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

Primary Purpose

HIV Infections, Tuberculosis

Status
Completed
Phase
Phase 2
Locations
South Africa
Study Type
Interventional
Intervention
rifabutin in combination with efavirenz
rifabutin in combination with nevirapine
rifabutin in combination with lopinavir/ritonavir
Sponsored by
French National Agency for Research on AIDS and Viral Hepatitis
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring HIV, Tuberculosis, Rifabutin, Pharmacokinetics, South Africa

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Unit for Clinical and Biomedical TB Research (Medical Research Council)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

1

2

3

Arm Description

RBT associated with EFV based ART

RBT associated with NVP based ART

RBT associated with LPV/r based ART

Outcomes

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)

Secondary Outcome Measures

Area under the curve (AUC) of efavirenz, nevirapine and lopinavir/ritonavir in combination with two doses of rifabutine
Safety : proportion of patients with grade 3 and grade 4 adverse events

Full Information

First Posted
February 6, 2008
Last Updated
June 17, 2011
Sponsor
French National Agency for Research on AIDS and Viral Hepatitis
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1. Study Identification

Unique Protocol Identification Number
NCT00640887
Brief Title
Pharmacokinetics of Rifabutin Combined With Antiretroviral Therapy in Patients With TB/HIV Co-infection in South Africa
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2011
Overall Recruitment Status
Completed
Study Start Date
February 2009 (undefined)
Primary Completion Date
October 2010 (Actual)
Study Completion Date
October 2010 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
French National Agency for Research on AIDS and Viral Hepatitis

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections, Tuberculosis
Keywords
HIV, Tuberculosis, Rifabutin, Pharmacokinetics, South Africa

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
48 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
RBT associated with EFV based ART
Arm Title
2
Arm Type
Experimental
Arm Description
RBT associated with NVP based ART
Arm Title
3
Arm Type
Experimental
Arm Description
RBT associated with LPV/r based ART
Intervention Type
Drug
Intervention Name(s)
rifabutin in combination with efavirenz
Intervention Description
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);
Intervention Type
Drug
Intervention Name(s)
rifabutin in combination with nevirapine
Intervention Description
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);
Intervention Type
Drug
Intervention Name(s)
rifabutin in combination with lopinavir/ritonavir
Intervention Description
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).
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
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
Title
Safety : proportion of patients with grade 3 and grade 4 adverse events
Time Frame
through out the trial

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anthony D Harries, MD, PhD
Organizational Affiliation
The international Union Against Tuberculosis and Lung Diseases (IUATLD), Paris, France
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Alexander PYM, MD
Organizational Affiliation
Medical Research Council, South Africa
Official's Role
Principal Investigator
Facility Information:
Facility Name
Unit for Clinical and Biomedical TB Research (Medical Research Council)
City
Durban
ZIP/Postal Code
4067
Country
South Africa

12. IPD Sharing Statement

Citations:
PubMed Identifier
26482301
Citation
Hennig S, Naiker S, Reddy T, Egan D, Kellerman T, Wiesner L, Owen A, McIlleron H, Pym A. Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis. Antimicrob Agents Chemother. 2015 Oct 19;60(1):617-20. doi: 10.1128/AAC.01195-15. Print 2016 Jan.
Results Reference
derived
PubMed Identifier
25406657
Citation
Naiker S, Connolly C, Wiesner L, Kellerman T, Reddy T, Harries A, McIlleron H, Lienhardt C, Pym A. Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy. BMC Pharmacol Toxicol. 2014 Nov 19;15:61. doi: 10.1186/2050-6511-15-61.
Results Reference
derived

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

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