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Pharmacokinetics of Rifabutin Combined With Antiretroviral Therapy in Patients With TB/HIV Co-infection in South Africa

This study has been completed.
Sponsor:
Information provided by:
French National Agency for Research on AIDS and Viral Hepatitis
ClinicalTrials.gov Identifier:
NCT00640887
First received: February 6, 2008
Last updated: June 17, 2011
Last verified: June 2011
History of Changes
  Purpose

The overall aim of the project is to evaluate rifabutin (RBT) as a replacement for rifampicin (RMP), for the combined treatment of tuberculosis and HIV infection. RBT represents an alternative to RMP for HIV infected patients as its half-life is longer and the enzymatic induction effect appears to be less important on the associated antiretroviral therapy (ART) drugs.

This phase II trial is to determine precisely the pharmacokinetics parameters of RBT in combination with different ART regimens in Vietnamese HIV infected patients with pulmonary tuberculosis, in order to define optimal doses that will be further tested in a larger phase III trial comparing safety, tolerability and efficacy of RBT and RMP regimens.


Condition Intervention Phase
HIV Infections
Tuberculosis
 Drug: rifabutin in combination with efavirenz
Drug: rifabutin in combination with nevirapine
Drug: rifabutin in combination with lopinavir/ritonavir
 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacokinetics of Rifabutin Combined With Antiretroviral Therapy in the Treatment of Tuberculosis Patient With HIV Infection in South Africa: A Phase II Trial

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by French National Agency for Research on AIDS and Viral Hepatitis:

Primary Outcome Measures:
  • Area under the curve (AUC) of rifabutine measured (a)before introduction of ART;(b)after ART initiation (two different doses of RBT in combination with efavirenz, nevirapine or lopinavir/ritonavir) [ Time Frame: 2, 6 and 10 weeks after randomisation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Area under the curve (AUC) of efavirenz, nevirapine and lopinavir/ritonavir in combination with two doses of rifabutine [ Time Frame: 6 and 10 weeks after randomisation ] [ Designated as safety issue: No ]
  • Safety : proportion of patients with grade 3 and grade 4 adverse events [ Time Frame: through out the trial ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 48
Study Start Date: February 2009
Study Completion Date: October 2010
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
RBT associated with EFV based ART
 Drug: rifabutin in combination with efavirenz

Ia. arm 1a:

D4T/3TC/EFV(600mg)+INH/Rifabutin(450 mg OD 4 wks switch to 600 mg OD 4 wks);

Ib. arm 1b:

D4T/3TC/EFV(600mg)+INH/Rifabutin(600 mg OD 4 wks switch to 450 mg OD 4 wks);
Experimental: 2
RBT associated with NVP based ART
 Drug: rifabutin in combination with nevirapine

IIa. arm 2a:

D4T/3TC/NVP(200mg)+INH/Rifabutin(300 mg OD 4 wks switch to 450 mg OD 4 wks);

IIb. arm 2b :

D4T/3TC/NVP(200mg)+INH/Rifabutin(450 mg OD 4 wks switch to 300 mg OD 4 wks);
Experimental: 3
RBT associated with LPV/r based ART
 Drug: rifabutin in combination with lopinavir/ritonavir

IIIa. arm 3a :

D4T/3TC/LPV/r(2 tabs BD)+INH/Rifabutin(150 mg TPW 4 wks switch to 150 mg OD 4 wks);

IIIb. arm 3b:

D4T/3TC/LPV/r(2 tabs BD)+INH/Rifabutin(150 mg OD 4 wks switch to 150 mg TPW 4 wks).

Detailed Description:

Patients will be offered to participated in the study after the first 6 weeks of the nationally recommended TB treatment. All the enrolled patients will be switched to rifabutin and randomized, two weeks later, to one of the three study ARV regimens. The RBT doses will be then adapted to the allocated ARV regimen according to a cross over scheme. Three full pharmacokinetics profile will be performed at different time point : before initiation of ARV, after one month of the first RFB dosage and one month after the second RFB dosage.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pulmonary tuberculosis (proven by AFB positive sputum or culture)
  • Having completed and adhered to 6 wks of intensive phase TB chemotherapy
  • Positive HIV antibody and CD4 count >50 /mm3 and <=200
  • Weight > 50 kg
  • No ART in the preceding 3 months
  • No more than 2 weeks or ART previously
  • No grade 3 or 4 clinical or laboratory findings
  • Negative pregnancy test and appropriate contraceptive measures during the duration of the trial for female of childbearing age
  • Having a firm home address that is readily accessible
  • Karnofsky score>=80%

Exclusion Criteria:

  • History of TB within the 3 years preceding the presenting episode of TB
  • Previous treatment for MDR TB
  • Concomitant OI requiring additional anti-infectious treatment
  • Formal contraindication to any drug used in the trial
  • Diabetes mellitus requiring drug treatment
  • Recreational drug or alcohol abuse
  • History of drug hypersensitivity to TB or related medications
  • Interrupted TB therapy for more than 1 week
  • Less than 90% adherent to first 6 weeks of intensive phase chemotherapy
  • Mental illness that could impair ability to give informed consent or result in poor adherence to trial protocol and therapy
  • Neutropenia <1200 /L, anaemia <6.8 g/dL, liver function test > grade 2
  • Requiring concomitant medications that may potentially interact with study drugs
  • Pregnant or lactating women
  • Karnofsky score >80%
  • Any condition rendering the patient unable to understand the nature, scope, and possible consequences of thes study and to provide consent
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00640887

Locations
South Africa
Unit for Clinical and Biomedical TB Research (Medical Research Council)
Durban, South Africa, 4067
Sponsors and Collaborators
French National Agency for Research on AIDS and Viral Hepatitis
Investigators
Principal Investigator: Anthony D Harries, MD, PhD The international Union Against Tuberculosis and Lung Diseases (IUATLD), Paris, France
Principal Investigator: Alexander PYM, MD Medical Research Council, South Africa
  More Information

No publications provided

Responsible Party: Claire Rekacewicz, French National Agency for Research on AIDS and Viral Hepatitis
ClinicalTrials.gov Identifier: NCT00640887     History of Changes
Other Study ID Numbers: ANRS12150a
Study First Received: February 6, 2008
Last Updated: June 17, 2011
Health Authority: South Africa: Medicines Control Council

Keywords provided by French National Agency for Research on AIDS and Viral Hepatitis:
HIV
Tuberculosis
Rifabutin
Pharmacokinetics
South Africa

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Tuberculosis
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
 Bacterial Infections
Nevirapine
Ritonavir
Efavirenz
Lopinavir
Rifabutin
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on March 03, 2013