
2.29
|
1.74
|
2.85
|
|
|
Highest 95%
|
6.19
|
4.37
|
3.05
|
5.69
|
Obtained from Table 27 of
Summary of Clinical Pharmacology Studies Study Report
Similar to the previous table, Table II below shows that as the exposure to melagatran
increases, the cumulative risk of hepatotoxicity (as measured by an ALAT >
3x ULN) increases. The increased risk of
toxicity with increased exposures to melagatran appears to be slightly less
pronounced for hepatotoxicity than that for major bleeding.
Table II: Cumulative risk of ALAT >3x ULN with
increasing exposure of study drug in SPORTIF III/V
|
Study
(SPORTIF III/V)
|
|
AUC value
|
Cumulative Risk (%)
|
95%CI
|
|
|
Lower (%)
|
Upper (%)
|
|
|
Lowest 5%
|
2.06
|
5.13
|
4.02
|
6.23
|
|
|
Lowest 25%
|
2.77
|
5.59
|
4.64
|
6.55
|
|
|
Median
|
3.46
|
6.08
|
5.22
|
6.94
|
|
|
Highest 75%
|
4.38
|
6.80
|
5.83
|
7.77
|
|
|
Highest 95%
|
6.19
|
8.47
|
6.38
|
10.6
|
Obtained from Table 27 of
Summary of Clinical Pharmacology Studies Study Report
Just under 1/3 of the patients
randomized in the SPORTIF studies were females.
The direction and magnitude of the ximelagatran effect with respect to
the primary efficacy endpoint was similar in males and females.
Less than 5% of the study
population in the SPORTIF studies was Black and thus limited conclusions can be
made of efficacy or safety of ximelagatran in that population.
It was not unexpected that both
SPORTIF studies randomized predominantly a geriatric population with a mean age
of just over 70 years as the prevalence of atrial fibrillation increases with
increasing age.
Melagatran, the active
metabolite of ximelagatran is predominantly excreted in the urine
unchanged. Thus, patients with severe
renal impairment can have up to 5 times the exposure compared to those with
normal renal function.
There are no adequate and well
controlled studies of ximelagatran use in pregnant women. Reproductive toxicity studies with
ximelagatran in pregnant rats, rabbits, and minipigs have been conducted and
have not shown any risk of harm to the fetus at doses that do not produce maternal
bleeding. Please refer to the
Pharmacology/Toxicology review for further details.
Proposed trade name: EXANTAÒ
Drug Class:
Reversible, oral thrombin inhibitor
Proposed indications: The sponsor is seeking a total of 3
indications. Two of the indications are
related to the prevention and treatment of venous thromboembolism. The third indication that is the purpose of
this review is “prevention of stroke and other thromboembolic complications
associated with atrial fibrillation.”
Dose/Regimen: Fixed dose of 36 mg orally twice daily
Age groups: Older
adults will be the primary recipients of this therapy. The prevalence of atrial fibrillation is much
higher in older adults than in younger adults.
Chronic ximelagatran therapy has not been studied in pediatric
populations because atrial fibrillation is a rare, atypical arrhythmia in
children.
B.
State
of Armamentarium for Indication(s)
EXANTA is the first in a new class of oral
anticoagulants. The primary mechanism of
action involves reversible inhibition of thrombin. The most commonly used oral anticoagulants
worldwide are the vitamin K antagonists.
Warfarin is an approved Vitamin K antagonist that is available in the U.S. Warfarin is generally recognized as a very
effective oral anticoagulant. Its main
side effect is risk of bleeding that is predictable from its pharmacologic
action. One drawback of using warfarin
is that it requires therapeutic drug monitoring to ensure that efficacy is
being maximized while minimizing bleeding risk.
Table III: Important milestones in Product development
|
January 16, 1998
|
Patent
issue date
|
|
August 14, 1998
|
IND filed for the oral tablet
formulation of ximelagatran
|
|
June 16, 2000
|
End
of Phase 2 meeting to discuss SPORTIF protocols
|
|
July 14, 2003
|
Pre-NDA
meeting
|
|
October 9, 2003
|
Meeting
to discuss risk management strategies
|
|
December 23, 2003
|
NDA
filed to Division of GI/Coagulation Drug Products
|
Please refer to the Medical Officer Review by Dr. Ruyi He
(Primary Medical Officer in Division of GI/Coagulation Drug Products) for
further details.
Please refer to the Clinical Pharmacology,
Biopharmaceutics Review for details.
Melagatran is a potent, competitive and reversible direct
inhibitor of the serine protease a-thrombin.
Thrombin converts fibrinogen to fibrin in the coagulation cascade. In addition thrombin also produces platelet
aggregation. Inhibition of thrombin by
ximelagatran prevents thrombus development and reduces platelet
aggregation. Melagatran inhibits both free
and fibrin-bound thrombin and thrombin-induced aggregation of platelets.
Ximelagatran is a prodrug, which after oral administration
yields melagatran as the dominant metabolite.
As shown in Figure
1 below, there are two intermediate metabolites in the
pathway from the prodrug to melagatran:
ethyl-melagatran and OH-melagatran.
Ximelagatran and OH-melagatran are essentially inactive as thrombin
inhibitors while melagatran and ethyl-melagatran are both active inhibitors of
thrombin. The formation of melagatran
primarily occurs via formation of the OH-melagatran intermediate
metabolite. The formation of melagatran
via ethyl-melagatran is a relatively minor pathway.
Figure
1: The metabolic pathways of ximelagatran for
the formation of melagatran (Figure taken from Figure 1 of Summary of Clinical
Pharmacology Studies).
The conversion (hydrolysis) from
ximelagatran to OH-melagatran is rapid and mediated primarily by
esterases. The reduction reaction from
OH-melagatran to melagatran is a reduction reaction through a yet unidentified
metabolic pathway. No cytochrome P450
enzymes have been identified in the reduction of OH-melagatran to melagatran.
Ximelagatran, melagatran,
ethyl-melagatran, or OH-melagatran has not been shown shown to inhibit human
drug metabolizing enzymes in various in vitro studies (e.g. human liver
microsomes). In vivo studies in rats
showed that ximelagatran did not induce P450 enzymes that were studied.
Melagatran is eliminated primarily by excretion in urine
with a renal clearance that corresponds to the glomerular filtration rate.
Summary of key
pharmacokinetic (PK) findings in healthy subjects
·
The pharmacokinetics are dose proportional
·
The bioavailability is approximately 20%
·
The half-life of melagatran is approximately 3
hours
·
Inter-individual variability in exposure: CV = 20%,
while intra-individual variability in exposure: CV = 10%
·
Melagatran is main excreted unchanged in urine
Summary
of key PK findings in patients
- The
pharmacokinetics are dose proportional
- The
half-life of melagatran is approximately 5 hours
- Inter-individual
variability in exposure: CV =
50%, Intra-individual variability
in exposure: CV = 25%
Effects of renal
impairment on PK of melagatran
The
effects of renal impairment on ximelagatran PK were evaluated in an open-label,
randomized, single dose study. Subjects
enrolled in this study were given single oral doses of Ximelagatran 24 mg. Plasma concentrations and amount of
melagatran, the active metabolite of ximelagatran, excreted in urine were measured
up to 24 hours post dose.
Study
subjects were between the ages of 20 to 80 yeas old and were enrolled into 3
groups. Note that the creatinine
clearance (CrCL) was calculated according to the Cockcroft & Gault formula.
Group 1
CrCL > 50 ml/min/1.73m2
Group 2
CrCL 20-30 ml/min/1.73m2
Group 3
CrCL 10-19 ml/min/1.73m2
12
subjects were enrolled into Group 1 and this group was considered as having
normal renal function. Groups 2 and 3
were lumped together as one group and were considered as having renal
impairment. There were a total of 12
subjects in these 2 groups. In Group 1,
the mean Cr CL (using Cockcroft Gault) was 107.7 + 24.3 ml/min (min 63.9
ml/min and max 151.1 ml/min). In groups
2 and 3, the mean CrCL was 27.1 + 9.7 ml/min (min 13.9 ml/min and max
43.1 ml/min).
The
effects of renal impairment on melagatran PK are summarized in
Table IV
below. As shown in the table, the
exposure to melagatran in terms of AUC is approximately 5 fold higher in
patients with renal impairment compared to “Normals.” Similarly Cmax is about 2 fold
higher.
Table IV: Effects of renal
impairment on the pharmacokinetics of melagatran, the active metabolite of
ximelagatran. Values represent the ratio
of subjects with renal impairment to patients with normal renal function.
|
Variable
|
Group comparison
|
Estimate
|
|
95% CI
|
|
|
|
|
|
Lower
|
|
Upper
|
|
AUC
|
Renally impaired/normal
|
5.33
|
3.76
|
|
7.56
|
|
Cmax
|
Renally impaired/normal
|
1.83
|
1.42
|
|
2.37
|
|
t1/2
|
Renally impaired/normal
|
2.60
|
2.07
|
|
3.26
|
|
Frel
|
Renally impaired/normal
|
1.32
|
1.04
|
|
1.67
|
|
CL/F
|
Renally impaired/normal
|
0.188
|
0.132
|
|
0.266
|
|
CLR
|
Renally impaired/normal
|
0.106
|
0.065
|
|
0.173
|
Data in this table obtained
from synopsis report of study SH-TP1-0026
The oral clearance (CL/F) of melagatran correlates very
well with CrCL calculated using Cockcroft Gault as shown in Figure 2 below. This
type of relationship makes justification of a fixed dose of ximelagatran for
all patients rather problematic particularly in the setting of increased risk
of serious adverse events with increasing exposure to drug.
Figure 2: Mean CrCL (ml/min) versus CL/F (l/h) after
oral ximelagatran administration (This figure taken from Figure 11:9 of Sponsor’s
Clinical Pharmacology Study Report for study SH-TP1-0026)
Effect of hepatic impairment on PK of
melagatran
An
open-label, single dose study was conducted in patients with hepatic impairment
and controls matched in terms of age, sex, and weight. A total of 12 liver patients and 12 controls
were studied. The subjects ranged in age
from 45-69 years. Among the patients
with hepatic impairment, 7 had mild impairment (Child Pugh A) while 5 had
moderate impairment (Child Pugh B). The
results of this study showed that the pharmacokinetics of melagatran were
similar in patients with or without hepatic impairment.
Melagatran, the active metabolite of ximelagatran,
prolongs the activated partial thromboplastin time (aPTT) and INR ratio. Melagatran is an inhibitor of thrombin which
happens to be Factor II in the coagulation cascade. aPTT is prolonged by abnormalities in factors
involved in the intrinsic coagulation cascade (e.g. FVIII, FIX, XI, XII, etc),
fibrinogen, and also factors in the common pathway (e.g. FII, V, X). Prolongation of aPTT occurs in a
concentration dependent manner and is non-linear. The relationship between melagatran concentrations
and aPTT prolongation is illustrated in Figure
3 and Figure 4 below. It is
important to note that the pharmacodynamic data in the figures below has been
generated from healthy subjects.
Figure 3: Relationship between aPTT levels and plasma
concentrations of melagatran (obtained from Figure 18 of the Sponsor’s Summary
of Clinical Pharmacology Studies).
As shown in Figure 4 below, after oral dosing
with ximelagatran, the aPTT starts to prolong within 20 minutes of dosing and
peak prolongations are observed 2 hours post dosing. The effect of ximelagatran on aPTT at the end
of 12 hours is approximately at the same level seen pre-dose. Based on this figure it appears as though a
once a day dosing strategy would be sub-optimal. It can not be determined from this trial
whether a more than twice a day dosing regimen would result in greater efficacy
compared to twice a day dosing.
Figure 4: Relationship between the PK time course of
melagatran and the PD time course of aPTT (obtained from Figure 19 of the
Sponsor’s Summary of Clinical Pharmacology Studies)
In addition to effects on aPTT, ximelagatran can also
affect the prothrombin time (PT) and INR.
In vitro studies in human plasma have demonstrated that the PT was
prolonged by melagatran but that the corresponding INR varied considerably
depending on the ISI of the thromboplastin.
It is predicted that INR’s of approximately 1.2 to 1.8 are expected at
steady-state trough and peak plasma concentrations of melagatran in atrial
fibrillation receiving 36 mg bid. At
very high plasma melagatran concentrations the INR ranged from approximately
2.8 to 6 depending on the ISI of the thromboplastin used. Figure
5 below summarizes the relationship between melagatran
plasma concentrations and INR based on an in vitro study using two different
thromboplastins with differing ISI levels.
Figure
5: INR
values plotted versus plasma melagatran concentration (Figure obtained from
Figure 27 of Summary of Clinical Pharmacology Studies)
The sources of data used in generating this review include:
·
Electronic NDA submission for N21686
·
Sponsor’s reply to an Information Request dated March 23, 2004, June 3, 2004
·
NDA21686 4-month Safety Update Report
Table V: Summary of the clinical trials submitted in
support of the atrial fibrillation indication
|
SPORTIF
V
“Efficacy and Safety of the Oral Direct
Thrombin Inhibitor H376/95 Compared with Dose-Adjusted Warfarin (Coumadin) in
the Prevention of Stroke and Systemic Embolic Events in Patients with Atrial
Fibrillation.”
|
- Pivotal Phase 3 study
- Randomized, Double-blind
·
U.S. and Canada
·
Active control (warfarin INR 2 – 3)
·
Fixed dose ximelagatran 36 mg bid
·
Patients with nonvalvular atrial fibrillation + at least one
additional risk factor for stroke
|
|
SPORTIF
III
“Efficacy
and Safety of the Oral Direct Thrombin Inhibitor H376/95 Compared with
Dose-Adjusted Warfarin (Coumadin) in the Prevention of Stroke and Systemic
Embolic Events in Patients with Atrial Fibrillation.”
|
·
randomized, Unblind
·
Europe and Asia
·
Active control (warfarin INR 2 – 3)
·
Fixed dose of ximelagatran 36 mg bid
·
Population of patients with nonvalvular atrial fibrillation + at
least one additional risk factor for stroke
|
|
SPORTIF
II, SPORTIF IV
|
- Non-pivotal, phase 2
studies
·
Unblind with respect warfarin arm
·
Dose ranging (20 mg, 40mg, 60mg)
·
Active control (warfarin INR 2 – 3)
·
Primarily designed to assess long term safety of ximelagatran
|
No post-marketing safety data are available. Marketing authorization was received in France
in December 2003 for the prevention of venous thromboembolism (VTE) in patients
undergoing hip or knee replacement surgery.
However, ximelagatran has not yet obtained full approval by the European
Union and thus is not commercially available as of April 2004.
The studies in support of the efficacy of ximelagatran
(H376/95) are active control, non-inferiority trials. The active control chosen for both studies
was warfarin titrated to an INR of 2 to 3.
One aspect in trying to understand whether ximelagatran is non-inferior
to warfarin is to understand the efficacy of warfarin over placebo.
Table
VI below summarizes a total of 6 randomized controlled
trials of warfarin in patients with chronic, non-rheumatic atrial
fibrillation. The 6 studies (or portions
of them) listed in the table were used to derive the benefit of warfarin
relative to placebo. Please refer to Dr.
John Lawrence’s Statistical Review for further details regarding the benefit of
warfarin over placebo to use in the non-inferiority analysis.
Similarities and
differences in terms of study design
In terms of study design, 2 of the listed studies were
blinded while 4 were unblind. One of the
SPORTIF trials was blinded while the other was not. Also in terms of design, the studies differed
significantly from each other and from the SPORTIF studies with respect to the
target INR (e.g. BAATAF Target INR 1.5 – 2.7, AFASAK Target INR 2.8 –
4.2). In the SPORTIF studies the target
INR was 2 – 3.
Lack of blinding may be less problematic for “hard”
endpoints such as death or severely disabling stroke. However, lack of blinding may be more
problematic when evaluating “softer” endpoints such as TIA’s.
Similarities and differences
with respect to patient demographics
Patients in the 6 listed warfarin studies were similar in
age and gender to those patients in the SPORTIF studies. However, in 5/6 listed studies, fewer
patients had a prior history of stroke/TIA compared to the SPORTIF
studies. In addition, there were fewer
patients with a history of hypertension in the 6 warfarin studies compared to
the SPORTIF studies.
Similarities and
differences with respect to endpoints
The definitions of stroke varied in some of the studies. For example in the Veterans Affairs Stroke
Prevention study (5th study in Table
VI), stroke was defined as a new neurologic deficit that
persisted for longer than 12 hours. Most
other studies used a new neurologic deficit lasting > 24 hours to
define stroke. The AFASAK study (1st
study in Table VI) defined a “minor stroke” as a focal neurologic
deficit lasting more than 24 hours but less than one week. Most of the other studies did not define such
a subgroup of patients. Also in terms of
differences in endpoints, the EAFT study included death from vascular disease
and non-fatal MI in its primary endpoint and thus the overall event rate was
significantly higher in that study compared to either of the SPORTIF
studies.
It is important to note that in many of the studies listed
in Table VI, intracranial bleed/hemorrhage was not included as
part of the primary efficacy endpoint but was rather a secondary endpoint or
assessed as a safety endpoint. On the
other hand, in the two SPORTIF studies, the primary endpoint included all
strokes both ischemic and hemorrhagic.
In addition, the two SPORTIF studies did not include TIA’s as part of
their primary endpoint unlike what was done in the AFASAK study. Hemorrhagic strokes or TIA’s did not occur in
large numbers in any of the studies listed in Table
VI.
In summary, it seems acceptable to use the studies listed
in Table VI to define the benefit of warfarin relative to placebo
despite differences in study design, endpoints, target INR’s, and patient
population. Based on the 6 studies in
this table, the benefit of warfarin over placebo appears to be a rather large
64% (95% CI à 47%, 75%) relative risk reduction. The studies listed in Table VI clearly suggest that warfarin is an effective oral
anti-coagulant in terms of preventing the composite endpoint of stroke and
systemic embolic events.
I spent the majority of time
reviewing the two pivotal SPORTIF trials submitted in support of the chronic
use of ximelagatran in patients with atrial fibrillation. Relatively less time was spent in reviewing
SPORTIF II/IV, as this was a smaller, non-pivotal, dose ranging study. Each of the SPORTIF trials was reviewed
separately. The efficacy and safety data
from the 2 SPORTIF studies were not pooled as one was a blinded study while the
other was not. In addition, the results
particularly with respect to efficacy were different in the two studies.
With respect to safety, I spent
relatively more time reviewing hepatobiliary adverse events. Case narratives of all hepatobiliary serious
adverse events and discontinuations due to hepatobiliary AE’s in both SPORTIF
trials were read in detail by the reviewer.
Line listings of the causes of death from both studies were reviewed and
narratives from selected cases of death were read in depth.
The materials used in this review
include the electronic NDA submissions, Sponsor’s responses to Information
requests, Literature references, and Sponsor’s 4 month safety update.
I evaluated the case narratives
for selected AE’s and cross checked the statements in the narratives with Case
Report Forms (CRF) for consistency. It
is important to note that in at least one instance the case narrative referred
to abnormal or elevated liver enzyme values but no such documentation was
reported in the CRF. The reason was that
only liver enzymes obtained at pre-specified time points and measured by the
Central Lab were recorded in the CRF.
Local lab tests of liver enzymes were not recorded in the study database
regardless of whether they were abnormal or not.
One study site in SPORTIF V was
evaluated by the Division of Scientific Investigation (DSI) where the source
documents were reviewed and compared to the case report forms. In addition, DSI reviewed inclusion and
exclusion criteria, protocol deviations, and also adverse event reporting. One study site in the SPORTIF III study is
also to be inspected by DSI.
The sponsor’s analysis of the primary endpoint in SPORTIF V
was re-analyzed and confirmed by the statistical reviewer Dr. John
Lawrence. The primary endpoint in SPORTIF
III was not re-analyzed and confirmed by Dr. Lawrence.
The studies conducted were
performed in accordance with the ethical principles that have their origin in
the Declaration of Helsinki and that are consistent with Good Clinical
Practice.
The sponsor submitted FDA Form 3454 for each of the two pivotal studies,
SPORTIF III and SPORTIF V. In Form 3454,
the sponsor attested that they had not entered into any financial arrangements
with investigators whereby the value of compensation to the investigator could
be affected by the outcome of the study.
The sponsor also certified that each investigator/sub-investigator in
the study was required to disclose to the sponsor whether the investigator had
a proprietary interest in the product or a significant equity interest in the
sponsor. Finally the sponsor also
certified that no investigator was the recipient of significant payments of
other sorts.
The sponsor received financial disclosure forms in the vast majority of
investigators/sub-investigators. There
were 4 sub-investigators that participated in SPORTIF III that did not complete
financial disclosure forms. These 4
sub-investigators had moved from their respective facilities and no forwarding
addresses were available. These 4 sites
enrolled 39 (1.1%) of the 3410 patients randomized. There were 5 investigators
that did not complete financial disclosure forms despite attempts to contact
them by the sponsor. These 5
investigators enrolled a total of 64 (1.9%) of the 3410 patients
randomized.
Two investigators in SPORTIF III, disclosed that they held “significant
equity interest” as defined by 21CFR54.2.
The first of these investigators was Dr. Bertil Olsson, who was co-chair
of the Executive Steering Committee and Principal investigator at center
312. Center 312 randomized 33
patients. The second investigator was
Dr. Jan Hysing, a sub-investigator at site 253.
This center randomized 15 patients.
I do not believe the financial disclosure issues discussed above
significantly impacted the study outcomes as the number of patients enrolled at
each center was a small fraction of the total number of subjects
randomized.
SPORTIF III and SPORTIF V are two Phase III, active control,
non-inferiority studies that were provided in support of NDA21-686. Both studies compared the effectiveness of a
fixed dose of ximelagatran 36 mg administered twice a day to warfarin targeting
an INR of 2 to 3 in patients with nonvalvular atrial fibrillation and at least
one additional risk factor for stroke.
The studies were very similar in design except that SPORTIF III was open
label while SPORTIF V was double-blind.
The primary endpoint was the composite of all strokes (fatal and
non-fatal) and systemic embolic events.
The sponsor pre-specified a non-inferiority margin of 2% points in the
event rate in both studies. A margin of
that size could leave open the possibility that ximelagatran is only half as
effective as warfarin and still be considered “non-inferior.”
The two studies produced divergent results despite their similar
designs. In SPORTIF V, the event rate
was higher in the ximelagatran arm compared to the warfarin arm while in
SPORTIF III, the event rate was higher in the warfarin arm compared to the
ximelagatran arm. In both studies, the
efficacy of ximelagatran was within the sponsor’s pre-specified non-inferiority
margin of 2%. Comparing the event rates
in the common arm of both studies, the rate in the ximelagatran arm was
approximately the same at 1.6%/year.
However, the event rate in the warfarin arm varied nearly 2-fold between
the studies: 1.2% in SPORTIF V and 2.3%
in SPORTIF III. Differences in the
patient populations in the two studies at baseline could be a possible
explanation of the differences in the event rate in the treatment arms. Patients in SPORTIF V were slightly older,
had lower blood pressures on average, had fewer patients with histories of
transient ischemic attacks (TIA’s) or strokes, and had greater consumption of
HMG CoA reductase inhibitors than did patients enrolled in SPORTIF III. However, it is difficult to explain why such
differences would lead to differences in event rates in the warfarin arm while
leaving the event rate in the ximelagatran arm unaffected. In a setting where two studies produce
divergent results, I would favor the results from the double-blind study. The event rate in both studies was primarily
driven by the occurrence of ischemic strokes.
More than 80% of the events in both studies were ischemic strokes.
SPORTIF III and SPORTIF V were the two studies submitted
in support of efficacy. Each of these
studies was reviewed separately as the former was unblinded while the latter
was a blinded study.
Study
Title: “Efficacy and Safety of the Oral Direct Thrombin Inhibitor H376/95
Compared with Dose-Adjusted Warfarin (Coumadin) in the Prevention of Stroke and
Systemic Embolic Events in Patients with Atrial Fibrillation”
a.
Study dates
Date first
patient enrolled: July 24, 2000
Date
enrollment ended: December 7, 2001
Date study
closure procedures began: January 13,
2003
Date final
patient completed study: June 19, 2003
Date of
Clinical Study Report: October 9, 2003
b.
Protocol amendments:
Table VII below summarizes the date at which the original
protocol was issued along with the dates of all subsequent amendments to the
original protocol. Below Table VII are listed the summaries of each protocol
amendment.
Table
VII: Summary of the issue dates of the original
protocol and protocol amendments to Study 0005
|
Version
of Protocol or Protocol Amendment
|
Date
of issue
|
|
Original
Protocol
|
May 19, 2000
|
|
Approval
amendment 1
|
July 18, 2000
|
|
Approval
amendment 2
|
July 11, 2001
|
|
Approval
amendment 3
|
October 31, 2001
|
|
Approval
amendment 4
|
August 8, 2002
|
|
Approval
amendment 5
|
November 7, 2002
|
Amendment
1:
·
Additional pregnancy testing was to be done at 3
month intervals
·
Occult bleeding determined by the laboratory
would not be classified as a minor bleed
·
Recommendations for managing patients that may
experience ALT elevations were broadened to include all liver enzymes (e.g.
ALAT, ASAT, alkaline phosphatase, and bilirubin). In addition, treatment discontinuation would
be considered if there is a rapid increase in liver enzymes to > 5x
ULN.
·
A melagatran PK sample was to be obtained from
patients with persistent LFT elevations.
·
The study was to remain open until the sponsor
collected a minimum of 2000 patient-years of exposure data per treatment arm.
Amendment 2:
·
A sub study to measure pancreas volumes and
plasma CCK concentrations was added
·
Definitions of lone atrial fibrillation and
prosthetic heart valves were clarified
·
Clarifies the exclusion of a patient with known
intracardiac thrombus
·
Clarifies that the intent to treat population
(ITT) includes all randomized patients regardless of whether the study
medication had been taken.
·
Clarifies the data to record once a patient had
discontinued study medication. Once a
patient prematurely discontinued the study the adverse events (AE’s) that were
to be recorded included the primary events of stroke and systemic embolic
events in addition to death. After
premature study drug discontinuation, patients were contacted via phone on a
monthly basis to ascertain these events.
It was not necessary to record other AE’s.
·
The timing of the study medication on the day of
a point of care INR determination was clarified
·
The limit on the period of study drug interruption
was clarified. There were 30 consecutive
days (60 days for cardioversion) during which a patient was allowed to
temporarily discontinue study drug.
During the course of the entire study, a patient could be temporarily
off study drug for a total of 60 non-consecutive days.
·
The concomitant medications to be recorded in
the 14 day period following a serious adverse event was clarified
Amendment
3
·
The total number of patients randomized and the
total number of sites was increased. The
Data Safety Monitoring Board (DSMB) noted that the aggregate primary event rate
was substantially below what was anticipated.
Based on this information from the DSMB, the Executive Steering
Committee (ESC) recommended increasing exposure to 5000 patient-years via
increasing both duration of patient exposure and through an increase in the
total number of subjects enrolled in the trial.
·
The time period for enrollment was increased
·
Instructions were revised for management of
patients with elevated liver enzymes.
Patients with LFT’s > 2x ULN would undergo weekly LFT testing until
the affected entity returns to below the ULN or the baseline measurement. Patients with an LFT elevation > 3x ULN
will have a blood sample drawn for extensive liver function testing. If the affected entity did not demonstrate a
tendency to decrease or an alternative reason for the elevation was found,
patients were to be withdrawn from study drug.
Patients with an LFT > 5x ULN were to be withdrawn from study
drug.
Amendment
4
·
A new plan for the transition from study
medication to open label warfarin at the termination visit was implemented to
provide additional protection against too little anticoagulation.
·
The amendment provided clarity regarding the
frequency of measurement of full safety laboratory values and INR’s.
·
There was also clarification as to when to
obtain blinded and unblinded INR’s during interruptions of study
medication.
Amendment
5
The treatment period of “active”
patients and the follow-up period of “inactive” patients (those prematurely
discontinued) were increased to a maximum of 36 months. Consequently additional office visits and
procedures were added.
c.
Study Design:
SPORTIF V
was a multi-centered, randomized, double-blind, double-dummy, active controlled
(warfarin), parallel group study in patients with chronic, non-valvular atrial
fibrillation (AF). This study was
conducted primarily in the United States
and Canada.
The study
randomized a total of 3922 patients. The
treatment period ranged between 12 to 36 months. As shown in Figure
6 below, patients were randomized to either fixed doses
of Ximelagatran 36 mg bid or to Warfarin titrated to an INR of 2 to 3 via
monthly blood tests.
Figure 6: Study Schema for SPORTIF V (Figure taken
from Figure 1 of SPORTIF V CSR)
Patients
that prematurely discontinued study medication (e.g. to bleeding or
hepatobiliary AE) were not withdrawn from the trial but were followed up via
monthly telephone contacts until the end of the study with regard to primary
events (e.g. strokes and SEE’s) and death.
Patients that discontinued from study medication and withdrew from study
were not followed for primary efficacy endpoints or death.
Patients
were stratified based on aspirin use and a previous history of stroke/TIA.
The
primary analysis consisted of events adjudicated by the CEAC. Events that were “suspected” by the study
site investigator were eligible for adjudication. If an event was not “suspected” it would not
have been forwarded to the CEAC for adjudication.
If an
investigator suspected an event, an initial fax describing the event was to be
sent to the CEAC committee within 24 hours of the knowledge of the event. The initial fax was followed up with more
complete forms within 14 days of knowledge of the event. Data that were to be submitted to the CEAC
for purposes of adjudication could have included documentation of the patient’s
history and physical exam, discharge summary, neurology consultation, CT scans,
Angiograms, X-rays, ECG’s, or appropriate enzyme levels.
The CEAC
was to work in accordance with the principles described in a written
charter. Pairs of primary reviewers were
to independently assess each event and if in agreement, this adjudication would
be accepted. In cases of disagreement, a
second, final review would be performed by a third independent reviewer.
The trial
included a Data Safety Monitoring Board (DSMB), Clinical Events Adjudication
Committee (CEAC), and an Executive Steering Committee (ESC).
The DSMB
was composed of the following members:
·
Prof. Robert Hart (Chairman), Department of
Medicine (Neurology), University of Texas
Health Science Centre, USA.
·
Prof. David DeMets, Department of Biostatistics,
University of Wisconsin Medical School, USA.
·
Prof. Gudrun Boysen, Bispebjerg
Hospital, Neurologisk
Afd, Denmark.
·
Prof. Desmond Julian, London,
UK.
The CEAC
was composed of the following members listed below. All were based at University
Hospital in Dresden,
Germany.
·
Prof. Rüdiger von Kummer (Chairman) Department
of Neuroradiology
·
Dr. Angela Müller, Department of Neuroradiology
·
Dr. Dirk Mucha, Department of Neuroradiology
·
Prof. Heinz Reichmann, Department of Neurology
·
Dr. Georg Gahn, Department of Neurology
·
Dr. Thomas Schwarz, Department of Internal
Medicine
·
Dr. Alexander Schmeisser, Department of
Cardiology
·
Olaf Wunderlich (Administrator)
The
Executive steering committee members included:
·
Jonathan Halperin, MD (Co-chairman), Mount
Sinai Medical Center, New York, USA
·
Bertil Olsson, MD
PhD (Co-chairman) University Hospital,
Lund, Sweden
·
Gregory Albers, MD,Stanford
Stroke Center,
Palo Alto, USA
·
Hans Christoph Diener, MD, PhD, University
of Essen, Germany
·
Palle Petersen, MD, PhD, University Hospital of
Copenhagen, Hvidovre Hospital, Hvidovre, Denmark
·
Alec Vahanian, MD Hospital Tenon, Paris,
France
·
Margaretha Grind,
MD, PhD, AstraZeneca R&D Charnwood, UK
·
Lars Frison, PhD, AstraZeneca R&D Molndal, Sweden
·
Stephen Partridge, PhD, AstraZeneca R&D
Charnwood, UK
·
Mark Nevinson, BPharm (Secretary) AstraZeneca
R&D Charnwood, UK
·
Jay Horrow, MD, AstraZeneca LP, Wilmington,
DE, USA
d.
Rationale for doses selected
Rationale
for warfarin dose:
Warfarin
is the most widely used oral anticoagulant worldwide. Treatment guidelines recommend the use of
long-term oral anticoagulant therapy, aiming for an INR of 2 – 3, for all
patients who are at high risk of stroke.
Over anticoagulation increases the risk of bleeding events while under
anticoagulation increases the risk of ischemic stroke. Warfarin has proven to be highly effective at
preventing strokes and SEE in previous placebo controlled clinical trials.
Please
refer to Section VI D “Literature Review” for further details regarding placebo
controlled studies involving warfarin.
Rationale
for ximelagtran dose:
The
sponsor took into consideration an array of data in selecting the fixed dose of
36 mg bid used in both SPORTIF studies.
These include:
·
A phase 2 study (SPORTIF II), suggested that
there were fewer minor bleeding events in the 20 and 40 mg bid dose groups
relative to a 60 mg bid dose group. In
addition, there was some concern about possible dose related increase in liver
enzyme abnormalities based on SPORTIF II.
·
A phase 2 study conducted in patients for the
prevention of venous thromboembolism showed enhanced efficacy of doses of 24 mg
bid versus doses of 12 mg bid.
·
Pre-clinical thrombosis models showing that
acceptable antithrombotic effect was achieved at plasma concentrations of 0.05
to 0.5 mmol/L.
·
Capillary bleeding time study showed that mean
plasma levels of 0.31 mmol/L caused a small, non-significant prolongation of
bleeding time.
e.
Blinding/Randomization
A double-dummy technique was used to preserve blinding
during this trial. Real INR values and
warfarin doses were entered into a centralized interactive voice response
system (IVRS) that would issue a standardized report containing a real INR
value if the patient was randomized to warfarin or a sham value if the patient
was randomized to ximelagatran (H736/95).
At the End of Treatment visit, a plan was implemented by
the sponsor that retained study blinding while transitioning patients from
ximelagatran to warfarin. This was
necessary for patients in the ximelagatran arm because of the risk of reduced
anti-coagulation due to the quick offset of ximelagatran and the slow onset of
open-label warfarin (details of this plan are in the sponosor’s clinical study
report).
A centralized and automated IVRS was used to manage the
randomization process, allowing for stratification factors, and to aid the
efficient distribution of study drugs.
f.
Pre-specified Study Objectives
Primary objective:
To determine whether H376/95 is non-inferior compared to
dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the prevention of all
strokes (fatal and non-fatal) and systemic embolic events in patients with
chronic non-valular AF.
Secondary objectives:
·
To compare the efficacy of H376/95 to that of
dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the combined endpoint of
prevention of death, non-fatal strokes, non-fatal systemic embolic events and
non-fatal acute myocardial infarction (AMI).
·
To compare the efficacy of H376/95 to that of
dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the combined endpoint of
prevention of ischemic strokes, TIA’s, and systemic embolic events
·
To assess the safety of H376/95 compared to
dose-adjusted warfarin aiming for INR 2.0 – 3.0 with an emphasis on major and
minor bleeding events and any treatment discontinuations
Tertiary objectives
·
To compare the efficacy of H376/95 and
dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the prevention of all
strokes with a poor outcome (defined by a Modified Rankin score of > 3 at 3
months post-stroke or a Barthel score of < 60 at 3 months post-stroke).
·
To compare the efficacy of H376/95 and
dose-adjusted warfarin aiming for an INR 2.0 – 3.0 for the prevention of all
strokes and systemic embolic events in patients > 75 years of age
with AF and to compare this with patients below the age of 75 years.
It is important to note that patients that prematurely
discontinued study medication but agreed to remain in the study were followed
up for primary events (e.g. strokes and SEE’s) and death via regular telephone
contact.
g.
Definitions of study endpoints
Definition of stroke and TIA:
Stroke was defined as the abrupt onset over minutes to
hours of a focal neurological deficit persisting for more than 24 h and caused
by altered cerebral circulation in the distribution of a cervical or cerebral
artery. If the focal neurological deficit lasted for less than 24 h, the event
was classified as a TIA. Patients that died within 30 days of the onset of the
stroke were regarded as having had a fatal stroke. Patients who had a stroke
and then died 30 or more days after the onset of the stroke were regarded as
having non-stroke death.
Definition of stroke with poor outcome:
A stroke
was defined as having a poor outcome if it met 1 or more of the following
criteria:
• An increased (relative to baseline) Modified Rankin score to ≥3
at 3 months post stroke
• A Barthel score of <60 at 3 months post-stroke
• A fatal stroke. This component was not specified in the protocol, but
added in the
statistical analysis plan (SAP) before unblinding of study data;
Definition of Systemic embolic events
(SEE’s):
SEE was
defined as abrupt vascular insufficiency associated with clinical or radiologic
evidence of arterial occlusion in the absence of other likely mechanisms, eg,
atherosclerosis instrumentation. In the presence of atherosclerotic peripheral
vascular disease, diagnosis of embolism to the lower extremities should be made
with caution and requires arteriographic demonstration of abrupt arterial
occlusion.
Definition of acute myocardial infarction:
AMI was
defined as the presence of at least 2 of the following:
·
Typical retrosternal chest pain indicating AMI
for at least 20 minutes
·
Electrocardiogram showing changes typical of AMI
·
Elevation of the cardiac enzyme creatine
phosphokinase, myocardial band (CK-MB) or troponin to more than twice ULN.
The
occurrence of AMI was documented only in patients that were on study drug at
the time
of the
event.
Definition of Major Bleed:
Major
bleed was defined as one or more of the following:
• Fatal bleeding
• Clinically overt bleeding associated with a fall in hemoglobin of 20
g/L (2 g/dL) or
more
• Clinically overt bleeding leading to transfusion of 2 or more units of
whole blood or
erythrocytes
• Bleeding in areas of special concern, such as intracranial,
intraspinal, intraocular,
retroperitoneal, pericardial or atraumatic intra-articular bleeding.
Subdural
and epidural bleeds, but not intracerebral bleeds were treated as major bleeds.
Intracerebral
bleeding events were handled in the same way as stroke and were not
documented
on the “Major Bleed” Form. Major bleeds
were reported only for active patients at
the time
of the event.
Definition of Minor
Bleed:
Any bleeding event other than a major bleed was considered
a minor bleed. Bleeding events initially
characterized by the investigator as a major bleed but subsequently rejected by
CEAC, as such, were considered minor bleeds.
h.
Inclusion/Exclusion Criteria
Inclusion Criteria
1. Chronic
non-valvular AF (constant or paroxysmal) verified by at least 2 ECG readings in
the last year separated by at least one week; the second ECG being carried out
within the 2 weeks prior to randomization.
Historical evidence of the first ECG showing AF (i.e. tracing available
in patient notes) is required. In
addition one of the items under 2 must be present.
2. At least one of
the following risk factors for stroke:
·
Hypertension requiring anti-hypertensive
treatment, and which is below 180/100 mmHg on randomization
·
Age ≥75 years
·
Previous cerebral ischemic attack (stroke or
TIA)
·
Previous systemic embolism
·
Left ventricular dysfunction (either LVEF
<40% or symptomatic CHF)
·
Age ≥65 years AND coronary artery disease
·
Age ≥65 years AND diabetes mellitus.
3. Aged 18 years or older.
4. Willing and able to give signed informed consent.
Exclusion Criteria
1. Stroke within the previous 30 days or TIA within the
previous 3 days.
2. The following conditions associated with increased risk
of bleeding:
·
History of intracranial, intraocular, spinal,
retroperitoneal or atraumatic intra-articular bleed
·
Overt gastrointestinal bleed in the previous
year
·
Endoscopically verified ulcer disease in the
previous 30 days
·
Major surgical procedure or trauma in the
previous 30 days
·
Persistent blood pressure ≥180/100 mmHg
(with or without antihypertensive therapy)
·
Hemorrhagic disorder.
3. Lone AF (atrial fibrillation in the absence of overt
cardiovascular disease or precipitating illness).
4. Transient AF caused by reversible disorders, e.g.
current thyrotoxicosis, pulmonary embolism.
5. Rheumatic valve disease, a prosthetic heart valve or
valve surgery.
6. Active endocarditis.
7. Diagnosis of current atrial myxoma or left ventricular
thrombus.
8. Hospitalization for acute coronary syndromes or percutaneous
coronary artery intervention within the last 30 days.
9. Planned cardioversion (electrical or chemical).
10. Concomitant treatment with antiplatelet or
fibrinolytic agents (or use of these within 10 and 30 days, respectively,
before randomization); other anticoagulant agents or continuous treatment with
NSAID drugs. However, aspirin ≤100
mg/day is allowed during the whole study period.
11. Requirement for chronic anticoagulant treatment other
than for atrial fibrillation
(eg repeated deep vein thrombosis, hereditary
thrombophilia).
12. Renal impairment defined as a calculated creatinine
clearance <30 mL/min
13. Active liver disease or persistent elevation of liver
enzymes > 2 times the upper limit of the normal level defined by
central laboratories.
14. Anemia (Hb <100 g*L-1) or a platelet
count <100 x 109 L-1.
15. Childbearing potential (female patients should be at
least 2 years post-menopausal, surgically sterile or using medically accepted
contraceptive measures as judged by the investigator).
16. Pregnancy or lactation (see Section 10.2).
17. Drug addiction and/or alcohol abuse in the past 3
years.
18. Participation in any clinical study involving an
investigational drug within one month prior to randomization; previous
randomization in this study or any other 376/95 study.
19. Other diseases that give an estimated life survival
less than 36 months as judged by the treating physician.
20. Inability to complete the study according to the
protocol, eg inability to comply with the monitoring required for therapy
control, significant mental impairment or geographic inaccessibility to a
laboratory.
21. Previous significant disabling stroke (defined as
Modified Rankin score ≥3).
22. Planned major surgery.
23. Allergy or intolerance to warfarin.
i.
Statistical considerations (please refer to statistical
review for details)
Major changes to
planned analyses:
Please refer to the statistical review by Dr. John Lawrence
for further details regarding amendments to the statistical analysis plan.
The major
changes to the planned analyses that were implemented prior to unblinding the
database were:
·
The methodology for the analysis of the primary
endpoint was changed to a patient-years calculation assuming an exponentially
distributed event rate.
·
The definition of the ITT population was
modified to include all randomized patients.
The original protocol and SAP stated that patients needed two baseline
ECG’s demonstrating atrial fibrillation to be eligible for study entry.
The major changes to the planned analyses that were
implemented after the database was unblinded were:
·
AE’s were counted in all periods where they
occurred instead of only in the period when they started.
·
The analyses of the tertiary objectives and
liver function tests were performed for the ITT population instead of the OT
analysis set.
Analysis of primary
endpoint:
The primary objective of the study was to be addressed with
an intention to treat (ITT) approach. In
this approach, all randomized patients were included until the date of each
patient’s study closure visit or final contact, irrespective of their protocol
adherence. The primary objective was to
be addressed with a life table analysis.
Primary events (e.g. all strokes or SEE’s, and death) were reported for
all patients in the trial including patients who had already suffered a study
endpoint. For example, if a patient
suffered an MI as a study endpoint (and assuming he/she did not withdraw
consent), this patient would continued to be followed for the occurrence of
death or a primary endpoint event such as stroke or SEE. For patients with multiple occurrences of
events the time to first event was used.
Each patient was counted once in any composite endpoint that included at
least one of the events that the patient had experienced. In this non-inferiority trial, the margin of
non-inferiority chosen was 2% points in the annual event rate of stroke and
SEE.
As part of a sensitivity analysis, the primary objective
was also analyzed using the On Treatment (OT) approach. This was done to examine the robustness of
the primary analysis using the ITT approach.
While the ITT approach is a conservative approach particularly when
dealing with superiority study designs, the OT approach may be a more
appropriate when trying to interpret the results of a non-inferiority
study. The OT approach included all
patients in the ITT population but only their time on active study drug was
used for analysis. A maximum continuous
interruption of up to 30 days without active study drug was allowed. For patients undergoing cardioversion, a
maximum 60 continuous days of study drug interruption was allowed. A maximum of 60 accumulated days of
interruption was also permitted.
Analyses of the secondary and tertiary
endpoints:
Analyses
related to the secondary and tertiary objectives, as well as descriptive and
exploratory analyses were to be based on an On Treatment approach according to
the statistical analysis plan. In this
approach, all patients in the ITT population would be included as long as they
remained on study medication. A maximum
continuous interruption of up to 30 days without active study drug was
allowed. For patients undergoing
cardioversion, a maximum 60 continuous days of study drug interruption was
allowed. Any patient with a study drug
interruption (H376/95 or warfarin) of more than 60 days would not be included
in the On Treatment analysis.
It is
important to note that in the clinical study report the sponsor analyzed the
tertiary endpoint using the ITT population, a change from what was proposed in
the statistical analysis plan. This
change was implemented after the database was unblinded.
Analysis of adverse events(AE’s):
AE’s were
actively collected up to the End of Treatment Visit. AE’s that started in 1
time period and continued into a subsequent time period(s) were counted once in
each period. This was a difference from the SAP where AE’s were to be counted
only in the period of onset. If an ongoing AE worsened in a subsequent period,
it was reported as a new AE at the time of worsening and was then counted
twice; at the time of initial onset and at the time of worsening onset.
All
analyses of liver function tests were performed using the ITT analysis, which
utilized the full time pattern for liver function elevations. This is a change
from the SAP, which had specified the OT analysis.
Other analysis considerations:
No
Analyses based on a per protocol approach were performed.
The
sponsor was to make every effort to trace all patients until the very end of
the study and to record their status with regard to occurrence of stroke,
systemic embolism and mortality.
Determination of Sample Size:
It was
estimated that the combined rate of ischemic stroke, hemorrhagic stroke and
systemic embolism for patients in this study protocol would be 3.1% per year
for both treatment groups. In order to
obtain 90% statistical power, adopting a one sided a = 0.025, approximately
1600 patient years of follow-up per treatment group would be necessary to
establish a non-inferiority of H376/95 compared to adjusted-dose warfarin
within 2% per year. Assuming an average
follow-up of 16 months about 2400 patients would be required in total. In the protocol it was stated that if the
aggregate event rate (stroke + SEE) was low, follow-up could be extended to
ensure a minimum of 80 events.
DSMB Interim safety
analysis:
The DSMB was to formally compare the two treatment arms
for safety with respect to:
·
All cause mortality
·
All cause mortality, all strokes, and all
systemic embolic events
·
All strokes and all systemic embolic events
·
Major bleeding
This was to be done when approximately 12.5%, 25%, 50%,
and 75% of the expected total number of patient exposure years have been
reached. Pre-determined stopping rules
for a positive or a negative trend were described in a DSMB charter. No adjustments to the significance levels in
the final statistical analyses of the primary, secondary or tertiary endpoints
were made.
j.
Study patient disposition
A total of 4763 patients were enrolled into the study from which 3922
were randomized. Patients were
randomized from a total of 422 centers in the U.S.
(n = 361) and Canada
(n = 61). A total of 1960 and 1962
patients were randomized to H376/95 and warfarin respectively. These patients formed the ITT
population.
The population used for the analysis of the safety data was equal to 3906
patients (3922 – 16). Of the 16 patients
excluded in the safety population, 15 were randomized but never received study
drug. One patient received a dose of
study drug but no post-randomization data are available.
Please refer to Figure
7 below for a summary of patient disposition in SPORTIF
V.
Figure 7: Patient disposition in SPORTIF V (Figure
taken from Figure 4 of SPORTIF V CSR)
As seen in Figure 7 above, 841 patients were enrolled but not
randomized. Approximately 2/3 of these
patients were not eligible because they failed to meet inclusion/exclusion
criteria. Sixty three percent of
patients remained on ximelagatran at the time of study closure, while 67%
remained on warfarin. A total of 300
patients prematurely withdrew from the ximelagatran arm while 286 did soon the
warfarin arm.
As shown in Figure 7, there were a total of 586 study withdrawals that
were pre-mature in SPORTIF V (300 ximelagatran, 286 warfarin). It is important to note that these patients
were not followed up for primary endpoint events (e.g. stroke or SEE) or
death. Although not shown in this
review, the reasons for pre-mature withdrawal were similar in both study
arms.
Unlike patients that pre-maturely withdrew from the study, patients that
discontinued study drug were followed up for primary endpoint events or
death. As shown in Figure 7 above, there were 424 study drug discontinuations in
the ximelagatran arm and 362 study drug discontinuations in the warfarin
arm.
As shown in Table VIII below, the total number of study drug
discontinuations was greater on ximelagatran compared to warfarin by an
absolute value of 3.7%. A large portion of this excess
discontinuation on ximelagatran could be attributed to adverse events
specifically liver enzyme abnormalities.
Table
VIII: Table summarizing the primary reason for
discontinuing study drug (ITT population)a
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
Reason for study drug
discontinuation
|
N=1960
|
N=1962
|
N=3922
|
|
Total
|
720
|
(36.7%)
|
646
|
(33.0%)
|
1366
|
(34.8%)
|
|
Eligibility
criteria not fulfilled
|
15
|
(0.8%)
|
8
|
(0.4%)
|
23
|
(0.6%)
|
|
Adverse
event
|
238
|
(12.1%)
|
175
|
(8.9%)
|
413
|
(10.5%)
|
|
Patient
decision (Consent withdrawn from study drug)
|
207
|
(10.6%)
|
197
|
(10.0%)
|
404
|
(10.3%)
|
|
Endpoint
events
|
|
|
|
|
|
|
|
Acute myocardial infarction
|
10
|
(0.5%)
|
12
|
(0.6%)
|
22
|
(0.6%)
|
|
Major bleed
|
30
|
(1.5%)
|
41
|
(2.1%)
|
71
|
(1.8%)
|
|
Stroke
|
24
|
(1.2%)
|
24
|
(1.2%)
|
48
|
(1.2%)
|
|
Systemic embolic event
|
6
|
(0.3%)
|
5
|
(0.3%)
|
11
|
(0.3%)
|
|
Transient ischemic attack
|
16
|
(0.8%)
|
8
|
(0.4%)
|
24
|
(0.6%)
|
|
Death
|
44
|
(2.2%)
|
47
|
(2.4%)
|
91
|
(2.3%)
|
|
Other
|
130
|
(6.6%)
|
129
|
(6.6%)
|
259
|
(6.6%)
|
aThe data in this table
obtained from table 18 of SPORTIF V CSR
As shown in Table
IX below, even after excluding patients with ALAT >
3x ULN, the total study drug discontinuation rate was numerically higher on
ximelagatran compared to warfarin.
Table IX: Comparison of total study drug
discontinuation rates including and excluding patients with ALAT > 3x ULNa
|
|
Ximelagatran
|
Warfarin
|
Totals
|
|
Total discontinuation rate
(including patients with ALAT > 3x ULN)
|
720/1960 (36.7%)
|
646/1962 (33.0%)
|
1366 (34.8%)
|
|
Total discontinuation rate
(excluding patients with ALAT > 3x ULN)
|
640/1843 (34.7%)
|
635/1947 (32.6%)
|
1275 (33.6%)
|
aData in this table obtained
from Tables 18 and 19 of SPORTIF V CSR
After
study closure activities, vital status and primary event status were unknown
for a total of 226 subjects: 119 Ximelagatran, 107 warfarin. Efforts were made to contact these subjects
and information related to the primary event or death was obtained on 203/226
subjects. In 188 of the 203 patients in
whom follow-up information was available, the information was obtained prior to
unblinding the database. In 15 of the
203 patient in whom follow-up information was available, the information was
obtained after unblinding the database.
Information on these 203 patients was not entered into the
database. In these 203 patients,
follow-up information revealed that there was one stroke in a patient that
received warfarin. There were a total of
15 deaths (8 ximelagatran, 7 warfarin).
A total of 23 patients (226 – 203) were lost to follow-up and for whom
there is no primary event or vital status information.
k.
Protocol deviations
In the
clinical study report for SPORTIF V the sponsor summarizes 4 different classes
of protocol deviations that occurred: Enrollment deviations, Study drug
administration deviations, Deviations relating to interruption of study drug,
Unblinding deviations. Each of these is
summarized below.
Enrollment deviations (violations of
inclusion/exclusion criteria):
For Table X below, please refer to Section VII, C, 1, h
(“Inclusion/Exclusion Criteria”) for reference to each criteria #.
Table X: Summary of inclusion/exclusion criteria
violations by treatment groups (Please refer to inclusion/exclusion criteria
section of this review to match the number with the description of the
criteria)a
|
|
Ximelagatran (n = 1960)
|
Warfarin (n = 1962)
|
Total (n = 3922)
|
|
Criteria #
|
Inclusion Criteria violations
|
|
1
|
27
|
18
|
45
|
|
2
|
3
|
1
|
4
|
|
Criteria #
|
Exclusion Criteria violations
|
|
1
|
0
|
1
|
1
|
|
2 (bullet 1)
|
0
|
3
|
2
|
|
2 (bullet 2)
|
2
|
2
|
4
|
|
2 (bullet 5)
|
0
|
1
|
1
|
|
3
|
1
|
0
|
1
|
|
5
|
2
|
2
|
4
|
|
8
|
1
|
0
|
1
|
|
9
|
1
|
0
|
1
|
|
10
|
2
|
0
|
2
|
|
12
|
5
|
2
|
7
|
|
13
|
4
|
1
|
5
|
|
14
|
3
|
4
|
7
|
|
17
|
0
|
4
|
4
|
|
21
|
1
|
1
|
2
|
aData in this table obtained
from Table 11.1.20 of SPORTIF V NDA submission
Study drug administration deviations:
The sponsor reported a drug shipment error in which a study drug
(Coumadin 2.5 mg YY series) from a different AstraZeneca study bearing similar
bottle numbers had been shipped to numerous sites. SPORTIF V and THRIVE V shared common bottle
numbers and bottle appearances. Five
patients were affected by this shipping error.
Drug dispensing errors resulted in
13 patients receiving a total of 14 bottles of the incorrect active
medication. In 11 instances (8
ximelagatran, 3 warfarin), patients took both active medications together for
various durations. In 2 instances,
patients returned the incorrect bottles.
No endpoints occurred during the time of dispensing error. Endpoints occurred for 3 of the 13 patients 6
months or more after the administration error and are unlikely to be related to
the error.
Deviations relating to interruption of
study drug:
A greater
number of warfarin patients (61.6%) interrupted study drug for any duration
compared with ximelagatran patients (41.7%) as shown in Table XI below. One of
the factors that might be responsible for the discrepancy in treatment
interruption between the two groups is that patients in the warfarin arm with
an INR > 3 would have their treatment interrupted until the INR had returned
to less than 3. It is unclear if this
was the only reason in the discrepancy between the two study arms or if there
are other reasons.
Table XI: Number (%) of patients by total days of
treatment interruption, and treatment groupa
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
Treatment interruption
|
N=1952
|
N=1952
|
N=3904
|
|
No
interruption
|
1138
|
(58.3)
|
749
|
(38.4)
|
1887
|
(48.3)
|
|
Any
interruption
|
814
|
(41.7)
|
1203
|
(61.6)
|
2017
|
(51.7)
|
|
1 to 7 days
|
463
|
(23.7)
|
660
|
(33.8)
|
1123
|
(28.8)
|
|
8 to 30 days
|
274
|
(14.0)
|
431
|
(22.1)
|
705
|
(18.1)
|
|
31 to 60 days
|
63
|
(3.2)
|
83
|
(4.3)
|
146
|
(3.7)
|
|
>60 days
|
14
|
(0.7)
|
29
|
(1.5)
|
43
|
(1.1)
|
aData in this table obtained
from Table 27 of SPORTIF V CSR.
Unblinding deviations:
Three
patients were unblinded during the study.
Two unblindings were intentional and one was unintentional.
Intervals greater than 28 + 3 days
between INR measurements:
As shown
in Table XII below, more than 75% of patients had INR’s measured
at an interval of < 31 days as specified in the protocol.
Table XII: INR measurements for warfarin patients in
SPORTIF V
|
|
Number
(%)
|
|
INR
measurement interval
|
of
INR measurements
|
|
Total number of INR
measurements
|
44108 (100)
|
|
Number of INR’s with
interval <31 days (<1 month)
|
33758 (77)
|
|
Number of INR’s with
interval >31 days (at least 1 month)
|
10350 (23)
|
|
Number of INR’s with
interval > 31 but <61 days
|
10099 (23)
|
|
(between 1 and 2 months)
|
|
|
Number of INR’s with
interval 61 days
|
251 (<1)
|
|
(at least 2 months)
|
|
Data in this table obtained
from Table 6 of 5May2004 FDA Information request
l.
Demographics and other patient characteristics
The
characteristics of the patients enrolled in SPORTIF V are described in the Table XIII below. The
majority of patients were males, Caucasians, and > 65 years old. Approximately 75% had two or more risk
factors for stroke (in addition to non-valvular atrial fibrillation). In general, the baseline characteristics were
similar in the two treatment arms suggesting that randomization in the trial
was successful.
Comparing
the population in SPORTIF V to that in SPORTIF III, there were fewer
non-smokers and more non-drinkers in the former compared to the latter
study. In addition, the number of
patients using aspirin at baseline was greater in SPORTIF V compared to SPORTIF
III.
Table XIII: Patient characteristics at screening:
number (%) of patients by treatment group (ITT population)a
|
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
Characteristic
|
|
N=1960
|
N=1962
|
N=3922
|
|
Sex
|
Male
|
1365
|
(69.9)
|
1353
|
(69.0)
|
2718
|
(69.3)
|
|
|
Female
|
595
|
(30.4)
|
609
|
(31.0)
|
1204
|
(30.7)
|
|
Race
|
Caucasian
|
1875
|
(95.7)
|
1888
|
(96.2)
|
3763
|
(95.9)
|
|
|
Black
|
67
|
(3.4)
|
58
|
(3.0)
|
125
|
(3.2)
|
|
|
Oriental
|
15
|
(0.8)
|
10
|
(0.5)
|
25
|
(0.6)
|
|
|
Other
|
3
|
(0.2)
|
6
|
(0.3)
|
9
|
(0.2)
|
|
Age
|
<65
|
383
|
(19.5)
|
401
|
(20.4)
|
784
|
(20.0)
|
|
|
³65 to <75
|
739
|
(37.7)
|
741
|
(37.8)
|
1480
|
(37.7)
|
|
|
³75
|
838
|
(42.8)
|
820
|
(41.8)
|
1658
|
(42.3)
|
|
Number
of unique
|
0
|
3
|
(0.2)
|
4
|
(0.2)
|
7
|
(0.2)
|
|
stroke
risk factors
|
1
|
490
|
(25.0)
|
509
|
(25.9)
|
999
|
(25.5)
|
|
(In
addition to AF)
|
2
|
600
|
(30.6)
|
597
|
(30.4)
|
1197
|
(30.5)
|
|
|
3
|
472
|
(24.1)
|
459
|
(23.4)
|
931
|
(23.7)
|
|
|
4
|
274
|
(14.0)
|
273
|
(13.9)
|
547
|
(13.9)
|
|
|
5
|
100
|
(5.1)
|
96
|
(4.9)
|
196
|
(5.0)
|
|
|
6
|
20
|
(1.0)
|
21
|
(1.1)
|
41
|
(1.0)
|
|
|
7
|
1
|
(0.0)
|
3
|
(0.2)
|
4
|
(0.1)
|
|
Smoking
|
Non-smoker
|
711
|
(36.3)
|
689
|
(35.1)
|
1400
|
(35.7)
|
|
|
Previous
smoker
|
1085
|
(55.4)
|
1108
|
(56.5)
|
2193
|
(55.9)
|
|
|
Occasional
|
27
|
(1.4)
|
31
|
(1.6)
|
58
|
(1.5)
|
|
|
smoker
|
|
|
|
|
|
|
|
|
Daily
smoker
|
137
|
(7.0)
|
134
|
(6.8)
|
271
|
(6.9)
|
|
Alcohol
use
|
No
|
1151
|
(58.7)
|
1163
|
(59.3)
|
2314
|
(59.0)
|
|
|
Yes
|
808
|
(41.2)
|
799
|
(40.7)
|
1607
|
(41.0)
|
|
|
Missing
|
1
|
(0.1)
|
0
|
(0.0)
|
1
|
(0.0)
|
|
Drinks
per week
|
None
|
1151
|
(58.7)
|
1163
|
(59.3)
|
2314
|
(59.0)
|
|
|
>0
to £5 drinks
|
450
|
(23.0)
|
458
|
(23.3)
|
908
|
(23.2)
|
|
|
>5
to £10 drinks
|
208
|
(10.6)
|
200
|
(10.2)
|
408
|
(10.4)
|
|
|
>10
to £15 drinks
|
103
|
(5.3)
|
102
|
(5.2)
|
205
|
(5.2)
|
|
|
>15
to £20 drinks
|
5
|
(0.3)
|
7
|
(0.4)
|
12
|
(0.3)
|
|
|
>20
drinks
|
39
|
(2.0)
|
30
|
(1.5)
|
69
|
(1.8)
|
|
|
Missing
|
4
|
(0.2)
|
2
|
(0.1)
|
6
|
(0.2)
|
|
Undergone
any
|
No
|
452
|
(23.1)
|
501
|
(25.5)
|
953
|
(24.3)
|
|
major
surgery
|
Yes
|
1506
|
(76.8)
|
1458
|
(74.3)
|
2964
|
(75.6)
|
|
|
Missing
|
2
|
(0.1)
|
3
|
(0.2)
|
5
|
(0.1)
|
|
Current
ASA use
|
No
|
1398
|
(71.3)
|
1393
|
(71.0)
|
2791
|
(71.2)
|
|
|
Yes
|
542
|
(27.7)
|
544
|
(27.7)
|
1086
|
(27.7)
|
|
|
Missing
|
20
|
(1.0)
|
25
|
(1.3)
|
45
|
(1.1)
|
|
Rankin
score
|
0
|
1481
|
(75.6)
|
1479
|
(75.4)
|
2960
|
(75.5)
|
|
|
1
|
310
|
(15.8)
|
311
|
(15.9)
|
621
|
(15.8)
|
|
|
2
|
159
|
(8.1)
|
165
|
(8.4)
|
324
|
(8.3)
|
|
|
3
|
6
|
(0.3)
|
5
|
(0.3)
|
11
|
(0.3)
|
|
|
4
|
2
|
(0.1)
|
0
|
(0.0)
|
2
|
(0.1)
|
|
|
5
|
0
|
(0.0)
|
0
|
(0.0)
|
0
|
(0.0)
|
|
|
Missing
|
2
|
(0.1)
|
2
|
(0.1)
|
4
|
(0.1)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
aData in this table obtained
from Table 29 of SPORTIF V CSR
Patients in the two treatment arms were also comparable
with respect to various demographic factors listed in Table XIV below.
Patients in SPORTIF V were slightly older compared to
patients in SPORTIF III – 71.6 years versus 70.2 years. In addition, the mean blood pressure at
baseline for patients enrolled in SPORTIF V was lower compared to that for
patients in SPORTIF III.
Table
XIV: Mean (+SD) of patient characteristics
at screening (ITT population)a
|
|
Ximelagatran (N = 1960)
|
Warfarin (N = 1962)
|
Total (N = 3922)
|
|
Mean
Age (years)
|
71.6
+ 9.2
|
71.6
+ 9.0
|
71.6
+ 9.1
|
|
Mean
Height (cm)
|
173.0
+ 10.8
|
173.1
+ 10.6
|
173.1
+ 10.7
|
|
Mean
Weight (kg)
|
90.1
+ 21.9
|
89.1
+ 21.3
|
89.6
+ 21.6
|
|
Mean
BMI ((kg/m2)
|
30.0
+ 6.6
|
29.6
+ 6.2
|
29.8
+ 6.4
|
|
Mean
estimated CrCL (mL/min)
|
87.0
+ 40.5
|
86.1
+ 38.3
|
86.6
+ 39.4
|
|
Mean
Sitting SBP (mm Hg)
|
132.6
+ 17.7
|
132.4
+ 17.6
|
132.5
+ 17.7
|
|
Mean
Sitting DBP (mm Hg)
|
77.4
+ 10.5
|
77.2
+ 10.3
|
77.3
+ 10.4
|
aData in this table obtained
from Table 30 of SPORTIF V CSR.
As shown in Table
XV below, hypertension was by far the most prevalent
risk factor in SPORTIF V. Less than 1/5
of the randomized patients had a prior history of stroke or TIA. The distribution of risk factors was similar
between the two treatment arms.
In SPORTIF V, fewer patients had a history of stroke or
TIA compared to patients in SPORTIF III: 18% versus 24%.
Table XV: Number (%) of patients with the presence of
the listed risk factor at study entry.
|
|
Ximelagatran (N = 1960)
|
Warfarin (N = 1962)
|
Total (N = 3922)
|
|
Hypertension
|
1584
(80.8)
|
1582
(80.6)
|
3166
(80.7)
|
|
Age
> 75 years
|
838
(42.8)
|
820
(41.8)
|
1658
(42.3)
|
|
History
of stroke or TIA
|
369
(18.8)
|
348
(17.7)
|
717
(18.3)
|
|
History
of SEE
|
92
(4.7)
|
85
(4.3)
|
177
(4.5)
|
|
Left
ventricular dysfunction
|
735
(37.5)
|
788
(40.2)
|
1523
(38.8)
|
|
Age
> 65 and CAD
|
822
(41.9)
|
803
(40.9)
|
1625
(41.4)
|
|
Age
> 65 and DM
|
389
(19.8)
|
373
(19.0)
|
762
(19.4)
|
Data
in this table obtained from Table 32 of SPORTIF V CSR
As shown in Table
XVI below, the use of study medications at study entry
was similar between the two treatment arms.
Approximately 20% of the randomized patients were on aspirin at study
entry and the majority of those were on doses less than 100 mg/day. In SPORTIF III, just under 30% of the
randomized patients were on aspirin at study entry, the majority being on doses
less than 100 mg/day. The use of HMG CoA
reductase inhibitors at study entry was more prevalent in SPORTIF V (36.8%)
than in SPORTIF III (19%).
Table XVI: Number (%) of patients with concomitant
medication use at study entry by treatment group (ITT population)a
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
|
Therapya
|
N=1960
|
N=1962
|
N=3922
|
|
|
Vitamin
K antagonists
|
1617
|
(82.5)
|
1661
|
(84.7)
|
3278
|
(83.6)
|
|
|
Heparin
group
|
15
|
(0.8)
|
4
|
(0.2)
|
19
|
(0.5)
|
|
|
ASA
£100 mg/day
|
227
|
(11.6)
|
251
|
(12.8)
|
478
|
(12.2)
|
|
|
ASA
>100 mg/day
|
160
|
(8.2)
|
135
|
(6.9)
|
295
|
(7.5)
|
|
|
ASA
(dose unknown)
|
31
|
(1.6)
|
25
|
(1.3)
|
56
|
(1.4)
|
|
|
Digoxin/Digitoxin
|
1058
|
(54.0)
|
1056
|
(53.8)
|
2114
|
(53.9)
|
|
Beta
blockers
|
972
|
(49.6)
|
937
|
(47.7)
|
1909
|
(48.6)
|
|
Calcium
antagonists
|
754
|
(38.5)
|
743
|
(37.8)
|
1497
|
(38.1)
|
|
Diuretics
|
1274
|
(65.0)
|
1275
|
(64.9)
|
2549
|
(65.1)
|
|
ACE
inhibitors
|
937
|
(47.8)
|
938
|
(47.8)
|
1875
|
(47.8)
|
|
Angiotensin
II-antagonists
|
213
|
(10.9)
|
189
|
(9.6)
|
402
|
(10.2)
|
|
Acetaminophen
|
351
|
(17.9)
|
299
|
(15.2)
|
650
|
(16.6)
|
|
Amiodarone
|
83
|
(4.2)
|
94
|
(4.8)
|
177
|
(4.5)
|
|
HMG
CoA reductase inhibitors
|
733
|
(37.4)
|
709
|
(36.1)
|
1442
|
(36.8)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
aData in this table obtained
from Table 39 of SPORTIF V CSR.
Table XVII below shows the proportion of time patients took
concomitant aspirin between the first and last dose of study drug. As discussed earlier in the
inclusion/exclusion criteria, patients were permitted to take ASA < 100
mg/day during the trial. As shown in the
table below, the overall percentage of time that patients in the ximelagatran
arm were on aspirin during the study was greater than in the warfarin arm.
Table XVII: Proportion of time patients took
concomitant ASA between the first and last dose of study drug (ITT population)a
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
Proportion of time
|
N=512
|
N=535
|
N=1047
|
|
>0%
to 25%
|
160
|
(31.3)
|
178
|
(33.3)
|
338
|
(32.3)
|
|
>25%
to 50%
|
22
|
(4.3)
|
28
|
(5.2)
|
50
|
(4.8)
|
|
>50%
to 75%
|
22
|
(4.3)
|
18
|
(3.4)
|
40
|
(3.8)
|
|
>75%
to 100%
|
308
|
(60.2)
|
311
|
(58.1)
|
619
|
(59.1)
|
|
Overall
% of time on ASA
|
64.4
|
60.4
|
62.3
|
aData in this table obtained
from Table 40 of SPORTIF V CSR.
As shown in Table
XVIII below, the number of patients on the various listed
medications between the first and last dose of study drug were similar in the 2
treatment arms.
Table XVIII: Number (%) of patients using other
cardiovascular medications between the first and last dose of study drug, by
treatment group (ITT population)a
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
Medicationa
|
N=1960
|
N=1962
|
N=3922
|
|
Digoxin/Digitoxin
|
1122
|
(57.2)
|
1132
|
(57.7)
|
2254
|
(57.5)
|
|
Beta
blockers
|
1149
|
(58.7)
|
1187
|
(60.6)
|
2336
|
(59.6)
|
|
Calcium
antagonists
|
905
|
(46.1)
|
910
|
(46.5)
|
1815
|
(46.2)
|
|
Diuretics
|
1603
|
(81.9)
|
1681
|
(85.9)
|
3284
|
(83.8)
|
|
ACE
inhibitors
|
1091
|
(55.7)
|
1121
|
(57.2)
|
2212
|
(56.4)
|
|
Angiotensin
II-antagonists
|
301
|
(15.4)
|
296
|
(15.1)
|
597
|
(15.2)
|
|
Acetaminophen
|
654
|
(33.4)
|
642
|
(32.7)
|
1296
|
(33.0)
|
|
Amiodarone
|
130
|
(6.6)
|
139
|
(7.1)
|
269
|
(6.9)
|
|
HMG
CoA reductase inhibitors
|
923
|
(47.1)
|
926
|
(47.2)
|
1849
|
(47.1)
|
aData in this table was
obtained from Table 41 SPORTIF V CSR.
m.
Primary endpoint results
The results of the primary
pre-specified endpoint from SPORTIF V are summarized in Table
XIX below. The
results of the sponsor’s primary endpoint analysis was re-analyzed and
confirmed by the statistical reviewer Dr. John Lawrence.
Table XIX: Number of patients with stroke and/or SEE
by treatment group (primary prespecified endpoint)a
|
|
|
|
Event
|
95% CI
|
|
|
|
|
Patient
|
Rate
|
|
|
|
|
Treatment
group
|
Eventsb,c
|
Years
|
(%/year)
|
Lower
|
Higher
|
p-value
|
|
Ximelagatran
|
51
|
3160
|
1.61
|
1.17
|
2.06
|
|
|
Warfarin
|
37
|
3186
|
1.16
|
0.79
|
1.54
|
|
|
Ximelagatran
– warfarin
|
|
|
0.45
|
-0.13
|
1.03
|
0.133
|
aData in this table obtained
from Table 45 of SPORTIF V CSR
bEvents represent CEAC
adjudicated events
cThis table only informs of
the number of patients with their first event.
If a patient had more than one event, it is not reflected in this
table.
As shown in Table
XX below, the most striking finding was a total of 10
fatal strokes on ximelagatran versus 3 fatal strokes on warfarin. In terms of overall number of events, the
majority of strokes were non-fatal and ischemic in nature. Relatively few were hemorrhagic in
nature. SEE’s were also relatively rare
comprising less than 10% of the total number of primary events.
Table XX: Breakdown of primary endpoint by type of event and whether
fatal or non-fatala.
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
Endpoint eventb
|
N=1960
|
N=1962
|
N=3922
|
|
Fatal
stroke
|
10
|
(0.5)
|
3
|
(0.2)
|
13
|
(0.3)
|
|
Ischemic stroke
|
8
|
(0.4)
|
3
|
(2.0)
|
11
|
(0.3)
|
|
Hemorrhagic stroke
|
2
|
(0.1)
|
0
|
(0.0)
|
2
|
(0.1)
|
|
Non-fatal
stroke
|
38
|
(1.9)
|
34
|
(1.7)
|
72
|
(1.8)
|
|
Ischemic stroke
|
38
|
(1.9)
|
33
|
(1.7)
|
71
|
(1.8)
|
|
Hemorrhagic stroke
|
0
|
(0.0)
|
2
|
(0.1)
|
2
|
(0.1)
|
|
Non
fatal SEE
|
6
|
(0.3)
|
1
|
(0.1)
|
7
|
(0.2)
|
|
Total
number of events
|
57
|
(2.9)
|
40
|
(2.0)
|
97
|
(2.5)
|
|
Total
number of patients with at least 1 event
|
51
|
(2.6)
|
37
|
(1.9)
|
88
|
(2.2)
|
aData in this table obtained
from Table 46 of SPORTIF V CSR.
bPatients are counted once in
each category of event if they had one or more events of that type.
Figure 8: Cumulative proportion of patients with
stroke and/or SEE over time-estimated Kaplan-Meier curves (Figure taken from
Figure 12 of SPORTIF V CSR).
Figure 9 below summarizes the results of the primary endpoint
as a function of various prognostic factors.
The point estimates of the event rates were generally consistent across
various subgroups and favored warfarin with the exception of patients with a
BMI < 25.
Figure
9: Event
rate difference (ximelagatran – warfarin) for the primary endpoint (stroke
and/or SEE) according to prognostic factors (Figure taken from Figure 16 of
SPORTIF V CSR)
n.
Secondary and Tertiary endpoint results
The
results of the secondary and tertiary endpoints are summarized in Table XXI through Table
XXIV.
SECONDARY
ENDPOINTS
Table XXI below summarizes the results of the secondary
endpoint. There were a total of 229
patients with at least one event.
However, the total number of events was 261 because of the fact that a
patient could have had more than one event.
Of the 229 patients with one event, just under 50% were deaths.
Table XXI: Number of patients with all cause
mortality/stroke/ SEE/AMI by treatment group (secondary prespecified endpoint
based on OT analysis)a
|
|
|
|
Event
|
95% CI
|
|
|
|
|
Patient
|
Rate
|
|
|
|
|
|
Treatment
|
Eventsb,c
|
years
|
(%/year)
|
Lower
|
Higher
|
p-value
|
|
|
Ximelagatran
|
110
|
2612
|
4.21
|
3.42
|
5.00
|
|
|
|
Warfarin
|
119
|
2738
|
4.35
|
3.56
|
5.13
|
|
|
|
Ximelagatran
– warfarin
|
|
|
-0.13
|
-1.24
|
0.98
|
0.839
|
|
aData in this table obtained
from Table 58 of SPORTIF V CSR
bEvents represent CEAC
adjudicated events
cIf a patient had more than
one event, it is not reflected in this table.
The total number of events was 127 and 134 on ximelagatran and warfarin
respectively.
Table
XXII below shows the results of one of the secondary
prespecified endpoints which evaluated the number of patients with
stroke/TIA/SEE. There were numerically
more TIA’s in the ximelagatran arm compared to the warfarin arm.
Table XXII: Number of patients with ischemic
stroke/TIA/SEE by treatment group (secondary prespecified endpoint based on OT
analysis)a
|
|
|
|
Event
|
95% CI
|
|
|
|
|
Patient
|
Rate
|
|
|
|
|
|
Treatment
|
Eventsb,c
|
Years
|
(%/year)
|
Lower
|
Higher
|
p-value
|
|
|
Ximelagatran
|
67
|
2606
|
2.57
|
1.96
|
3.19
|
|
|
|
Warfarin
|
52
|
2728
|
1.91
|
1.39
|
2.42
|
|
|
|
Ximelagatran
– warfarin
|
|
|
0.66
|
-0.14
|
1.47
|
0.115
|
|
aData in this table obtained
from Table 62 of SPORTIF V CSR
bEvents represent CEAC
adjudicated events
cIf a patient had more than
one event, it is not reflected in this table.
The total number of events was 80 and 57 on ximelagatran and warfarin
respectively.
TERTIARY
ENDPOINTS
It is important to note that the
analysis of the tertiary endpoint was changed to include the ITT population after the database was unblinded.
Table XXIII: Number of patients with strokes with a poor
outcome by treatment group (tertiary prespecified endpoint based on ITT
analysis)a
|
|
|
|
Event
|
95% CI
|
|
|
|
|
Patient
|
Rate
|
|
|
|
|
|
Treatment
|
Eventsb
|
years
|
(%/year)
|
Lower
|
Higher
|
p-value
|
|
|
Ximelagatran
|
16
|
3190
|
0.50
|
0.26
|
0.75
|
|
|
|
Warfarin
|
10
|
3207
|
0.31
|
0.12
|
0.51
|
|
|
|
Ximelagatran
– warfarin
|
|
|
0.19
|
-0.12
|
0.50
|
0.246
|
|
aData in this table obtained
from Table 64 of SPORTIF V CSR
bEvents represent CEAC
adjudicated events
Table XXIV: Number of patients with stroke or SEE as a
function of age (<, > 75 years of age) (tertiary prespecified
endpoint based on ITT analysis)a
|
|
|
|
|
|
95% CI
|
|
|
|
|
|
|
Event
|
|
|
|
|
Age
|
|
|
Patient
|
rate
|
|
|
|
|
group
|
Treatment
|
Eventsb
|
Years
|
(%/year)
|
Lower
|
Higher
|
p-value
|
|
Age
³75
|
Ximelagatran
|
23
|
1322
|
1.74
|
1.03
|
2.45
|
|
|
Years
|
|
|
|
|
|
|
|
|
|
Warfarin
|
18
|
1311
|
1.37
|
0.74
|
2.01
|
|
|
|
Ximelagatran
- warfarin
|
|
|
0.37
|
-0.59
|
1.32
|
0.530
|
|
Age
<75
|
Ximelagatran
|
28
|
1840
|
1.52
|
0.96
|
2.09
|
|
|
Years
|
|
|
|
|
|
|
|
|
|
Warfarin
|
19
|
1875
|
1.01
|
0.56
|
1.47
|
|
|
|
Ximelagatran
- warfarin
|
|
|
0.51
|
-0.22
|
1.23
|
0.187
|
aData in this table obtained
from Table 66 of SPORTIF V CSR
bEvents represent CEAC
adjudicated events
o.
Adequacy of anticoagulation in the warfarin arm
The
adequacy of anticoagulation in the warfarin group was assessed in the OT (on
treatment) population. Overall, the
number of patients in the warfarin group with an:
·
INR < 2.0 occurred 20.3% of total time
·
INR 2.0 to 3.0 occurred 68% of the time
·
INR > 3.0 occurred 11.7% of the time
Figure 10 below shows the percentage of patients with INR’s
< 2.0, between 2.0 and 3.0, and > 3.0 as a function of time since
randomization.
Figure 10: Adequacy of anticoagulation as assessed by
INR in patients assigned to warfarin (OT population); (Figure taken from Figure
23 of SPORTIF V CSR).
In
general, the adequacy of anticoagulation with warfarin in SPORTIF V was good
and comparable to that seen in historical studies of warfarin. Please refer to Table VI for details of the adequacy of anticoagulation in
studies involving warfarin. Using the
AFASAK study as an example of the worst case scenario, the INR was in the
“therapeutic” range (2.8 to 4.2) 42% of the time. In the best case scenario, the BAATAF study
showed that the “therapeutic” range (1.5 to 2.7) was achieved 83% of the time.
A total of
172 (8.8%) of patients had intervals between INR measurements of more than 2
months.
2.
SPORTIF III
Study Title: “Efficacy and Safety of the Oral Direct
Thrombin Inhibitor H376/95 Compared with Dose-Adjusted Warfarin in the
Prevention of Stroke and Systemic Embolic Events in Patients with Atrial
Fibrillation”
SPORTIF III (SH-TPA-0003) was the second of the 2 pivotal
Phase 3 studies submitted by the sponsor for the indication of prevention of
stroke and SEE in patients with atrial fibrillation. SPORTIF III was very similar in design to
SPORTIF V except for the aspect of blinding.
The former was open-label while the latter was double-blind.
a.
Study dates
Date first
patient enrolled: July 25, 2000
Date
enrollment ended: September 13, 2001
Date study
closure procedures began: July 1, 2002
Date final
patient completed study: September 30,
2002
Date of Clinical Study Report: September 26, 2003
b.
Protocol Amendments
Table XXV
below summarizes the date at which the original protocol was issued along with
dates at which all subsequent amendments to the original protocol were issued. Below
Table XXV
are listed the summaries of each protocol amendment.
Table XXV:
Original Protocol and Protocol Amendment Issue dates for SPORTIF III
|
Version
of Protocol or Protocol Amendment
|
Date
of issue
|
|
Protocol
Version 1
|
March 8, 2000
|
|
Protocol
amendment 1 to Version 1
|
May 3, 2000
|
|
Protocol
Version 2
|
May 3, 2000
|
|
Protocol
Amendment 1 to Version 2
|
October 30, 2001
|
|
Protocol
Amendment 1 to Version 3
|
June 12, 2002
|
Amendment
entitled: “Protocol amendment 1 to Version 1”
- Change
in exclusion criteria relating to active liver disease and persistent
elevation of liver enzymes has been changed from “more than 3 times the
upper limit of normal” to“≥2 times the upper limit of normal”.
- Additional
laboratory assessments, hematology and clinical chemistry, were scheduled
at the following time points: 6 weeks, 2 months, 4, 5, 8, 10, 15 and 21
months. Additional clinic visits
were added to accommodate the extra laboratory assessments.
- The
protocol was amended to include specific instructions for the investigator
to follow in the event of liver enzyme abnormalities. If, at any time during the study, the
liver enzyme, S-ALAT (GPT) is ≥3 times the upper limit of normal
(ULN) and this is confirmed in a repeat test then the patient will be
recalled for a third check-up visit when a 14-15 mL blood sample will be
drawn for extended liver function tests evaluating various etiologies for
liver enzyme abnormalities. Once
an increase of S-ALAT to > 3x ULN has been confirmed in a repeat test,
weekly liver enzyme test check-ups, i.e. S-ASAT, S-ALAT, S-ALP and
S-Bilirubin will be performed until S-ALAT is either less than 2x ULN or
has returned to normal values.
- Specific
instruction regarding when to discontinue a patient for liver enzyme
abnormalities were added. A patient
was to be discontinued from the study if repeated measurements showed that
S-ALAT remains elevated 3 to 7x ULN during a 2-month period without any
tendency to decrease or other clinical explanation being found. Any patient with a S-ALAT > 7x ULN at
any time was to be discontinued from the study.
- The
number of patients was increased from 2700 to 3000.
- The
study start date was changed from April 2000 to July 2000.
- The
treatment period was changed from 30 months to 26 months.
Amendment
entitled: “Protocol amendment 1 to Version 2”
- The
threshold for discontinuing a patient due to liver enzyme abnormalities
was reduced. Patients with an
increase of >5 times the upper limit of normal (ULN) in any liver
enzyme test, i.e. S-ASAT, S-ALAT, S-ALP and S-Bilirubin, were to be
withdrawn from study treatment, unless it was agreed with the AstraZeneca
responsible physician that it is acceptable for the patient to remain on
treatment.
- For
any patient that showed a persistent elevation of any LFT (not just
restricted to ALAT elevation) >3 times the ULN but < 5
times the ULN for 8 weeks then study treatment must be discontinued.
- If
an increase of >3 times ULN was seen in any LFT then the patient
was to be recalled for a visit where further work-up occurred. No confirmation or repeat lab test was
necessary to confirm the enzyme abnormality – unlike that required in
Amendment 1 to Version 1.
Amendment entitled: “Protocol amendment 1 to Version 3”
- The
following was added: “It is
important that the final health status of all patients is known at the end
of the study. For patients who withdraw from the study due to death,
stroke or systemic embolic event, their final health status is considered
known. Patients who withdraw completely from the study due to other
reasons are considered to have an unknown final health status. These
patients will be contacted during the 3-month closeout period and will be
asked to consent to provide follow-up information regarding their health
status. If consent is provided, the patient will be asked to confirm that
they are still alive and whether or not they have suffered a stroke or a
systemic embolic event.”
- With
regards to the statistical analysis of the primary endpoint it was decided
to analyze the primary endpoint with an Intention to Treat approach using
adjudication from the Clinical Events Committee.
c.
Study Design:
SPORTIF III was similar in design to SPORTIF V except that
it was open-label. It was a randomized,
active control, parallel group study in patients with non-valvular atrial
fibrillation. SPORTIF III was conducted
in Europe and Asia whereas
SPORTIF V was conducted in the U.S.
and Canada. Please refer to section VIII, C, 2, j for
details of the countries that enrolled patients into this study.
SPORTIF III randomized a total of 3410 patients. As shown in Figure
11, patients were randomized to either fixed doses of
ximelagatran 36 mg bid or to adjusted dose warfarin, titrating to an INR of 2-3
via monthly blood tests.
Figure 11: Study Schema for SPORTIF III (Figure
obtained from Figure 1 of SPORTIF III CSR)
Stratification in SPORTIF III was based on:
Aspirin Use
Previous stroke/TIA
Country
Study duration: The
study is to continue until 4000 patient years are collected and/or at least 80
primary endpoints are achieved.
The study included a DSMB, CEAC, and ESC. The members of the DSMB, CEAC and ESC were
the same as in SPORTIF V and are listed in Section VIII, C, 1, c of this
review.
d.
Rationale for doses selected
Please
refer to Section VIII, C, 1, d of this of this review for details.
e.
Blinding/Randomization:
Unlike SPORTIF V, this study was conducted open-label. All primary events (stroke and systemic
embolic events), secondary events (deaths, acute MI’s, TIA’s) and major
bleeding events were adjudicated by a CEAC.
f.
Pre-specified study objectives
The primary, secondary, and tertiary endpoints were almost
identical to those in SPORTIF V. Please
refer to Section VIII, C, 1, f of this review for details.
g.
Definitions of study endpoints
Please
refer to Section VIII, C, 1, g of this review for details
h.
Inclusion/Exclusion Criteria:
The inclusion and exclusion criteria were identical to those
is SPORTIF V. Please refer to Section
VIII, C, 1, h of this review for details.
i.
Statistical Considerations (please refer to the
statistical review for details):
The general statistical considerations and sample size
calculations were very similar for both studies. Please refer to Section VIII, C, 1, i of this
review for further details.
j.
Study patient disposition
Patients were enrolled from a total of 259 centers in 23
countries (Australia,
Belgium, Czech
Republic, Denmark,
Finland, France,
Germany, Hong
Kong, Hungary,
Iceland, Ireland,
Italy,
Japan,
Malaysia, New
Zealand, Norway,
Poland, Philippines,
Portugal, Spain,
Sweden,
Taiwan
and UK). A total of 3697 patients were enrolled from
which 3407 patients were randomized and received at least one dose of study
drug (1704 to ximelagatran and 1703 to warfarin).
As seen in Figure
12 below, 287 patients were enrolled but not
randomized. The top two reasons for
screening failures were eligibility criteria being unfulfilled and withdrawal
of consent. A total of 81.5% of patients
remained on ximelagatran at the time of study completion, while 85.4% of
patients remained on warfarin at the time of study completion.
Figure 12: Patient disposition in SPORTIF III (Figure
obtained from Figure 4 of SPORTIF III CSR)
As shown in Table
XXVI below, the total number of study drug
discontinuations was greater on ximelagatran compared to warfarin by an
absolute value of 4% and was consistent with the findings seen in SPORTIF
V. A large portion of this excess
discontinuation on ximelagatran could be attributed to adverse events (e.g.
liver enzyme abnormalities).
Table XXVI: Summary of the reasons for discontinuing
study drug (ITT population)a
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
Reason for study drug
discontinuation
|
N=1704
|
N=1703
|
N=3407
|
|
Total
|
309
|
(18%)
|
246
|
(14%)
|
555
|
(16%)
|
|
Adverse
event
|
132
|
(8)
|
61
|
(4)
|
193
|
(6)
|
|
Patient
decision (Consent withdrawn from study drug)
|
49
|
(3)
|
49
|
(3)
|
98
|
(3)
|
|
Endpoint
events
|
52
|
(3)
|
61
|
(4)
|
113
|
(3)
|
|
Other
|
29
|
(2)
|
30
|
(2)
|
59
|
(2)
|
aThe data in this table
obtained from table 15 of SPORTIF III CSR
As seen in Table
XXVII below, even after excluding patients with ALAT >
3x ULN, the total drug discontinuation rate was slightly higher on ximelagatran
compared to warfarin. Again, this
pattern of study drug discontinuations was consistent with the pattern seen in
SPORTIF V.
Table
XXVII:
Comparison of total study drug discontinuation rates including and
excluding patients with ALAT > 3x ULNa
|
|
Ximelagatran
|
Warfarin
|
Totals
|
|
Total discontinuation rate
(including patients with ALAT > 3x ULN)
|
309/1704 (18%)
|
246/1703 (14%)
|
555/3407 (16%)
|
|
Total discontinuation rate
(excluding patients with ALAT > 3x ULN)
|
261/1597 (16%)
|
242/1689 (14%)
|
503/3286 (15%)
|
aData in this table obtained
from Tables 15 and 16 of SPORTIF V CSR
In SPORTIF III, there were 97 patients with missing vital
status or primary event data during study closure procedures. All these patients were asked to re-consent
to provide follow-up information regarding the primary endpoint event or
death. The results are summarized in
Table XXVIII
below. The sponsor’s attempt to collect
vital status or primary event data during this process yielded no additional
primary events or deaths. Note that 12
patients on ximelagatran and 15 patients on warfarin were lost to
follow-up.
Table XXVIII: Number of patients that discontinued the
study and had missing vital status or primary event data at time of study
closure procedures but were asked to re-consent to provide follow-up
information.
|
|
Ximelagatran
(N =53)
|
Warfarin
(N = 44)
|
Total
(N = 97)
|
|
Provided re-consent
|
19 (37.3%)
|
14 (30.4%)
|
33 (34%)
|
|
IEC approval not obtained
prior to study closure
|
14 (27.5%)
|
11 (23.9%)
|
25 (25.8%)
|
|
Refused to re-consent
|
8 (15.7%)
|
4 (8.7%)
|
12 (12.4%)
|
|
Lost to follow-up
|
12 (23.5%)
|
15 (32.6%)
|
27 (27.8%)
|
Data in this table obtained from Table 14 of SPORTIF III
CSR
k.
Protocol deviations
There were no exclusions from any analyses due to protocol
deviations.
Enrollment violations
The major inclusion criteria violations involved either
criteria 1 (AF verified by 2 ECG’s) or criteria 2 (at least one other risk
factor for stroke). The most common
exclusion criteria violation involved the use of disallowed concomitant
medication.
Table XXIX: Inclusion/exclusion criteria violations by
treatment group
|
|
Ximelagatran
(N = 1704)
|
Warfarin
(N = 1703)
|
Total
(N = 3407)
|
|
Inclusion criteria
violations
|
9
|
7
|
16
|
|
Exclusion criteria
violations
|
21
|
20
|
41
|
Study drug administration violation
There was one patient (#4167) that was assigned to receive
warfarin but was treated with ximelagatran by the investigator. This patient is included in the warfarin
group for the efficacy analyses but in the ximelagatran group for the analysis
of AE’s.
Violations relating to interruption of study drug
Table
XXX below summarizes the cumulative duration of treatment
interruption by treatment group.
Slightly more patients on warfarin had treatment interruptions of any duration
compared to patients on ximelagatran.
These findings contrast to those in SPORTIF V, where there was a more
pronounced discrepancy in the percentage of patients with treatment
interruption between the two study arms.
Table XXX: Number (%) of patients by total days of
treatment interruption, and treatment groupa
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
Treatment interruption
|
N=1952
|
N=1952
|
N=3904
|
|
No
interruption
|
1208
|
(71%)
|
1139
|
(67%)
|
2347
|
(69%)
|
|
1
to 7 days
|
313
|
(18%)
|
304
|
(18%)
|
617
|
(18%)
|
|
8
to 30 days
|
143
|
(8%)
|
220
|
(13%)
|
363
|
(11%)
|
|
31
to 60 days
|
31
|
(2%)
|
30
|
(2%)
|
61
|
(2%)
|
|
>60
days
|
9
|
(1%)
|
10
|
(1%)
|
19
|
(1%)
|
aData in this table obtained
from Table 20 of SPORTIF III CSR.
Intervals greater than 28 + 3 days between INR
measurements:
Per the
protocol, patients were to have INR measurements every 28 + 3 days. A total of 225 (13.2%) patients had at least
one interval between INR measurements of more than 2 months.
l.
Demographics and other patient characteristics
The
characteristics of the patients enrolled in SPORTIF III are described in Table XXXI below. The
majority of patients were males, Caucasians, and > 65 years old. Approximately 69% had two or more risk
factors for stroke in addition non-valvular AF.
Baseline characteristics between the two treatment arms were similar.
There were
some notable differences in the baseline characteristics of the patients in
SPORTIF III compared to SPORTIF V. On
average, the patient population in SPORTIF III had fewer risk factors for
stroke, was younger, and had fewer patients taking aspirin at the time of
enrollment compared to SPORTIF V. In
addition, SPORTIF III also had more patients that drank alcohol and more that
never smoked. Finally there were a
greater proportion of Oriental patients in SPORTIF III compared to SPORTIF
V.
Table XXXI: Patient characteristics at screening:
number (%) of patients by treatment group (ITT population)a
|
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
|
|
N=1704
|
N=1703
|
N=3407
|
|
Sex
|
Male
|
1158
(68%)
|
1196
(70%)
|
2354
(69%)
|
|
|
Female
|
546
(32%)
|
507
(30%)
|
1053
(31%)
|
|
Race
|
Caucasian
|
1494
(88%)
|
1500
(88%)
|
2994
(88%)
|
|
|
Black
|
0
|
3
(0%)
|
3
(0%)
|
|
|
Oriental
|
201
(12%)
|
196
(12%)
|
397
(12%)
|
|
|
Other
|
9
(1%)
|
4
(0%)
|
13
(0%)
|
|
Age
|
<65
|
386
(23%)
|
397
(23%)
|
783
(23%)
|
|
|
[65,75)
|
737
(43%)
|
741
(44%)
|
1478
(43%)
|
|
|
>=75
|
581
(34%)
|
565
(33%)
|
1146
(34%)
|
|
Number
of risk factors
|
0
|
5
(0%)
|
5
(0%)
|
10
(0%)
|
|
(in
addition to AF)
|
|
|
|
|
|
|
1
|
508
(30%)
|
544
(32%)
|
1052
(31%)
|
|
|
2
|
612
(36%)
|
572
(34%)
|
1184
(35%)
|
|
|
3
|
370
(22%)
|
378
(22%)
|
748
(22%)
|
|
|
4
|
150
(9%)
|
143
(8%)
|
293
(9%)
|
|
|
5
|
52
(3%)
|
51
(3%)
|
103
(3%)
|
|
|
6
|
7
(0%)
|
10
(1%)
|
17
(0%)
|
|
Smoking
|
No
|
844
(50%)
|
857
(50%)
|
1701
(50%)
|
|
|
Previous
smoker
|
680
(40%)
|
677
(40%)
|
1357
(40%)
|
|
|
Occasional
smoker
|
46
(3%)
|
36
(2%)
|
82
(2%)
|
|
|
Habitual
smoker
|
134
(8%)
|
133
(8%)
|
267
(8%)
|
|
Does
the patient drink alcohol
|
No
|
835
(49%)
|
852
(50%)
|
1687
(50%)
|
|
|
Yes
|
869
(51%)
|
851
(50%)
|
1720
(50%)
|
|
Undergone
any major surgery
|
No
|
809
(47%)
|
780
(46%)
|
1589
(47%)
|
|
|
Yes
|
895
(53%)
|
923
(54%)
|
1818
(53%)
|
|
Is
the patient taking aspirin
|
No
|
1359
(80%)
|
1344
(79%)
|
2703
(79%)
|
|
|
Yes
|
345
(20%)
|
359
(21%)
|
704
(21%)
|
|
Modified
Rankin score
|
0
|
1319
(77%)
|
1308
(77%)
|
2627
(77%)
|
|
|
1
|
264
(15%)
|
271
(16%)
|
535
(16%)
|
|
|
2
|
114
(7%)
|
119
(7%)
|
233
(7%)
|
|
|
3
|
6
(0%)
|
4
(0%)
|
10
(0%)
|
|
|
4
|
1
(0%)
|
1
(0%)
|
2
(0%)
|
|
Alcohol
consumption
|
0
|
838
(49%)
|
856
(50%)
|
1694
(50%)
|
|
(units/week)
|
0.1-5
|
460
(27%)
|
484
(28%)
|
944
(28%)
|
|
|
6-10
|
229
(13%)
|
190
(11%)
|
419
(12%)
|
|
|
11-15
|
82
(5%)
|
91
(5%)
|
173
(5%)
|
|
|
16-20
|
29
(2%)
|
13
(1%)
|
42
(1%)
|
|
|
21-
|
66
(4%)
|
69
(4%)
|
135
(4%)
|
aData in this table obtained
from Table 22 of SPORTIF III CSR
Table
XXXII below summarizes some additional patient
characteristics. As mentioned earlier,
patients in SPORTIF III were younger than patients in SPORTIF V. In addition, patients in SPORTIF III, had a lower
BMI compared to patients in SPORTIF V.
Table XXXII: Mean (+SD) of patient characteristics at
screening (ITT population)a
|
|
Ximelagatran
(N = 1960)
|
Warfarin
(N = 1962)
|
Total
(N = 3922)
|
|
Mean
Age (years)
|
70.3
+ 8.6
|
70.1
+ 8.6
|
70.2
+ 8.6
|
|
Mean
Height (cm)
|
169.5
+ 9.8
|
170.1
+ 9.5
|
169.8
+ 9.6
|
|
Mean
Weight (kg)
|
80.7
+ 16.8
|
81.7
+ 16.9
|
81.2
+ 16.9
|
|
Mean
BMI ((kg/m2)
|
28.0
+ 4.9
|
28.1
+ 4.8
|
28.1
+ 4.9
|
|
Mean
estimated CrCL (mL/min)
|
82.8
+ 31.9
|
83.3
+ 34.1
|
83.1
+ 33.0
|
|
Mean
SBP (mm Hg)b
|
139.0
+ 17.9
|
138.6
+ 18.1
|
138.8
+ 18.0
|
|
Mean
DBP (mm Hg)b
|
81.8
+ 9.7
|
81.9
+ 10.1
|
81.9
+ 9.9
|
aData in this table obtained
from Table 23 of SPORTIF III CSR.
bBlood pressure data was not
provided in Sponsor’s table but was obtained by analyzing the dataset “HRBP2”
of SPORTIF III. Visit 1 blood pressure data were used to
obtain baseline data.
Table XXXIII below summarizes the number of patients with presence
of the listed risk factor in patients enrolled into SPORTIF III.
More
patients in SPORTIF III had a history of stroke and/or TIA at study enrollment
compared to patients in SPORTIF V (24% vs. 18%). However, fewer patients in SPORTIF III had a
history of hypertension (72% vs. 81%) and left ventricular dysfunction (34% vs.
39%) compared to patients in SPORTIF V.
Table XXXIII: Number (%) of patients with presence of the
listed risk factor at study entrya
|
|
Ximelagatran (N = 1704)
|
Warfarin (N = 1703)
|
Total (N = 3407)
|
|
Previous
stroke
|
265
(16%)
|
254
(15%)
|
519
(15%)
|
|
Systemic
embolism
|
74
(4%)
|
77
(5%)
|
151
(4%)
|
|
Previous
TIA
|
189
(11%)
|
188
(11%)
|
377
(11%)
|
|
Previous
stroke and/or TIA
|
417
(24%)
|
405
(24%)
|
822
(24%)
|
|
Hypertension
|
1229
(72%)
|
1230
(72%)
|
2459
(72%)
|
|
LV dysfunction
|
574
(34%)
|
584
(34%)
|
1158
(34%)
|
|
Diabetes
mellitus
|
370
(22%)
|
377
(22%)
|
747
(22%)
|
|
Age
>=65 and DM
|
288
(17%)
|
290
(17%)
|
578
(17%)
|
|
CAD
|
682
(40%)
|
675
(40%)
|
1357
(40%)
|
|
Age
>=65 and CAD
|
581
(34%)
|
558
(33%)
|
1139
(33%)
|
|
Clinically
significant bleeding
|
78
(5%)
|
68
(4%)
|
146
(4%)
|
aData
in this table obtained from Table 26 of SPORTIF III CSR
Table
XXXIV below summarizes the medications that patients were
using before randomization into the study.
The use of the listed medications was similar at baseline in the 2 study
arms. There was less use of Vitamin K
antagonists (73% vs. 84%), diuretics (51% vs. 65%), and HMG-CoA reductase
inhibitors (19% vs. 37%) in SPORTIF III patients compared to SPORTIF V
patients. There was a relatively higher
use of low dose aspirin in SPORTIF III compared to SPORTIF V (21% vs.
12%).
Table XXXIV: Number (%) of patients with concomitant
medication use at study entry by treatment group (ITT population)a
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
|
N=1704
|
N=1703
|
N=3407
|
|
Antifibrinolytics
|
0
(0%)
|
1
(0%)
|
1
(0%)
|
|
Vitamin
K antagonists
|
1266
(74%)
|
1235
(73%)
|
2501
(73%)
|
|
Heparin
group
|
62
(4%)
|
57
(3%)
|
119
(3%)
|
|
Aspirin
<=100 mg
|
348
(20%)
|
356
(21%)
|
704
(21%)
|
|
Aspirin
>100 mg
|
99
(6%)
|
87
(5%)
|
186
(5%)
|
|
Aspirin
(dose unknown)
|
51
(3%)
|
35
(2%)
|
86
(3%)
|
|
NSAID
|
94
(6%)
|
83
(5%)
|
177
(5%)
|
|
Digoxin/Digitoxin
|
928
(54%)
|
934
(55%)
|
1862
(55%)
|
|
Beta
blockers
|
774
(45%)
|
816
(48%)
|
1590
(47%)
|
|
Calcium
antagonists
|
578
(34%)
|
565
(33%)
|
1143
(34%)
|
|
Diuretics
|
846
(50%)
|
877
(51%)
|
1723
(51%)
|
|
ACE
inhibitors
|
829
(49%)
|
873
(51%)
|
1702
(50%)
|
|
Angiotensin
II-antagonists
|
133
(8%)
|
134
(8%)
|
267
(8%)
|
|
Paracetamol
|
91
(5%)
|
82
(5%)
|
173
(5%)
|
|
Amiodarone
|
104
(6%)
|
115
(7%)
|
219
(6%)
|
|
HMG
CoA reductase inhibitors
|
310
(18%)
|
329
(19%)
|
639
(19%)
|
aData in this table obtained
from Tables 30 and 31 of SPORTIF III CSR.
As shown in Table
XXXV below, patients in the ximelagatran arm were more
often on aspirin compared to patients in the warfarin arm during the course of
SPORTIF III.
Table XXXV: Proportion of time patients took
concomitant ASA between the first and last dose of study drug (ITT population)a
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
|
N=369
|
N=334
|
N=703
|
|
>0-25%
|
128
(35%)
|
147
(44%)
|
275
(39%)
|
|
26-50%
|
19
(5%)
|
14
(4%)
|
33
(5%)
|
|
51-75%
|
16
(4%)
|
14
(4%)
|
30
(4%)
|
|
76-100%
|
206
(56%)
|
159
(48%)
|
365
(52%)
|
|
overall
% of time on aspirin
|
64%
|
54%
|
59%
|
aData in this table obtained
from Table 33 of SPORTIF III CSR
In general, the use of the listed medications during the
study was similar in the 2 treatment arms as shown in Table XXXVI below. The
most striking finding was the difference in use of HMG CoA reductase inhibitors
between SPORTIF III and SPORTIF V patients: 27% of patients in SPORTIF III
compared to 47 % of patients in SPORTIF V.
Table
XXXVI: Number (%) of patients using other
cardiovascular medications between the first and last dose of study drug, by
treatment group (ITT population)a
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
|
N=1697
|
N=1700
|
N=3397b
|
|
Digoxin/Digitoxin
|
961
(57%)
|
980
(58%)
|
1941
(57%)
|
|
Beta
blockers
|
828
(49%)
|
896
(53%)
|
1724
(51%)
|
|
Calcium
antagonists
|
647
(38%)
|
655
(39%)
|
1302
(38%)
|
|
Diuretics
|
942
(56%)
|
1012
(60%)
|
1954
(58%)
|
|
ACE
inhibitors
|
880
(52%)
|
947
(56%)
|
1827
(54%)
|
|
Angiotensin
II-antagonists
|
174
(10%)
|
201
(12%)
|
375
(11%)
|
|
Paracetamol
|
331
(20%)
|
334
(20%)
|
665
(20%)
|
|
Amiodarone
|
106
(6%)
|
119
(7%)
|
225
(7%)
|
|
HMG
CoA reductase inhibitors
|
426
(25%)
|
500
(29%)
|
926
(27%)
|
aData in this table was
obtained from Table 41 SPORTIF V CSR.
bThis table excludes the 10 patients
who did not receive any study drug.
m.
Primary endpoint results
Table XXXVII
below summarizes the results of the primary prespecified endpoint. The results of the primary endpoint analysis
were taken directly from the sponsor’s analysis and were not re-analyzed and
validated by the reviewer.
Table XXXVII: Number of patients with stroke and/or SEE
by treatment group (primary prespecified endpoint)a
|
|
Eventsb
|
Patient years
|
Event rate
|
95% CI
|
p-value
|
|
|
|
|
(%/year)
|
Lower
|
Higher
|
|
|
Ximelagatran
|
40
|
2446
|
1.64
|
1.13
|
2.14
|
|
|
Warfarin
|
56
|
2440
|
2.29
|
1.69
|
2.9
|
|
|
Ximelagatran-Warfarin
|
|
|
-0.66
|
-1.45
|
0.13
|
0.100
|
aData in this table obtained
from Table 39 of SPORTIF III CSR
bEvents represent CEAC adjudicated
events
As seen in Table
XXXVIII below, the vast majority (> 80%) of primary events
that occurred were ischemic strokes.
Hemorrhagic strokes and SEE accounted for less than 20% of the total
number of events.
Table XXXVIII: Listing of the individual components of the
primary endpoint in SPORTIF IIIa
|
|
Ximelagatran
|
Warfarin
|
Total
|
|
Hemorrhagic
stroke
|
4
(3)
|
9
(5)
|
13
(8)
|
|
Ischemic
stroke
|
32
(7)
|
46
(4)
|
78
(11)
|
|
SEE
|
4
(2)
|
2
(0)
|
6
(2)
|
|
Totala
|
40
(12)
|
56
(9)
|
96
(21)
|
aData in this table obtained
from Table 40 of SPORTIF III CSR.
Figure 13: Cumulative proportion of patients with
stroke and/or SEE (primary endpoint) over time – estimated Kaplan-Meier curves
(This figure obtained from Figure 12 of SPORTIF III CSR).
As shown in Figure
14 below, the results in various sub-groups were
consistent with the results of the general population.
Figure 14: Event rate difference (ximelagatran –
warfarin) for the primary endpoint (stroke and/or SEE) according to prognostic
factors (This figure obtained from Figure 13 of SPORTIF III CSR).
n.
Secondary and Tertiary endpoint results
SECONDARY ENDPOINTS
The results of the secondary endpoint are summarized in Table XXXIX and Table
XL below.
Table XXXIX: Number of patients with all cause
mortality/stroke/ SEE/AMI by treatment group (secondary prespecified endpoint
based on OT analysis)a
|
|
Eventsb
|
Patient
|
Event rate
|
95% CI
|
p-value
|
|
|
|
years
|
(%/year)
|
Lower
|
Higher
|
|
|
Ximelagatran
|
96
|
2276
|
4.22
|
3.37
|
5.06
|
|
|
Warfarin
|
116
|
2348
|
4.94
|
4.04
|
5.84
|
|
|
Ximelagatran-Warfarin
|
|
|
-0.72
|
-1.95
|
0.51
|
0.261
|
aData in this table obtained
from Table 51 of SPORTIF III CSR
bEvents represent CEAC
adjudicated events
Ishcemic
strokes/SEE/TIA
Table XL: Number of patients with ischemic
stroke/TIA/SEE by treatment group (secondary prespecified endpoint based on OT
analysis)a
|
|
Events
|
Patient years
|
Event rate
|
95% CI
|
p-value
|
|
|
|
|
(%/year)
|
Lower
|
Higher
|
|
|
Ximelagatran
|
48
|
2267
|
2.12
|
1.52
|
2.72
|
|
|
Warfarin
|
67
|
2334
|
2.87
|
2.18
|
3.56
|
|
|
Ximelagatran-Warfarin
|
|
|
-0.75
|
-1.67
|
0.16
|
0.109
|
aData in this table obtained
from Table 56 of SPORTIF III CSR
TERTIARY ENDPOINTS
It is important to note that the analysis of the tertiary
endpoint was changed to include the ITT population after the database was unblinded.
Table XLI: Number of patients with strokes with a poor
outcome by treatment group (tertiary prespecified endpoint based on ITT
analysis)a
|
|
Events
|
Patient
|
Event rate
|
95% CI
|
p-value
|
|
|
|
years
|
(%/year)
|
Lower
|
Higher
|
|
|
Ximelagatran
|
15
|
2464
|
0.61
|
0.3
|
0.92
|
|
|
Warfarin
|
16
|
2467
|
0.65
|
0.33
|
0.97
|
|
|
Ximelagatran-Warfarin
|
|
|
-0.04
|
-0.48
|
0.4
|
1.000
|
aData in this table obtained
from Table 58 of SPORTIF III CSR
Table XLII: Number of patients with stroke or SEE as a
function of age (<, > 75 years of age) (tertiary prespecified
endpoint based on ITT analysis)a
|
|
|
Events
|
Patient years
|
Event rate
|
95% CI
|
p-value
|
|
|
|
|
|
(%/year)
|
Lower
|
Higher
|
|
|
Age
>=75 years
|
Ximelagatran
|
25
|
834
|
3
|
1.82
|
4.17
|
|
|
|
Warfarin
|
30
|
803
|
3.73
|
2.4
|
5.07
|
|
|
|
Ximelagatran-Warfarin
|
|
|
-0.74
|
-2.52
|
1.04
|
0.415
|
|
Age
<75 years
|
Ximelagatran
|
15
|
1612
|
0.93
|
0.46
|
1.4
|
|
|
|
Warfarin
|
26
|
1637
|
1.59
|
0.98
|
2.2
|
|
|
|
Ximelagatran-Warfarin
|
|
|
-0.66
|
-1.43
|
0.11
|
0.115
|
aData in this table obtained
from Table 60 of SPORTIF III CSR
o.
Adequacy of anticoagulation in the warfarin arm
The adequacy of anticoagulation in the warfarin group was
assessed in the OT population. Patients
in SPORTIF III were within the targeted INR range of 2 to 3 for 66% of the
time. This was very similar to the 68%
of the time that the INR was within the range of 2 to 3 in SPORTIF V. A stable INR was achieved by month 2. Between month 2 and the end of the study, the
percentage of time the INR was within the targeted range (2 to 3), ranged from
a low of 64% to a high of 72%. Figure 15 below summarizes the percentage of time with INR’s
within the targeted range of 2 to 3, and also the percentage of time above and
below this range. A total of 225 (13.2%)
patients had at least one interval between INR measurements of more than 2
months and 62 (3.6%) patients had intervals of more than 3 months.
Figure 15: Adequacy of anticoagulation as assessed by
INR in patients assigned to warfarin (OT population) (This figure was obtained from Figure 25 of
SPORTIF III CSR).
SPORTIF III and SPORTIF V are two Phase III, active control,
non-inferiority studies that were provided in support of NDA21-686. Both studies compared the effectiveness of a
fixed dose of ximelagatran, 36 mg administered twice a day to warfarin
targeting an INR of 2 to 3 in patients with nonvalvular atrial fibrillation and
at least one additional risk factor for stroke.
The studies were very similar in design except that SPORTIF III was open
label while SPORTIF V was double-blind.
The primary endpoint was the composite occurrence of all strokes (fatal
and non-fatal) and systemic embolic events.
The sponsor pre-specified a non-inferiority margin of 2% points in the
event rate in both studies. A margin of
that size could leave open the possibility that ximelagatran is only half as
effective as warfarin and still be considered “non-inferior.”
In both studies, the efficacy of ximelagatran was within
the sponsor’s pre-specified non-inferiority margin of 2% and it was concluded
by the sponsor that ximelagatran was as efficacious as warfarin. While the two studies could be considered
“successes” based on the sponsor’s pre-specified margin, the margin chosen was
too liberal.
The two studies produced
divergent results despite their similar designs. In SPORTIF V, the event rate was higher in
the ximelagatran arm compared to the warfarin arm while in SPORTIF III, the
event rate was higher in the warfarin arm compared to the ximelagatran
arm. Comparing the event rate in the
common arm of both studies, the event rate in the ximelagatran arm of both
studies was similar at approximately 1.6%.
However, the event rate in the warfarin arm varied by almost two-fold:
1.2% in SPORTIF V versus 2.3% in SPORTIF III.
Differences in the patient populations in the two studies at baseline
could be a possible explanation of the differences in the event rate in the
treatment arms. Patients in SPORTIF V
were slightly older, had lower blood pressures on average, had fewer patients
with histories of transient ischemic attacks (TIA’s) or strokes, and had
greater consumption of HMG CoA reductase inhibitors than did patients enrolled
in SPORTIF III. However, it is difficult
to explain why such differences would lead to differences in event rates in the
warfarin arm while leaving the event rate in the ximelagatran arm unaffected. In a setting where two studies produce
divergent results, I would favor the results from a double-blind study. The event rate in both studies was primarily
driven by the occurrence of ischemic strokes.
More than 80% of the events in both studies were ischemic strokes.
The studies submitted in support of safety are SPORTIF III, SPORTIF V,
and SPORTIF II/IV. The SPORTIF II/IV
studies are not discussed in this section but are discussed in detail in the
Appendix. The studies in aggregate
exceeded the ICH E1 guidelines for safety exposure for drugs intended for
chronic use. The exposure to
ximelagatran in SPORTIF III and SPORTIF V was approximately 2300 and 2600
patient-years respectively.
In SPORTIF III, there were a total of 145 deaths that occurred on
treatment or during the follow-up period: 75 Ximelagatran, 70 Warfarin. In SPORTIF V, there were a total of 237
deaths occurring on treatment or during the follow-up period: 116 Ximelagatran,
121 Warfarin. The etiologies of deaths
were consistent with what is to be expected from an elderly population with
co-morbidities. The common etiologies of
death for patients enrolled in these studies included sudden death, heart rate
and rhythm disorders, myocardial infarctions, and congestive heart
failure.
In terms of serious adverse events (SAE’s) not leading to death, the
frequency of reporting of SAE’s was similar in the 2 treatment arms in each of
the SPORTIF studies. In general, the reporting
rate was lower in SPORTIF III compared to SPORTIF V. The etiologies of the SAE’s not leading to
death were also consistent with what would be expected in an elderly
population. The most common etiologies
included congestive heart failure, cerebrovascular disorders, myocardial
infarctions, GI hemorrhage, pneumonia, and angina pectoris.
Discontinuations due to adverse events were numerically greater in the
ximelagatran arms of both SPORTIF studies.
The most common reason for study drug discontinuation from ximelagatran
was liver and biliary system disorders.
The incidence of aminotransferase abnormalities was significantly higher
on ximelagatran compared to warfarin regardless of the criteria used to define
abnormal (e.g. ALAT or ASAT > 3x ULN, > 5x ULN, or > 10 x ULN). The majority of patients that developed liver
enzyme abnormalities did so beginning 2 to 4 months after starting ximelagatran
therapy. There was one case of a biopsy
documented drug induced liver failure leading to death. There was a second probable case of drug
induced liver failure leading to coagulopathy and subsequently death. In addition there were multiple cases of
aminotransferase abnormalities greater than 3 times the upper limit of normal
temporally associated with a bilirubin increase of greater than 2 times the
upper limit of normal. In most of these
cases the patients were asymptomatic.
Liver enzyme abnormalities returned to normal after drug discontinuation
in these patients.
In terms of major bleeding events, the total number of bleeds was
numerically lower in the ximelagatran arm of both SPORTIF studies. In neither of the studies did this difference
achieve statistical significance. The
majority of major bleeds in both studies was due to bleeding with a fall in the hemoglobin level
of greater than or equal to 2 g/dL or due to overt bleeding requiring >
2 units of whole blood.
Finally in terms of commonly reported adverse events, the most common
reported adverse events on ximelagatran were respiratory infection, dizziness,
accident/injury, purpura, and pain. The
frequency of these adverse events was similar in the two treatment arms in both
SPORTIF studies.
As shown in Table
XLIII below, the safety population in the 2 SPORTIF studies
consisted of primarily Caucasian males with an average age of about 70 years.
Table
XLIII:
Demographic description of Safety population
|
|
SPORTIF IIIa
|
SPORTIF Vb
|
|
|
Ximelagatran
(N = 1698)
|
Warfarin
(N = 1699)
|
Ximelagatran
(N = 1953)
|
Warfarin
(N = 1953)
|
|
Male
|
1153
(68%)
|
1195
(70%)
|
1361
(70%)
|
1347
(69%)
|
|
Female
|
545
(32%)
|
504
(30%)
|
592
(30%)
|
606
(31%)
|
|
Caucasian
|
1490
(88%)
|
1497
(88%)
|
1870
(96%)
|
1879
(96%)
|
|
Black
|
0
|
3
(0.2%)
|
65
(3%)
|
58
(3%)
|
|
Oriental
|
199
(12%)
|
195
(12%)
|
15
(0.8%)
|
10
(0.5%)
|
|
Mean
age male (range)
|
69.1
(30 – 89)
|
68.9
(37 – 90)
|
70.6
(35 – 97)
|
70.4
(40 to 92)
|
|
Mean
age female (range)
|
72.6
(29-92)
|
72.8
(46 – 90)
|
73.7
(30 to 91)
|
74.3
(35 to 92)
|
Data
in this table obtained from Table 72 (SPORTIF III CSR) and Table 79 (SPORTIF V CSR)
aA total of 3407 patients
were formally randomized into this study.
10 of the randomized patients did not take the study drug and therefore
a total of 3397 (1698 + 1699) were randomized and received at least one dose of
study drug.
bA total of 3922 patients
were formally randomized into this study.
15 of the randomized patients did not take the study drug. One patient took study drug but all contact
was lost for this patient and thus did not provide safety data.
As shown in Table
XLIV, the mean duration on study drug was similar between
the 2 SPORTIF studies. The mean duration
on study drug was greater on warfarin relative to ximelagatran and consistent
across both studies. There were
significantly more patients with an exposure duration > 631 days in
SPORTIF V compared to SPORTIF III. There
was a difference in the mean post treatment follow-up between the 2 SPORTIF
studies as shown below. In SPORTIF V
there was a 14 day follow-up period for collecting AE’s that began on the
second day after the last dose of study drug and continued until the 14th
day after the last dose of study drug.
SPORTIF III did not have such a pre-specified follow-up period.
Table
XLIV: Summary of Exposure Data
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
(N = 1698)
|
Warfarin
(N = 1699)
|
Ximelagatran
(N = 1953)
|
Warfarin
(N = 1953)
|
|
Mean
Duration on study drug in days (SD)
|
485
(170)
|
502
(145)
|
478
(233)
|
506
(212)
|
|
Mean
Post treatment follow-up in days (SD)
|
26
(27)
|
33
(43)
|
12
(2)
|
12
(2)
|
|
Duration
of exposure > 91 days
|
1584
(93%)
|
1639
(97%)
|
1738
(89%)
|
1802
(92%)
|
|
Duration
of exposure > 361 days
|
1443
(85%)
|
1520
(90%)
|
1459
(75%)
|
1563
(80%)
|
|
Duration
of exposure > 631 days
|
311
(18%)
|
296
(17%)
|
590
(30%)
|
611
(31%)
|
Data in this table obtained from Table 75 (SPORTIF III CSR)
and Table
1.
Study population definitions
The definitions of the various safety populations are
described below.
Safety Population:
All patients with intake of at least 1 dose of study medication and for whom
post-dose information was available were included in the safety population and
used in the analysis of AE’s. Patients in the safety population were analyzed
according to the study treatment that they received. Other safety analyses, eg,
laboratory values, were to be performed on the OT analysis set. The total safety population in SPORTIF III
consisted of 3,397 patients (1698 X, 1699 W).
The total safety population in SPORTIF V consisted of 3,906 patients
(1953 X, 1953 W).
OT analysis
population: The OT approach included
all patients in the ITT population (i.e. all randomized patients) but only
their time on active study drug was used for analysis. A maximum continuous
interruption of up to 30 days without active study drug was allowed for
patients to remain in the OT analyses (except for cardioversion, for which the
patient was allowed to interrupt treatment for 60 continuous days). In addition, a maximum of 60 accumulated days
of interruption was permitted. Patients who deviated from the above criteria
had all subsequent data excluded from the OT analyses, although data obtained
prior to the deviation were included, i.e., data were excluded from the time
the criteria were violated. For the purposes of the analysis the time “On
Treatment” started at randomization, hence patients with events after
randomization but before the first dose intake were included.
ITT analysis
population: All randomized patients
were included in the ITT population until the date of each patient’s study
closure visit or final contact, irrespective of their protocol adherence to
study treatment or other protocol procedures. For those patients who withdrew
from the study, they were included up to the date of their study
termination. This population was used
primarily for the analysis of efficacy and therefore not necessarily applicable
to safety.
2.
Deaths
In SPORTIF V, there were a total of 239 deaths
reported. Of these 239 deaths, 116
deaths were reported in the ximelagatran arm and 123 were reported in the
warfarin arm. These 239 deaths, include
2 deaths (patients 5882 and 8818 both in the warfarin arm) that occurred
approximately 2 months after study termination and therefore should not have
been considered in the safety analysis.
A total of 74 deaths occurred on treatment (33 X, 41 W). A total of 163 deaths occurred during the
follow-up period (83 X, 80 W). Finally,
as discussed above, 2 deaths occurred after the follow-up period (both in the
warfarin arm) and therefore should not be considered in the final safety
analysis. In summary, 74 + 163 + 2 =
239.
In SPORTIF III, a total of 168 patients died. Of these 168 deaths, 85 were reported in the
ximelagatran arm and 82 were reported in the warfarin arm. Of these 168 deaths, 145 occurred during
treatment or during the follow-up period (75 X, 70 W). 23 deaths occurred after withdrawal from the
study and therefore were not required to be analyzed in the safety
population.
Table
XLV below lists the most common adverse events leading to
death. The reporting format in the table
below is as follows: The number shown before the parentheses represents the
total number of events occurring on treatment and during follow-up. The first number in parentheses represents
the total number of events on treatment while the second number in the
parentheses represents the total number of events during follow-up.
The most common adverse events leading to death were not
unexpected for the elderly population studied in these two trials.
Table
XLV: Listing of the most common adverse events
leading to deatha(PLEASE NOTE THAT NUMBER
OF EVENTS RATHER THAN PERCENTAGES ARE
REPORTED)
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
(N = 1698)
|
Warfarin
(N = 1699)
|
Ximelagatran
(N = 1953)
|
Warfarin
(N = 1953)
|
|
Total
deathsb
|
75
(48, 27)
|
70
(42, 28)
|
116
(33, 83)
|
121
(41, 82)
|
|
Sudden
death
|
17
(16, 1)
|
20
(19, 1)
|
8 (6, 2)
|
3
(0, 3)
|
|
Heart
rate and rhythm disordersc
|
6
(6, 0)
|
3
(2, 1)
|
26
(14, 12)
|
31
(18, 13)
|
|
Myocardial
infarction
|
10
(6, 4)
|
3
(0, 3)
|
11
(5, 6)
|
12
(7, 5)
|
|
Cardiac
failure/Aggravated cardiac failure
|
8
(4, 4)
|
9
(4, 5)
|
5
(0, 5)
|
9
(2, 7)
|
Note the format of reporting in this table: total number of reported deaths (deaths
“during treatment period”, deaths during follow-up or “post-treatment period”)
aData
derived from table 84 of SPORTIF III CSR and table 96 of SPORTIF V CSR
bFor
SPORTIF III, as stated in the text above, there were 168 deaths recorded by the
sponsor of which 23 occurred after study termination and therefore not included
in this table. For SPORTIF V, there were
239 deaths recorded by the sponsor of which 2 occurred after study termination
and therefore not included in this table.
c Includes
terms coded as “cardiac arrest”, “ventricular fibrillation”, “arrhythmia”,
“ventricular arrhythmia” and/or “cardio-respiratory arrest”
3.
Serious Adverse Events other than death
Table
XLVI below provides a summary of the serious adverse
events (SAE’s) reported in SPORTIF III and SPORTIF V. The format of reporting in the table below is
similar to that in the previous section dealing with deaths. The number shown before the parentheses
represents the total number of events occurring on treatment and during
follow-up. The first number in
parentheses represents the total # of events on treatment while the second
number in the parentheses represents the total #of events during
follow-up.
Shown in the table below are SAE’s that occurred with a frequency of >
1% based on the ximelagatran arm. In
addition, also shown are SAE’s that occurred with a frequency < 1% but were >
2x more common on ximelagatran versus warfarin.
The reporting of serious adverse events other than death was lower in
both study arms of the open-label SPORTIF III study versus the double-blind
SPORTIF V study despite correcting for patient-years of exposure. The most common serious adverse events not
leading to death were cardiac failure, cerebrovascular disorders, and
myocardial infarctions as would be expected in the target population
studied. Hepatic enzyme abnormalities
occurred with a greater frequency in the ximelagatran arm of both studies and
are discussed in depth later in this review.
SAE’s that occurred with a frequency < 1% but that were >2x
higher on ximelagatran versus warfarin and consistent in both studies included
peripheral ischemia, neuropathy, rectal carcinoma, and peripheral edema. These SAE’S are highlighted in the table
below. Due to the small number of
events, it is difficult to determine whether these findings represent noise in
the data or a real signal.
Table
XLVI: Listing of serious adverse events not
leading to deatha, b, c, d, e (PLEASE NOTE THAT NUMBER
OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED)
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
(N = 1698)
|
Warfarin
(N = 1699)
|
Ximelagatran
(N = 1953)
|
Warfarin
(N = 1953)
|
|
Total
number of patients with non-fatal SAE’s
|
497
(474, 23)
|
541 (525, 16)
|
896 (600, 296)
|
874 (609, 265)
|
|
Cardiac
Failure/ Aggravated Cardiac failure
|
35
(35, 0)
|
69 (69, 0)
|
122
(91, 31)
|
139
(108, 31)
|
|
Cerebrovascular
Disorder
|
55
(52,3)
|
79
(76, 3)
|
97
(56, 41)
|
78
(49, 29)
|
|
GI
hemorrhage
|
13
(12, 1)
|
14
(14, 0)
|
52
(31, 21)
|
47
(25, 22)
|
|
Pneumonia
|
23
(22, 1)
|
23
(23, 0)
|
32
(28, 4)
|
53
(53, 0)
|
|
Myocardial
Infarction
|
25
(23, 2)
|
14
(14, 0)
|
39
(26, 13)
|
48
(30, 18)
|
|
Angina
Pectoris
|
26
(26, 0)
|
36
(35, 1)
|
34
(25, 9)
|
44
(36, 8)
|
|
Atrial
fibrillation
|
11
(11, 0)
|
11
(11, 0)
|
26
(24, 2)
|
30
(21, 9)
|
|
Coronary
artery disorder
|
6
(6, 0)
|
6
(4, 2)
|
20
(20, 0)
|
15
(15, 0)
|
|
Hepatic
enzymes increased
|
7
(6, 1)
|
0
(0, 0)
|
41
(21, 20)
|
3
(2, 1)
|
|
Fracture
|
1
(1, 0)
|
5
(5, 0)
|
30
(20, 10)
|
28
(20, 8)
|
|
Chronic
obstructive airways disease
|
1
(1, 0)
|
4
(4, 0)
|
27
(19, 8)
|
20
(15, 5)
|
|
Accident/Injury
|
27
(27, 0)
|
30
(30, 0)
|
15
(11, 4)
|
24
(21, 3)
|
|
|
|
|
Adverse
events with an frequency < 1% on
the ximelagatran arm but occurring >
2x more often on ximelagatran vs. warfarin
in SPORTIF V (excluded are AE’s where 2 or fewer patients were
affected in the ximelagatran arm)
|
|
Bronchitis
|
3
(3, 0)
|
2
(2, 0)
|
17
(15, 2)
|
6
(6, 0)
|
|
Infection
|
1
(1, 0)
|
8
(8, 0)
|
11
(8, 3)
|
4
(3, 1)
|
|
Renal
function abnormal
|
NR
|
NR
|
16 (9, 7)
|
7
(6, 1)
|
|
Cardiomyopathy
|
1
(1, 0)
|
1
(1, 0)
|
13 (8, 5)
|
5
(4, 1)
|
|
Neoplasm
NOS
|
1
(1, 0)
|
1
(1, 0)
|
10
(7, 3)
|
1
(1, 0)
|
|
Retinal
Detachment
|
1
(1, 0)
|
1
(1, 0)
|
6
(5, 1)
|
0
(0, 0)
|
|
Peripheral
ischemia
|
2
(2, 0)
|
1
(1, 0)
|
9
(5, 4)
|
2
(2, 0)
|
|
Confusion
|
2
(2, 0)
|
3
(3, 0)
|
5
(4, 1)
|
2
(1, 1)
|
|
Renal
artery stenosis
|
NR
|
NR
|
5
(4, 1)
|
0
(0, 0)
|
|
Angina
pectoris aggravated
|
4
(4, 0)
|
6
(6, 0)
|
6
(4, 2)
|
2
(2, 0)
|
|
Urinary
bladder carcinoma
|
0
(0, 0)
|
4
(4, 0)
|
6
(4, 2)
|
1
(1, 0)
|
|
Neuropathy
|
4
(4, 0)
|
2
(2, 0)
|
5
(4, 1)
|
2
(1, 1)
|
|
Pulmonary
carcinoma
|
1
(1, 0)
|
1
(1, 0)
|
7 (3, 4)
|
2
(1, 1)
|
|
Small
cell lung cancer
|
NR
|
NR
|
4
(3, 1)
|
2
(1, 1)
|
|
Hypertension
aggravated
|
NR
|
NR
|
6
(3, 3)
|
1
(1, 0)
|
|
Esophageal
disorder
|
1
(1, 0)
|
0
(0, 0)
|
3
(3, 0)
|
1
(0, 1)
|
|
Esophagitis
|
0
(0, 0)
|
1
(1, 0)
|
3
(3, 0)
|
0
(0, 0)
|
|
Ventricular
fibrillation
|
1
(1, 0)
|
3
(3, 0)
|
4
(3, 1)
|
2
(1, 1)
|
|
Renal
failure NOS
|
1
(1, 0)
|
2
(2, 0)
|
6
(3, 3)
|
3
(0, 3)
|
|
Limb
embolism
|
NR
|
NR
|
6
(3, 3)
|
0
(0, 0)
|
|
|
Adverse
events with an frequency < 1% on the ximelagatran arm but occurring > 2x more often on ximelagatran
vs. warfarin in SPORTIF III (excluded
are AE’s where 2 or fewer patients were affected in the ximelagatran arm)
|
|
|
|
Retinal
hemorrhage
|
4
(4, 0)
|
0
(0, 0)
|
(0,
0)
|
(1,
0)
|
|
Depression
|
5
(4, 1)
|
2
(2, 0)
|
2
(1, 1)
|
2
(1, 1)
|
|
Abdominal
pain
|
6
(5, 1)
|
2
(2, 0)
|
6
(6, 0)
|
8
(7, 1)
|
|
Rectal
hemorrhage
|
7
(6, 1)
|
1
(1, 0)
|
3
(2, 1)
|
5
(3, 2)
|
|
Cholecystitis
|
7
(7, 0)
|
2
(2, 0)
|
5
(5, 0)
|
14
(11, 3)
|
|
Diabetes
mellitus
|
4
(4, 0)
|
2
(2, 0)
|
2
(1, 1)
|
5
(3, 2)
|
|
Gout
|
3
(3, 0)
|
1
(1, 0)
|
5
(4, 1)
|
3
(3, 0)
|
|
Hyponatremia
|
3 (3, 0)
|
0
(0, 0)
|
5
(4, 1)
|
4
(3, 1)
|
|
Hypertension
|
5
(5, 0)
|
1
(1, 0)
|
0
(0, 0)
|
2
(1, 1)
|
|
Tachycardia
|
6
(6, 0)
|
3
(3, 0)
|
1
(1, 0)
|
0
(0, 0)
|
|
Palpitations
|
3
(3, 0)
|
1
(1, 0)
|
0
(0, 0)
|
1
(1, 0)
|
|
Vertebrobasilar
insufficiency
|
4
(4, 0)
|
2
(2, 0)
|
NR
|
NR
|
|
Intermittent
claudication
|
3
(3, 0)
|
0
(0, 0)
|
NR
|
NR
|
|
Uterine
prolapse
|
3
(3, 0)
|
0
(0, 0)
|
1
(1, 0)
|
0
(0, 0)
|
|
Rectal
carcinoma
|
4
(4, 0)
|
2
(2, 0)
|
2
(1, 1)
|
1 (0, 1)
|
|
Peripheral
edema
|
3
(3, 0)
|
1
(1, 0)
|
2 (1, 1)
|
1
(1, 0)
|
aNote the
format of reporting in this table: total
number of reports of each adverse (events “during treatment period”, events
during follow-up or “post-treatment period”)
bEvents
reported in this table are those that occurred with a > 1% frequency
in the ximelagatran arm or occurred with a frequency < 1%
and
were > 2 fold higher in the ximelagatran arm relative to the warfarin
arm
cNote that
some patients had the same AE reported in both the “during tx” and “post tx”
period because AE’s were counted in all periods where they occurred instead of
only in the period when they started
dNote that
some patients had more than 1 serious adverse event.
eData
obtained from table 11.3.4.1.1 and 11.3.4.1.3 (SPORTIF V) and table 11.3.4.1.2
(SPORTIF III)
fNR
= none reported
4.
Discontinuations due to Adverse Events
Discontinuations
of study drug were more common in the ximelagatran arm in both clinical
trials. Table XLVII below lists the discontinuations due to AE’s that
occurred with an frequency of > 1% based on the ximelagatran
arm. In addition, also shown are SAE’s
that occurred with a frequency < 1% but were > 2x more common on
ximelagatran versus warfarin. The most
common reason for study drug discontinuation was liver and biliary system
disorders. This broad category included
preferred terms such as hepatic enzyme increases, SGPT or SGOT increases, and
abnormal hepatic function. These adverse
events could explain a substantial portion of the uneven distribution of study
drug discontinuations between the two study groups. Details of adverse hepatobiliary events are
described later in this review.
The most
common reasons for study drug discontinuation (> 1% frequency) in the
ximelagatran arm were hepatic enzyme abnormalities and cerebrovascular
disorders.
Table
XLVII: Listing of study drug discontinuations due
to adverse events. Listed are the total
number of AE’s occurring at a frequency of > 1% in the ximelagatran
group or were > 2x fold higher in the ximelagatran arm relative to
the warfarin arma (PLEASE NOTE THAT NUMBER
OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED)
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
(N = 1698)
|
Warfarin
(N = 1699)
|
Ximelagatran
(N = 1953)
|
Warfarin
(N = 1953)
|
|
Total
number of patients with an AE leading to study drug discontinuation
|
185
|
100
|
354
|
300
|
|
Adverse
events occurring with an absolute incidence of > 1% in the
ximelagatran arm of either SPORTIF III OR SPORTIF V
|
|
Hepatic
enzymes increased
|
20
|
0
|
39
|
4
|
|
Cerebrovascular
disorder
|
21
|
18
|
36
|
26
|
|
Hepatic
function abnormal
|
6
|
0
|
22
|
3
|
|
|
Corresponding
events in SPORTIF III
|
Adverse
events with an incidence < 1% on the ximelagatran arm but occurring at a
frequency > 2x on ximelagatran vs. warfarin in SPORTIF V (excluded are AE’s where 2 or fewer patients were affected in the
ximelagatran arm)
|
|
Hematuria
|
5
|
2
|
11
|
5
|
|
Diarrhea
|
1
|
1
|
10
|
5
|
|
Fracture
|
1
|
0
|
6
|
3
|
|
Fatigue
|
1
|
0
|
6
|
2
|
|
Pain
|
1
|
0
|
6
|
2
|
|
Chest
pain
|
1
|
1
|
5
|
2
|
|
Sudden
death
|
1
|
0
|
5
|
0
|
|
Cardiomyopathy
|
0
|
1
|
4
|
2
|
|
Hemorrhage
rectum
|
2
|
0
|
4
|
0
|
|
Ventricular
fibrillation
|
1
|
2
|
4
|
2
|
|
Colon carcinoma
|
2
|
1
|
3
|
0
|
|
Renal
failure NOS
|
1
|
0
|
3
|
1
|
|
Anxiety
|
NRb
|
NRb
|
3
|
1
|
|
|
Adverse
events with an frequency < 1% on the ximelagatran arm but occurring >
2x more often on ximelagatran vs. warfarin
in SPORTIF III (excluded are
AE’s where 2 or fewer patients were affected in the ximelagatran arm)
|
Corresponding
events in SPORTIF V
|
|
Cardiac
failure
|
6
|
3
|
8
|
13
|
|
Retinal
hemorrhage
|
3
|
0
|
NRb
|
NRb
|
|
Hemoptysis
|
3
|
0
|
1
|
2
|
|
Epistaxis
|
3
|
1
|
NRb
|
NRb
|
aData in this table obtained
from Table 11.3.5.1.1 of SPORTIF V CSR and Table 11.3.5.1 of SPORTIF III CSR.
bNR
= none reported
5.
Adverse Bleeding Events
The major bleeding events as adjudicated by the CEAC are
presented in this section. As shown in Table XLVIII, there were a total of 147 adjudicated major bleeds
in SPORTIF V and 70 in SPORTIF III. The
bleeding event rates were markedly different between the two studies even after
accounting for differences in patient-years of exposure. There were a total of 3 major bleeds that
were fatal in each of the studies, SPORTIF III and SPORTIF V.
Table
XLVIII: Summary Table of Major bleeding events
(Based on On Treatment – OT Analysis)a.
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
|
Warfarin
|
Ximelagatran
|
Warfarin
|
|
Major
Bleedsb
|
|
Patient
Years
|
2279
|
2347
|
2602
|
2724
|
|
#
of Events
|
29
|
41
|
63
|
84
|
|
|
P
= 0.228
|
P
= 0.155
|
aData in this table obtained
from Table 79 of SPORTIF III CSR and Table 87 of SPORTIF V CSR.
bCEAC
adjudicated events
Kaplan-Meier curves for major bleeding events in SPORTIF
III and SPORTIF V are shown in Figure
16 and Figure
17 below.
Figure 16: Cumulative percentage of patients with
major bleeding events over time – Estimated Kaplan-Meir Curves (OT analysis)
for SPORTIF III study (Obtained from Figure 32 of Sponsor’s SPORTIF III
Clinical Study report)
Figure 17: Cumulative percentage of patients with
major bleeding events over time; estimated Kaplan-Meier curves (OT Analysis).
(Obtained from Figure 25 of Sponsor’s SPORTIF V Clinical Study report)
As shown in Table
XLIX below, the majority of major bleeds in both SPORTIF
studies were those defined by “overt bleeding with a fall in Hb of 2 g/dL or
more.”
Table
XLIX: Number of patients with major bleeding
events according to the CEAC, by criteria for judgment according to local
criteria assessed and by treatment group (OT analysis)a.
|
|
SPORTIF III
|
SPORTIF Vb
|
|
|
Ximelagatran
|
Warfarin
|
Ximelagatran
|
Warfarin
|
|
#
of adjudicated events
|
29
|
41
|
63
|
84
|
|
Fatal
Bleeds
|
1
|
2
|
2
|
1
|
|
Overt
Bleeding with fall in Hb of 2.0 g/dL or more
|
16
|
20
|
44
|
61
|
|
Overt
Bleeding requiring > 2 units of whole blood
|
4
|
8
|
23
|
34
|
|
Critical
site Bleedingc
|
8
|
11
|
8
|
9
|
aData from Tables 80 and 88
of SPORTIF III and V Clinical study reports respectively.
bFor SPORTIF V, the “# of
adjudicated events” represents total number of patients with at least one
event. A major bleeding event may be
counted under more than 1 criteria.
cCritical site bleeding
includes intracranial, retroperitoneal, intraspinal, intraocular, pericardial
or atraumatic intra-articular bleeding.
Table L below shows the location and subtypes of major
bleeds.
Table
L: Locations/subtypes of major bleedsa
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
|
Warfarin
|
Ximelagatran
|
Warfarin
|
|
#
of adjudicated events
|
29b
|
41b
|
63e
|
84e
|
|
Gastrointestinal
|
16
|
16
|
29
|
33
|
|
“Other”
|
5c
|
10d
|
15
|
29
|
|
Subdural
Hematoma
|
6
|
4
|
|
|
|
Intraocular
|
3
|
4
|
2
|
5
|
|
Urinary
|
0
|
4
|
5
|
5
|
|
Retroperitoneal
|
0
|
2
|
3
|
5
|
|
Pericardial
|
0
|
2
|
2
|
1
|
|
Intra-articular
|
0
|
1
|
|
|
|
Intraspinal
|
0
|
1
|
|
|
|
Missing
information
|
|
|
8
|
12
|
aData obtained from Table
11.3.2.18 of sponsor’s Clinical Study report
bOne patient in the
ximelagatran group had 2 major events and 2 patients in the warfarin group had
2 major events. Therefore although the
total number of patients with major bleeds where 29, the total number of events
was 30. Similar for the warfarin group,
the total number of patients was 41 but the total of bleeding events was 43.
cOther includes operative and
post-op blood loss, arm bleed, leg bleed, scalp bleed, femoral neck fracture
operation
dOther includes nose bleed,
facial, cutaneous, bleeding from left inguinal catheterization channel, psoas
muscle, arm (brachial hematoma)
eThe number in this row
represents the total number of patients with an event and not the total number
of events. It is possible that one
patient could have had more than one event.
In SPORTIF
III, in various subgroups, most point estimates of major bleeds favored
ximelagatran. Exceptions included
patients with moderate renal dysfunction, patients with BMI < 25, female
patients, and Oriental patients.
Similar to SPORTIF III, In SPORTIF V, most point estimates favored
ximelagatran. Exceptional subgroups were
patients with moderate renal dysfunction and patients that weighed over 100
kg. Please refer to Figure 18 and Figure
19 below.
Figure 18: Summary of safety comparison: ximelagatran
vs. warfarin (difference in percent events, with 95% CI) for major bleed
events, according to prognostic factors (OT analysis) (SPORTIF III) (Obtained
from Figure 33 of SPORTIF III CSR).
Figure 19: Summary of safety comparison: ximelagatran
vs. warfarin (difference in percent events, with 95% CI) for major bleed
events, according to prognostic factors (OT analysis) (SPORTIF V) (Obtained
from Figure 26 of SPORTIF V CSR)
6.
Hepatobiliary Adverse Events
The
frequency of hepatic enzyme abnormalities is shown in Table LI below. There
is clearly a greater frequency of aminotransferase abnormalities on
ximelagatran relative to warfarin regardless of the cutoff level one considers
abnormal. Although not shown in this review, there was a strong correlation
between ALAT and ASAT enzyme abnormalities.
The correlation between ALAT elevations and ALP or Bilirubin elevations
was relatively poor.
Table
LI: Frequency of patients with elevated ALAT,
ASAT, ALP, and Bilirubin (ITT population)a (PLEASE NOTE THAT NUMBER OF EVENTS
RATHER THAN PERCENTAGES ARE REPORTED)
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
(N = 1704)
|
Warfarin
(N = 1703)
|
Ximelagatran
(N = 1960)
|
Warfarin
(N = 1962)
|
|
ALAT
> ULN
|
457
|
232
|
472
|
197
|
|
ALAT
> 2x ULN
|
170
|
37
|
200
|
35
|
|
ALAT
> 3x ULN
|
107
|
14
|
117
|
15
|
|
ALAT
> 5x ULN
|
57
|
7
|
59
|
5
|
|
ALAT
> 10x ULN
|
15
|
0
|
16
|
1
|
|
ASAT
> ULN
|
326
|
172
|
342
|
140
|
|
ASAT
> 2x ULN
|
109
|
29
|
112
|
21
|
|
ASAT
> 3x ULN
|
60
|
13
|
60
|
10
|
|
ASAT
> 5x ULN
|
28
|
5
|
25
|
2
|
|
ASAT
> 10x ULN
|
11
|
1
|
9
|
1
|
|
ALP
> ULN
|
250
|
222
|
325
|
291
|
|
ALP
> 2x ULN
|
30
|
16
|
36
|
19
|
|
ALP
> 3x ULN
|
13
|
4
|
12
|
3
|
|
ALP
> 5x ULN
|
|
|
5
|
0
|
|
ALP
> 10x ULN
|
|
|
2
|
0
|
|
Bilirubin
> 1.5x ULN
|
86
|
83
|
103
|
81
|
|
Bilirubin
> 2x ULN
|
24
|
26
|
28
|
20
|
|
Bilirubin
> 3x ULN
|
8
|
3
|
10
|
4
|
|
Bilirubin
> 5x ULN
|
3
|
1
|
4
|
2
|
|
Bilirubin
> 10x ULN
|
|
|
2
|
1
|
aData from Table 87 of
SPORTIF III CSR and Table 100 of SPORTIF V CSR
Table LII below shows that there were a greater number of
patients with a bilirubin increase of > 2 times the upper limit in close
temporal relationship to an elevated aminotransferase levels. Isolated elevations in aminotransferase
levels are suggestive of a hepatocellular injury that may be reversible if the
offending agent is removed. Elevations
in aminotransferase levels in conjunction with an elevated bilirubin level can
be a more ominous sign suggesting a disruption in synthetic liver
function. The combination of elevated
aminotransferase elevations in association with elevations in total bilirubin
has been dubbed by the Agency as “Hy’s Law.”
According to the Clinical White Paper on hepatotoxicity published in
November 2000 “instances (even very few of them) of transaminase elevation
accompanied by elevated bilirubin (even if obvious jaundice was not present)
have been associated with, and have often predicted, post-marketing serious
liver injuries (fatal or requiring transplant).” Several case narratives of patients that
fulfill Hy’s Law are described in the Appendix of this review.
Table
LII: Number of Patients with ALAT > 3x ULN
followed by a bilirubin level > 2x ULN within one month of the elevated ALAT
(PLEASE NOTE THAT NUMBER OF EVENTS RATHER THAN PERCENTAGES ARE REPORTED)
.
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
|
Warfarin
|
Ximelagatran
|
Warfarin
|
|
#
of patients with ALAT > 3x ULN
|
107
|
14
|
117
|
15
|
|
#
of patients with Bilirubin > 2x ULN within one month of raised ALAT
|
9
|
1
|
9
|
1
|
The time
course of ALAT abnormalities is shown in Figure
20 and Figure
21 below. In both
studies there were a large number of cases of ALAT abnormalities that appeared
between 2 and 4 months post randomization.
Figure 20: Cumulative risk of ALAT > 3x ULN versus
time after randomization (ITT population) (Figure obtained from Figure 36 of
SPORTIF III CSR).
Figure 21: Cumulative risk of ALAT > 3x ULN versus
time after randomization (ITT population) (Figure obtained from Figure 33 of
SPORTIF V CSR)
Figure 22 below summarizes the disposition of patients with
ALAT > 3x ULN in SPORTIF III. 59 of
the 107 ximelagatran patients with ALAT > 3x ULN were continued on
treatment. Of these 59 patients, 58
returned to normal limits despite continuing ximelagatran therapy. 48 of the 107 ximelagatran patients with ALAT
> 3x ULN were discontinued from therapy.
In 31 of these 48 patients, ALAT returned to normal limits. 9 of these 48 patients, had values that
returned to < 2x ULN during the study while 8 of the 48 continued to have
ALAT values > 2x ULN.
Figure 22: Summary of patients on ximelagatran with an
ALAT > 3x ULN in SPORTIF III
107 patients with ALAT > 3x ULN
|
|
In SPORTIF
V, there were 117 ximelagatran treated patients with ALAT elevations > 3x
ULN. It was not completely clear from
the SPORTIF V CSR as to how many of these patients continued study drug despite
an increased ALAT versus how many discontinued study drug because of an
increased ALAT. Forty five of the
patients that continued to be treated with study drug returned to normal
spontaneously during the study period.
Of the patients that discontinued study drug, 42 had returned to normal
at the last available blood test or during follow-up.
Case Narratives
of two patients with severe hepatotoxicity as manifested by evidence of hepatic
synthetic dysfunction
Patient
7259:
An 80 y/o
Caucasian male’s medical history included hyperlipidemia, atrial fibrillation,
hydronephrosis, urinary retention, fibromyalgia, coronary artery disease s/p
CABG, and colon cancer.
Medications:
digoxin, metoprolol, prednisone, tamsulosin
May 30, 2001: Baseline (screening)
June 11, 2001: Randomized to ximelagatran
August 6, 2001: At the month 2 visit, his liver
enzymes were noted to be mildly elevated.
September 4, 2001: Further elevations in liver enzymes were
noted compared to August 6. This led to
weekly blood monitoring. In the case
narrative, there was no documentation of this patient being symptomatic early on
in association with a rise in liver enzymes.
Patient was reported to be symptomatic only much later in his clinical
course.
September 7, 2001: Study drug was discontinued. The liver enzymes continued to
increase. Serologies for viral hepatitis
(A, B, C, CMV, EBV, HSV) were not consistent with a recent viral
infection. An ANA was also
negative. An abdominal ultrasound showed
a normal liver, gall bladder, and normal biliary tree.
September 24, 2001: The patient was referred to a hepatologist as
an outpatient.
September 27, 2001: Transaminases peaked. A biopsy was performed revealing “severe
active hepatitis with hepatocyte necrosis, areas of collapse and marked bile
ductular proliferation consistent with acute submassive necrosis.”
October 1, 2001: Patient noted to be coagulopathic with
an elevated PT of 16.3 sec and an INR of 1.7.
October 2, 2001: Patient was hospitalized with jaundice
but reportedly asymptomatic. Patient
began therapy with prednisone 40 mg daily, vitamin K, and ranitidine.
October 8, 2001: Patient was discharged in stable
condition.
October 29, 2001: During an outpatient visit, the patient
complained of increasing fatigue over a 2 week period. Liver enzymes were noted to be improving and
patient’s dose of prednisone decreased to 15 mg daily. Patient was noted to have developed ascites,
significant lower extremity edema and oliguria.
November 3, 2001: Patient found unresponsive at home.
An autopsy
was conducted revealing a large duodenal ulcer with erosions. A small, friable and diffusely mottled liver
was noted suggestive of severe diffuse hepatic necrosis.
Table LIII: Pattern of liver enzyme progression for
Patient 7259
|
|
5/30/01
|
7/9/01
|
8/6/01
|
9/4/01
|
9/12/01
|
9/19/01
|
10/4/01
|
10/10/01
|
10/29/01
|
|
ALAT (U/L)
|
16
|
14
|
103
|
970
|
1106
|
1440
|
1012
|
645
|
219
|
|
ASAT (U/L)
|
22
|
18
|
80
|
698
|
784
|
1296
|
671
|
411
|
175
|
|
ALP (U/L)
|
67
|
75
|
90
|
142
|
152
|
160
|
225
|
190
|
180
|
|
Bilia (mg/dL)
|
0.9
|
0.6
|
1
|
1.1
|
1.7
|
2.5
|
9
|
17.1
|
12.1
|
Data taken from Case Report
Form and/or Case narrative
aNormal bilirubin range is 0
to 1.3 mg/dL
Patient
7859:
A 77 y/o
Caucasian male’s past medical history included alcohol abuse, cholecystectomy
1999, duodenal ulcer, bleeding in bladder, psychosis, gout, osteoarthritis,
chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary
insufficiency, emphysema, idiopathic cardiomyopathy, mild tricuspid
insufficiency, mild mitral insufficiency, sick sinus syndrome, pacemaker
insertion, hypertension, carotid stenosis, abdominal aortic aneurysm repair,
coronary artery disease and benign prostatic hypertrophy.
Medications:
carvedilol, magnesium oxide, ramipril, tamsulosin, vitamin b
June 19, 2001: Randomized to receive ximelagatran
October 15, 2001: At the month 2 visit, elevated liver
enzymes were noted.
October 17, 2001: Patient “felt well” with no change in his
dietary behavior and was able to travel to another city to visit his son. Patient was instructed to get liver enzymes
checked in the city where he was visiting his son but apparently did not.
November 1, 2001: Patient took the last dose of his study
drug.
November 2, 2001: Patient awoke with stomach pains and
light-headedness. He had a bowel
movement that produced a bloody stool.
He was admitted to a hospital and was noted to be pale, hypotensive
(76/45 mm Hg), and tachycardiac.
Laboratory work-up revealed that the patient’s hematocrit was 20, INR =
3.4, PT = 37 sec, PTT = 69 sec, and his albumin was 2 grams/dL. Plasma melagatran concentrations at admission
revealed a value of 0.25 micromolar.
Patient was admitted to the intensive care unit and treated with Vitamin
K, packed red blood cells, fresh frozen plasma, cryoprecipitate and
fluids.
November 3, 2001: Patients anemia and coagulopathy improved
with the medical management described above.
The hematocrit increased to 27 while his INR decreased to 1.1, PT to 14
seconds, and PTT to 53 seconds. The
patient underwent a gastroscopy that revealed a Billroth II anastomosis. There was evidence of bleeding in the pre-anastomotic
area and epinephrine was injected to decrease bleeding. Later during the day, the patient’s
condition worsened when he developed respiratory failure necessitating tracheal
intubation. Gastric suction produced 200
mL of blood. Patient became hemodynamically
unstable and required vasopressors.
Shock persisted despite further treatment with intravenous fluids, 2
packed red blood cells, 10 units fresh frozen plasma, and 1 unit of platelets. An operation was deemed futile, support was
withdrawn, and patient died later that day.
No autopsy was conducted.
Table LIV: Pattern of liver enzyme progression for
patient 7859
|
|
Baseline
|
15Oct01
|
2Nov01
|
3Nov01
|
|
ALAT (U/L)
|
13
|
216
|
569
|
134
|
|
ASAT (U/L)
|
20
|
154
|
629
|
236
|
|
ALP (U/L)
|
125
|
156
|
173
|
49
|
|
Bili (mg/Dl)
|
1.1
|
1.3
|
|
6.2
|
Data taken from Case Report
Form and/or Case narrative
Similar to
patient 7259, this patient has evidence for dysfunction in the liver’s
synthetic function. Assuming that this
patient took his last dose of study medication in the evening of November 1st,
I would not expect this magnitude of elevation in the PT/INR from
ximelagatran’s pharmacologic effect. The
plasma concentration in this patient at the time of hospitalization on November
2nd was reported as 0.25 mmoL/L. This
concentration would not be expected to produce an INR of 3.4 based on Figure 5 of this review.
It is more likely that this elevation is due to synthetic dysfunction in
the liver as opposed to a pharmacologic effect of ximelagatran. In addition, this patient was noted to have
an elevated bilirubin of 6.2 on November 3rd further suggestive of
synthetic dysfunction as opposed to a pharmacologic effect of
ximelagatran.
Additional
cases of ximelagatran associated hepatotoxicity that meet the criteria for Hy’s
Law are described in the Appendix, Section XIII B.
7.
Most commonly reported adverse events (AE’s)
Table
LV below shows the most common adverse events reported
during both the SPORTIF III and SPORTIF V trials. In the table are listed adverse events that
occurred with a frequency of greater than or equal to 5% based on the
ximelagatran arm. Also shown in the table
are adverse events that occurred twice as often on ximelagatran compared to
warfarin.
Table LV: Most common AE’s with an absolute frequency
> 5% (based on the ximelagatran arm) or were > 2 fold
higher than on the control group (warfarin)a.
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
(N = 1698)
|
Warfarin
(N = 1699)
|
Ximelagatran
(N = 1953)
N (%)
|
Warfarin
(N = 1953)
N (%)
|
|
Respiratory
infection
|
312
(18.4)
|
306
(18)
|
438
(22.4)
|
458
(23.5)
|
|
Purpura
|
120
(7.1)
|
130
(7.7)
|
298
(15.3)
|
428
(21.9)
|
|
Accident
and/or injury
|
147
(8.7)
|
164
(9.7)
|
314(16.1)
|
381
(19.5)
|
|
Dizziness
|
130
(7.7)
|
152
(8.9)
|
327
(16.7)
|
312
(16.0)
|
|
Pain
|
113
(6.7)
|
123
(7.2)
|
276
(14.1)
|
320
(16.4)
|
|
Dyspnea
|
114
(6.7)
|
149
(8.8)
|
265
(13.6)
|
295
(15.1)
|
|
Diarrhea
|
112
(6.6)
|
106
(6.2)
|
240
(12.3)
|
242
(12.4)
|
|
Edema
peripheral
|
94
(5.5)
|
109
(6.4)
|
207
(10.6)
|
247
(12.6)
|
|
Fatigue
|
80
(4.7)
|
67
(3.9)
|
229
(11.7)
|
222
(11.4)
|
|
Epistaxis
|
117
(6.9)
|
197
(11.6)
|
151
(7.7)
|
282
(14.4)
|
|
Chest
pain
|
99
(5.8)
|
104
(6.1)
|
197
(10.1)
|
224
(11.5)
|
|
Back
pain
|
139
(8.2)
|
144
(8.5)
|
177
(9.1)
|
218
(11.2)
|
|
Headache
|
113
(6.7)
|
110
(6.5)
|
187
(9.6)
|
185
(9.5)
|
|
Coughing
|
105
(6.2)
|
100
(5.9)
|
183
(9.4)
|
175
(9.0)
|
|
Arthralgia
|
|
|
166
(8.5)
|
163
(8.3)
|
|
Bronchitis
|
95
(5.6)
|
102
(6.0)
|
158
(8.1)
|
164
(8.4)
|
|
Nausea
|
|
|
144
(7.4)
|
160
(8.2)
|
|
Sinusitis
|
|
|
139
(7.1)
|
145
(7.4)
|
|
Rash
|
|
|
128
(6.6)
|
132
(6.8)
|
|
Urinary
tract infection
|
|
|
128
(6.6)
|
130
(6.7)
|
|
Abdominal
pain
|
|
|
108
(5.5)
|
137
(7.0)
|
|
Hematuria
|
|
|
109
(5.6)
|
105
(5.4)
|
|
Insomnia
|
|
|
107
(5.5)
|
116
( 5.9)
|
|
Tooth
disorder
|
|
|
105
(5.4)
|
75
(3.8)
|
|
Rhinitis
|
|
|
106
(5.4)
|
95
(4.9)
|
|
Dyspepsia
|
|
|
104
(5.3)
|
90
(4.6)
|
|
Hepatic
enzymes increased
|
|
|
90
(4.6)
|
23
(1.2)
|
|
SGPT
increased
|
|
|
53
(2.7)
|
12
(0.6)
|
|
Hepatic
function abnormal
|
|
|
50
(2.6)
|
12
(0.6)
|
|
Angina
Pectoris aggravated
|
|
|
23
(1.2)
|
10
(0.5)
|
|
Viral
infection
|
90
(5.3)
|
76
(4.5)
|
|
|
aData in this table obtained
from Table 78 of SPORTIF III CSR, and Tables 86 and 11.3.2.9 of SPORTIF V CSR.
8.
Pancreatic Adverse Events
In
preclinical studies, pancreatic hyperplasia was observed in rats. This is thought to be an effect specific to
rats. Pancreatic adverse events were
monitored in both clinical studies.
There does not appear to be a difference between the two groups in terms
of pancreatic cancer or pancreatitis serious adverse events as shown in Table LVI below.
Table LVI: Summary of pancreatic adverse events in
SPORTIF III and SPORTIF V
|
|
SPORTIF III
|
SPORTIF V
|
|
|
Ximelagatran
|
Warfarin
|
Ximelagatran
|
Warfarin
|
|
Pancreatic
cancer
|
0
|
0
|
0
|
3
|
|
Pancreatitis
SAE’s
|
1
|
3
|
2
|
2
|
In the
SPORTIF V study a subset of patients underwent further monitoring for
pancreatic adverse events via measurement of cholecystokinin plasma
concentrations and pancreatic volumes via CT scans. A total of 62 patients in the ximelagatran
group and 68 in the warfarin group were randomized into this sub-study. The results are shown below.
As shown in
Table LVII below, there was marked variability in plasma CCK
levels. In general there did not appear
to be a significant difference in mean plasma CCK levels at month 3. At baseline, the median CCK plasma levels
were 6.6 and 4.5 in the ximelagatran and warfarin arm respectively.
Table
LVII: Comparison of cholecystokinin plasma
concentrations at month 3 in a subset of patients in the SPORTIF V studya
|
|
Ximelagatran (N = 56)
|
Warfarin (N = 63)
|
|
Mean (picomolar)
|
14.97
|
11.39
|
|
Standard deviation (SD)
|
18.32
|
16.51
|
|
Minimum
|
2.00
|
2.00
|
|
Median
|
6.63
|
4.50
|
|
Maximum
|
62.5
|
62.5
|
aData taken from Table 110 of
SPORTIF V clinical study report
As shown
in Table LVIII below, there were similar magnitudes of changes in
pancreatic volumes obtained via CT scans in the two treatment arms.
Table
LVIII: Pancreatic volume obtained via CT scan:
mean change from screening to last available value. (SPORTIF V study)a
|
|
Ximelagatran
|
Warfarin
|
|
|
Screening
|
Month 12/ end of treatment
|
Change
|
Screening
|
Month 12/ end of treatment
|
Change
|
|
N
|
39
|
34
|
34
|
33
|
28
|
28
|
|
Mean
|
81.6
|
69.7
|
-10.9
|
88.0
|
75.3
|
-10.5
|
|
SD
|
30.8
|
25.3
|
13.6
|
28.1
|
27.9
|
13.9
|
|
Minimum
|
24.2
|
27.2
|
-40.1
|
34.6
|
23.4
|
-35.9
|
|
Median
|
80.9
|
61.0
|
-11.3
|
86.1
|
75.2
|
-11.5
|
|
Maximum
|
159.1
|
140.1
|
20.5
|
147.7
|
128
|
21.9
|
|
P –value
|
|
|
0.0001
|
|
|
0.0004
|
aData taken from Table 111 of
SPORTIF V clinical study report
9.
Other Laboratory Test Adverse events
There was
no obvious adverse safety signal with respect to laboratory tests that were
noted in either SPORTIF III OR SPORTIF V except for the abnormalities in liver
enzymes as discussed above. Figure 23 below summarizes changes relative to baseline in
several chemistry lab parameters that were noted in SPORTIF V. The findings shown in the figure below were
consistent with the findings in SPORTIF III (not shown). There was a decrease in serum cholesterol,
triglycerides, LDL and albumin in the ximelagatran group relative to
baseline. Changes in cholesterol,
triglycerides, and albumin in the ximelagatran arm were statistically
significant compared to the warfarin arm.
The clinical significance of these findings is unclear.
Figure 23: Estimated within-group
ratios relative to baseline (each patient’s mean of all measurements
post-randomization divided by baseline) with 95% CI. Between-group comparisons
for those ratios made with unpaired t-test (OT analysis) (Figure taken from
Figure 41 of SPORTIF V CSR).
10.
Adverse events related to vital signs, ECG, physical
findings
There was
no obvious adverse safety signal with respect to vital signs, ECG analysis, and
physical exam findings.
In general the safety testing performed by the sponsor
appears to be adequate. The total and
long-term exposure to ximelagatran in patients with atrial fibrillation exceeds
the guidelines provided in ICH E1 for a drug intended for chronic use.
According to a recent draft ICH guidance on QT, all new
drugs that are systemically bioavailable should have a clinical evaluation of
their proarrhythmic potential. Such
studies assessing QT/QTc interval prolongation should be randomized and
double-blinded with concurrent placebo and positive controls. A positive control is necessary to ensure
assay sensitivity exists in the trial being conducted. I wasn’t able to find evidence that the
sponsor conducted a study fitting this description. The sponsor has conducted studies in which
they evaluated changes in the RR, QRS, PQ,
or QT interval at the time of peak levels of melagatran and/or
ximelagatran. The sponsor notes no
significant correlation between the QT interval and plasma concentrations of
study drug. However, it is unclear if
the results from the study were truly negative or that the study lacked assay
sensitivity.
Preliminary exposure-response relationships that have been
performed based on existing data suggest that there is a relationship between
higher exposure to melagatran, the active metabolite of ximelagatran, and risk
of major bleeding or hepatotoxicity (ALAT > 3x ULN). It would be useful to know in a randomized
control trial whether use of lower doses would reduce the risk of toxicity while
still preserving efficacy.
Ximelagatran is a pro-drug that
gets metabolized to melagatran, the active metabolite. The vast majority of melagatran is excreted
unchanged in urine. There is a strong
correlation between the oral clearance of melagatran and creatinine clearance
as discussed earlier in this review.
This relationship will have an impact on dosing and dosing regimen
particularly if ximelagatran is a narrow therapeutic index drug. The risk of major bleeding can be
significantly higher in patients with relatively high exposures to melagatran
relative to patients with relatively low exposures. Similarly, the risk of ALAT > 3x ULN can
also be significantly higher. Please
refer to Table I and Table
II of this review for further details. Knowing that there is a relationship between
extent of exposure and the risk of serious adverse events suggests that safe
use of ximelagatran could be improved through use of individualized dosing
rather than fixed doses for all patients.
Approximately 31% of the patients randomized in each of the
SPORTIF studies were females. The
direction and magnitude of the ximelagatran treatment effect with respect to
the primary efficacy endpoint was similar in males and females.
Due to the nature of the disease,
the population predominantly studied in the SPORTIF studies was an elderly
one. The mean ages of patients studied
were 70.2 and 71.6 years respectively.
Approximately 77% and 80% of patients randomized in SPORTIF III and V
respectively were > 65 years old. The direction and magnitude of
efficacy was similar in patients < 65 years of age, 65 to 74 years of age,
and > 75 years of age.
The vast majority of patients
studied in SPORTIF III and SPORTIF V were Caucasian: 88% in SPORTIF III and 96%
in SPORTIF V. 12% of the study
population was identified as Oriental in SPORTIF III while 3% of the study
population was identified as black in SPORTIF V. It is difficult to reliably make any conclusions
regarding the efficacy or safety of ximelagatran in Orientals or Blacks because
of the relatively few numbers of events in these patients.
The sponsor requests that the requirements to conduct
pediatric studies as per PREA (Pediatric Research Equity Act) be waived for the
indication of prevention of stroke and SEE in patients with nonvalvular atrial
fibrillation. The sponsor states that
the estimated number of pediatric patients diagnosed with atrial fibrillation
in the U.S. in
2002 is less than 1,500 children.
The sponsor has done studies in patients with renal and
hepatic impairment. In brief, these
studies showed that patients with renal impairment have altered significantly
altered exposure to ximelagatran while patients with hepatic impairment do
not. The results from these studies are
summarized in the section on Clinical Pharmacology above.
Ximelagatran is a reversible thrombin inhibitor that is being developed
as an alternative oral anticoagulant to warfarin, the current standard of
care. The indication that is the focus
of this review is the prevention of stroke and other thromboembolic
complications associated with atrial fibrillation. Two pivotal phase 3 studies (SPORTIF III and
SPORTIF V) have been submitted in support of the stated indication. The two studies are active controlled
studies designed to show that ximelagatran is non-inferior or “as good as”
treatment with warfarin.
The SPORTIF studies compared the effectiveness of a fixed dose of
ximelagatran, 36 mg administered twice a day, to warfarin, targeting an INR of
2 – 3 in patients with nonvalvular atrial fibrillation and at least one
additional risk factor for stroke.
SPORTIF III and SPORTIF V were similar in design except that the former
was open-label while the latter was blinded.
The primary endpoint was the composite occurrence of all strokes
(ischemic and hemorrhagic) and systemic embolic events. The sponsor pre-specified a non-inferiority
margin of 2% in the event rate.
Ximelagatran would be called non-inferior if an excess of 2% per year in
the event rate could be confidently excluded.
A margin of this magnitude could leave open the possibility that
ximelagatran was only half as effective as warfarin and still be considered
non-inferior to warfarin. The magnitude
of this non-inferiority margin was not formally agreed upon by the reviewing
division within the Agency and marked as a point of future
review/discussion. The two SPORTIF
studies produced divergent results despite similar designs. In such a setting I would favor the results
from a double-blind study.
In terms of safety, liver toxicity as assessed by serum aminotransferase
abnormalities occurred approximately 6 times more often on ximelagatran
compared to warfarin and was consistent across both trials. There was one well documented case (and most
probably a second case) of drug induced liver failure leading to coagulopathy
and death among the approximately 3700 patients randomized to the ximelagatran
arm of both studies. In terms of major
bleeding events, the total number of bleeds was numerically lower in the
ximelagatran arm of both studies. In
neither of the studies did the difference achieve statistical
significance. Bleeding events leading to
death were relatively few in both studies and similar in the two treatment
arms.
Melagatran, the active metabolite of ximelagatran, primarily excreted
unchanged in the urine. There is a
strong correlation between the oral clearance of melagatran and creatinine
clearance. Exposure differences can be
significant in the setting of renal impairment.
Renal impairment is expected in the patient population for which this
drug is targeted. There appears to be a
relationship between higher exposures and increased risk of major bleeds and
elevations in aminotransferases. Thus a
fixed dosing strategy of ximelagatran could potentially be harmful if
implemented.
SPORTIF II/SPORTIF IV STUDY
1.
SPORTIF II
“Tolerability and Safety of the Oral Thrombin Inhibitor
H376/95, Compared to Warfarin, as Stroke Prophylaxis with Atrial Fibrillation. A Dose-Guiding, Feasibility
Multicenter Study”
SPORTIF
II was a multi-center, randomized, parallel group, dose ranging, Phase II study
that compared the safety and tolerability of ximelagatran (20, 40, or 60 mg
bid) with warfarin, aiming for an INR of 2 – 3 in patients with nonvalvular
atrial fibrillation. The study was
double-blind with respect to ximelagatran dosing but unblinded with respect to
warfarin administration. The
inclusion/exclusion criteria were generally similar to those in SPORTIF III and
V. The duration of treatment in this
study was 12 weeks.
257
patients were randomized into the study (N’s = 66, 64, 60 in Ximelagatran 20
mg, 40 mg, 60 mg bid respectively; N =
67 in warfarin). 254 actually received
treatment. 207 patients completed
treatment. The mean age of patients in
the study was 69.5 years. The various
treatment groups were fairly similar with respect age, gender, ethnicity, risk
factors for Afib, use of medications at study entry, weight, and chronicity of Afib.
With
regards to efficacy, in the ximelagatran arm, 1 patient (60 mg bid) experienced
a TIA and 1 patient (60 mg bid) experienced an ischemic stroke. In the warfarin arm, 2 patients experienced
TIA’s. There were no reported events in
the 2 lower dose groups of ximelagatran.
There were no reported SEE’s or hemorrhagic strokes during this 12 week
study.
The
safety in SPORTIF II is summarized in Table
LIX below. Recall
that 257 patients were randomized into SPORTIF II but 254 actually received
treatment.
Table LIX: Summary of safety findings from SPORTIF II
study (shown are the numbers of patients with events)
|
|
Ximelagatran (H376/95) bid
|
Warfarin (N = 67)
|
Total
|
|
|
20 mg
(N = 66)
|
40 mg
(N = 62)
|
60 mg
(N = 59)
|
|
|
|
Death
|
1
|
0
|
0
|
0
|
1
|
|
Major bleed
|
0
|
0
|
0
|
1
|
1
|
|
Total bleeds (major +
minor)
|
4
|
5
|
7
|
7
|
23
|
|
Any LFT reported as AE
|
3
|
6
|
4
|
1
|
14
|
|
Discontinuation due to AE
|
7
|
4
|
5
|
6
|
22
|
Data obtained from Tables 12.2:1,
12.2.2:1, 12.3.1.3:1, and 12.3.1.4:3
2.
SPORTIF IV
“Long Term Treatment with the Oral Direct Thrombin Inhibitor
H376/95, Compared to Warfarin, as Stroke Prophylaxis in Patients with Atrial
Fibrillation. An Open 5-Year Follow-up
Study”
SPORTIF IV was a follow on study to SPORTIF II. 167 patients from the SPORTIF II study
initiated SPORTIF IV. The primary
objective of SPORTIF IV was to evaluate the tolerability of long-term treatment
with ximelagatran compared to warfarin.
It was conducted as an open-label study.
The study is still ongoing as of the time of submission of this
NDA. The results from interim study
reports are summarized below. The dose
of ximelagatran given to patients in this study was 36 mg bid (the proposed
commercial formulation). The safety and efficacy findings from SPORTIF IV are
summarized in Table LX below.
Table LX: Summary of findings from the SPORTIF IV
study
|
|
Ximelagatran
|
Warfarin
|
|
Summary of results of the first two years of IV (includes endpoints
that occurred in SPORTIF II); Results
up to 30 June 01;
|
|
# of patients that entered
SPORTIF IV
|
125
|
42
|
|
Deaths
|
3
|
2
|
|
Strokes
|
2
|
2
|
|
TIA
|
1
|
2
|
|
Major bleeds
|
2
|
2
|
|
Elevated liver enzymes
reported as SAE’s
|
16
|
4
|
|
Summary of results from the second two years of SPORTIF IV; New
events occurring between 30 June 01 and 27 June 03;
|
|
# of patients entering
this study period
|
102
|
33
|
|
Death
|
9
|
2
|
|
Stroke
|
2
|
1
|
|
TIA
|
1
|
0
|
|
Major bleeds
|
2
|
2
|
|
ALT >3x ULN
|
1
|
0
|
|
Summary of results from 27 June 03 through 27 March 04; New
events occurring during this time period.
|
|
# of patients entering
this study period
|
85
|
30
|
|
Death
|
5
|
0
|
Data obtained from the text and various tables
from SPORTIF IV Clinical study report dated 31 July 2003, SPORTIF IV Safety
Update dated 21 October 03, 4-month safety update report (4-MSU) for EXANTA
dated 22 April 2004.
The
Clinical White Paper on Hepatotoxicity published in November 2000 references
Dr. Hyman Zimmerman’s observation, noting that the combination of a pure hepatocellular
injury (transaminase elevation without much alkaline phosphatase elevation) and
jaundice is particularly ominous, with about 10-15% of such patients who show
such findings as a result of drug-induced injury going on to die. Case narratives of selected patients with
markedly elevated aminotransferase levels and temporally related elevation in
serum bilirubin levels and/or jaundice are described below.
Patient 3174 (SPORTIF III)
An 85 y/o Caucasian male’s past
medical history included atrial fibrillation, hypertension, diabetes mellitus
and coronary heart disease
Medications:
furosemide, glycerol trinitrate, human insulin, ramipril, zopiclone
February 27, 2001: Baseline visit
March 5, 2001: Randomized to receive ximelagatran 36 mg bid
April 30, 2001: Aminotransferase level elevation
first noted by central lab. Patient was
noted to have fatigue, troubling sleeping and nausea 13 days prior to ALT
elevation.
May 23, 2001: Patient received last dose of study drug
This
patient had an unrevealing work-up for his liver enzyme abnormalities including
negative ANA, Smooth muscle antibodies, IgG and IgM CMV antibodies, and viral
hepatitis titers. The patient’s
aminotransferase enzyme levels and bilirubin levels had normalized
approximately 2 months post study drug discontinuation.
Table LXI: Pattern of liver enzyme progression in
patient 3174
|
|
3/5/01
|
4/2/01
|
4/17/01
|
4/30/01
|
5/16/01
|
5/28/01
|
6/8/01
|
6/19/01
|
6/26/01
|
|
ALAT (U/L)
|
35
|
29
|
39
|
325
|
470
|
599
|
510
|
265
|
147
|
|
ASAT (U/L)
|
30
|
29
|
50
|
315
|
509
|
680
|
458
|
205
|
123
|
|
ALPa (U/L)
|
196
|
234
|
360
|
708
|
610
|
523
|
502
|
408
|
334
|
|
Bilib (mmol/L)
|
15
|
10
|
14
|
15
|
27
|
28
|
49
|
28
|
18
|
Data taken from Case Report
Form and/or Case narrative
aNormal alkaline phosphatase
range is 20-125 U/L
bNormal bilirubin range is 0 to
22 mmol/L
Patient 1967 (SPORTIF III)
A 71 y/o Caucasian male’s past
medical history included atrial fibrillation, stroke, heart failure, and
essential hypertension.
Medications:
Carvedilol, digoxin, furosemide, potassium, trandolapril
November 22, 2000: Baseline
visit in which baseline lab tests were done.
December 6, 2000: Patient was randomized to receive
ximelagatran.
December 8, 2000: Two days after initiating study
medication, the patient was noted problems of tiredness and problems with
balance.
December 11, 2000: Patient had sudden onset of double-vision
and dizziness and was admitted to the hospital.
He was diagnosed as having a brain stem stroke by a neurologist. Study drug was stopped. During the course of hospitalization, the
patient had several episodes of syncope causing his hospital stay to be
prolonged. Also during the course of
hospitalization, it was noted that the patient’s liver enzymes were elevated. The patient was also noted to be
jaundiced. An abdominal ultrasound was
done revealing a few gallstones but no reports of obstruction in the case
narrative.
December 18, 2000: The patient’s condition improved, his liver
enzymes were noted to be improving and he was discharged from the hospital.
An
extended liver laboratory panel was remarkable for an elevated CMV antibody
IgM, EIA. In the case narrative there
was no description of this patient having fever, abdominal pain, nausea,
vomiting, loss of appetite, etc. Blood
work at baseline revealed no evidence of lymphocytosis.
Table
LXII: Pattern of liver enzyme progression for patient 1967
|
|
Baseline (11/22/2000)
|
Early DC visit (12/14/2000)
|
|
WBC
|
7.9
|
7.1
|
|
Lymphocytes (%)
|
24
|
21
|
|
ALAT
|
30
|
414
|
|
ASAT
|
26
|
195
|
|
ALPa
|
77
|
215
|
|
Bilib (mmol/L)
|
13
|
127
|
Data taken from Case Report
Form and/or Case narrative
aNormal alkaline phosphatase
range is 20-125 U/L
bNormal bilirubin range is 0
to 22 mmol/L
Patient 7986 (SPORTIF V)
An 81 y/o
Caucasian female’s past medical history included atrial fibrillation, hypertension,
pericarditis, coronary artery disease, hyperlipidemia, mitral valve prolapse,
and eye hemorrhages.
Medications:
acetylsalicylic acid, ascorbic acid, tocopheryl acetate, retinol, zinc,
calcium, vitamins, minerals, atenolol, atorvastatin, doxazosin, conjugated
estrogens, furosemide, potassium chloride.
August 23, 2001: Patient was randomized to
ximelagatran
October 04, 2001: Patient was first noted to
have elevated liver enzymes (see table below).
Patient was asymptomatic despite liver enzyme abnormalities throughout
the time the enzymes were elevated.
November 8, 2001: Study medication discontinued
A little
more than one month after study drug discontinuation, the patient had an
abdominal ultrasound that revealed cholelithiasis that was not considered
clinically relevant. There was no
evidence of biliary duct dilatation. The
patient also had an extensive work-up ANA Antibody titer, Smooth Muscle
antibody titer, CMV IgG and IgM, EBV IgG and IgM, Hep A, B, C that were not
considered clinically significant.
Table LXIII: Pattern of liver enzyme progression for
patient 7986
|
|
8/16/01
|
9/20/01
|
10/4/01
|
10/17/01
|
10/25/01
|
11/8/01
|
11/21/01
|
11/29/01
|
12/7/01
|
1/10/02
|
|
ALAT (U/L)
|
24
|
20
|
60
|
120
|
220
|
689
|
673
|
548
|
329
|
46
|
|
ASAT (U/L)
|
16
|
16
|
37
|
120
|
182
|
670
|
648
|
529
|
307
|
55
|
|
ALP (U/L)
|
93
|
95
|
184
|
122
|
132
|
162
|
162
|
132
|
118
|
64
|
|
Bili (mg/dL)
|
0.7
|
0.8
|
1.0
|
0.7
|
1.4
|
1.4
|
2.3
|
2.7
|
2.2
|
1.2
|
Data taken from Case Report
Form and/or Case narrative
Patient 5402 (SPORTIF V):
A 73 y/o
Caucasian female’s medical history included atrial fibrillation, coronary
artery disease, carotid disease, pulmonary hypertension, mild chronic anemia,
and chronic nocturia with a rectocystocele.
Medications:
enalapril, conjugated estrogens, fexofenadine, iron, metoprolol
December 12, 2000: Patient
was randomized to ximelagatran
January 23, 2001: Elevated liver enzymes were noted (see
Table below). Patient was asymptomatic
despite liver enzyme elevations.
February 9, 2001: Study drug was discontinued. An abdominal ultrasound revealed a normal
liver, bile ducts, and pancreas.
Extended liver laboratory investigations were unrevealing including ANA
antibody, Smooth muscle antibody, CMV IgG and IgM, EBV IgG and IgM, Hepatitis
A,B, C.
March 5, 2001: Patient was seen in the Emergency department of a hospital
for chest pain, epigastric discomfort, hematuria, and to rule out an MI.
March 8, 2001: Patient was admitted to the hospital for weakness and
lethargy. On physical exam, the patient
had a blood pressure of 80-90/50 mm Hg.
She was also noted to be jaundiced.
Laboratory work-up revealed the patient to be anemic (hematocrit =
23). Patient also had guiaic positive
stools. The patient was treated with
vitamin K and 2 units of packed red blood cells. Further work-up during the hospitalization
included an upper and lower GI endoscopy both of which were unrevealing in
terms of an identifiable source of bleed.
March 15, 2001: Patient was discharged in stable
condition.
Table LXIV: Pattern of liver enzyme progression for
patient 5402
|
|
12/5/00
|
1/9/01
|
1/23/01
|
1/30/01
|
2/6/01
|
2/20/01
|
3/5/01a
|
3/8/01a
|
4/12/01
|
|
ALAT (U/L)
|
36
|
30
|
196
|
282
|
448
|
492
|
1483
|
707
|
78
|
|
ASAT (U/L)
|
34
|
29
|
145
|
270
|
446
|
556
|
1586
|
528
|
90
|
|
ALP (U/L)
|
82
|
120
|
199
|
195
|
178
|
140
|
230
|
145
|
110
|
|
Bili (mg/dL)
|
0.4
|
0.4
|
0.6
|
0.5
|
0.7
|
0.9
|
2.9
|
5.6
|
1.8
|
|
|
|
|
|
|
|
|
|
|
|
Data taken from Case Report
Form and/or Case narrative
aLabs on 3/5/01 and 3/8/01 were obtained from narrative
in sponsors clinical study report for SPORTIF V. These lab values were not available in the
Case Report Form of this patient.
Patient 8387(SPORTIF V):
An 80 y/o
Caucasian females past medical history included atrial fibrillation, permanent
pacemaker insertion, angina, coronary heart disease, bradycardia, torsades de
pointes, hypertension, hyperlipidemia, osteoporosis, and hypothyroidism.
Medications:
atenolol, calcium, digoxin, ergocalciferol,
retinol, calcium carbonate, estrogen, furosemide, levothyroxine, sodium
Phenobarbital, atropine methonitrate, glyceryl trinitrate, theophylline,
papaverine, potassium chloride, ramipril
October 10, 2001: Patient
was randomized to ximelagatran
December 10, 2001: Elevated liver enzymes were noted. There were no reports that the patient was
symptomatic in association with enzyme elevations.
December 14, 2001: Study drug permanently discontinued and
patient was started on open-label warfarin for stroke prophylaxis. Patient had an extensive liver work-up that
was negative (including ANA antibody; Smooth muscle antibody; CMV; EBV; Hepatitis
A,B, and C).
January 3, 2002: Liver enzyme elevations peaked. The patient remained asymptomatic.
January 14, 2002: After this date, there is evidence of
improvement in bilirubin levels. Liver
tests eventually returned to normal in this patient.
Table LXV: Pattern of liver enzyme progression for
patient 8387
|
|
Baseline
|
7Nov01
|
10Dec01
|
17Dec01
|
27Dec01
|
3Jan02
|
10Jan02
|
14Jan02
|
22Jan02
|
11Feb02
|
|
ALAT (U/L)
|
8
|
8
|
128
|
270
|
590
|
729
|
527
|
410
|
245
|
53
|
|
ASAT (U/L)
|
15
|
17
|
180
|
447
|
1240
|
1419
|
1158
|
903
|
544
|
76
|
|
ALP (U/L)
|
74
|
72
|
77
|
82
|
131
|
141
|
155
|
170
|
199
|
137
|
|
Bili (mmol/L)
|
8
|
6
|
8
|
6
|
14
|
48
|
158
|
238
|
202
|
54
|
|
|
|
|
|
|
|
|
|
|
|
|
Data
taken from Case Report Form and/or Case narrative
Abbreviations:
aPTT =
activated partial thromboplastin time
AE’s =
Adverse events
AF =
Atrial Fibrillation
ALAT =
Alanine Aminotransferase (also referred to as SGPT)
ANA =
Antinuclear Antibody
AMI =
Acute Myocardial infarction
ASAT =
Aspartate aminotransferase (also referred to as SGOT)
ALP =
Alkaline phosphatase
AUC = Area
under the plasma concentration time curve
Bid =
twice a day
Bili =
Total bilirubin
CEAC =
Clinical Events Adjudication Committee
CCK =
cholecystekinin
CRF = case
report form
CSR =
clinical study report
CrCL =
creatinine clearance
CV =
Coefficient of variation
DSMB =
Data Safety Monitoring Board
ECG =
Electrocardiogram
ESC =
Executive Steering Committee
H376/95 =
ximelagatran
INR =
International Normalized Ratio
ITT =
Intention to Treat
IVRS =
Interactive Voice response system
LFT’s =
liver function tests (this includes ALAT, ASAT, ALP, and Bilirubin)
MI =
Myocardial infarction
PT =
Prothrombin time
SAE =
Serious Adverse Event
SAP =
Statistical Analysis Plan
SEE =
systemic embolic event
ULN =
Upper limit of normal
WBC =
white blood count
95% CI =
95% confidence interval
