Interaction Between High Dose Rifampicine and Efavirenz in Pulmonary Tuberculosis and HIV Co-infection (RIFAVIRENZ)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Sponsor:
Information provided by (Responsible Party):
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier:
NCT01986543
First received: November 12, 2013
Last updated: April 1, 2014
Last verified: April 2014
  Purpose

We propose a first interaction study between efavirenz (EFV) and R20mg/Kg taking into consideration the absence of data about R induction at this dose. Due to an important inter-patient variability of the CYP2B6 polymorphism, the EFV pharmacokinetic (Pk) will be compared in same patients with and without TB treatment.

The main objective is to compare the Pk parameters of EFV in HIV-TB co-infected patients, with and without TB treatment, using R at 10 and 20mg/Kg/day and EFV at 600 and 800mg/day.


Condition Intervention Phase
Tuberculosis
HIV
Drug: drug administration
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Interaction Between High Dose Rifampicine and Efavirenz in Pulmonary Tuberculosis and HIV Co-infection

Resource links provided by NLM:


Further study details as provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):

Primary Outcome Measures:
  • Efavirenz through concentration before drug intake (Cmin); maximal concentration (Cmax); time to achieve the Cmax (Tmax) and area under the curve of concentrations vs time at steady state during a 24-hour dosing interval (AUC0-24) [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
  • Efavirenz Cmin; Cmax; Tmax; AUC0-24 [ Time Frame: Week 28 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pharmacokinetic parameters of R and H (Cmin, Cmax and AUC0-24) [ Time Frame: Week 2 ] [ Designated as safety issue: No ]
  • Pharmacokinetic parameters of R and H (Cmin, Cmax and AUC0-24) [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
  • Mycobacterium tuberculosis culture of sputum [ Time Frame: week 8 ] [ Designated as safety issue: No ]
  • Plasma HIV-1 RNA [ Time Frame: week 28 ] [ Designated as safety issue: No ]
  • Grade 3 and 4 adverse events [ Time Frame: 0-28 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 105
Study Start Date: December 2013
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
8 weeks R20mg/Kg + HZE and efavirenz 600mg
Drug: drug administration
Experimental: Arm 2
8 weeks R20mg/Kg + HZE and efavirenz 800mg
Drug: drug administration
Active Comparator: Standard arm
8 weeks R10mg/Kg + HZE and efavirenz 600mg
Drug: drug administration

Detailed Description:

Justification: In vitro and animal studies have shown that increasing the dose of rifampicin (R) improves the R sterilising effect. If a similar effect can be demonstrated in the clinical setting, this could allow shortening treatment duration from 6 to 4 months, with good tolerance. Several phase 2 trials in HIV-negative patients are ongoing. We propose a first interaction study between efavirenz (EFV) and R20mg/Kg taking into consideration the absence of data about R induction at this dose. Due to an important inter-patient variability of the CYP2B6 polymorphism, the EFV pharmacokinetic (Pk) will be compared in same patients with and without TB treatment.

Principal objective: To compare the Pk parameters of EFV in HIV-TB co-infected patients, with and without TB treatment, using R at 10 and 20mg/Kg/day and EFV at 600 and 800mg/day.

Secondary objectives: To describe the Pk parameters of R and isoniazid (H); the TB treatment réponse (Mycobacterium tuberculosis culture conversion after 8 weeks(w) and cure after 24w) ; the virological response; the occurrence of severe adverse events, especially hepatic and neurological events; the treatment adherence; the genes involved in the EFV metabolism of EFV, R and H, and its relation with the Pk parameters.

Primary endpoint: AUC0-24, Cmax, Cmin, Tmax of EFV after 4w of TB treatment + ARV, and 4w after interruption of TB treatment.

Study design : phase 2 randomized, open label 3 arms therapeutic trial:

  • Arm 1 : 8 weeks R20mg/Kg + H + pyrazinamide(Z)+ ethambutol(E) and EFV600mg/J + tenofovir-lamivudine
  • Arm 2: 8 weeks R20mg/Kg + H+Z+E and EFV800mg/J + tenofovir-lamivudine
  • Standard arm : 8 weeks R10mg/Kg + H+Z+E and EFV600mg/J + tenofovir-lamivudine

The ARV treatment will be initiated 4 weeks after starting TB treatment. After 8 weeks, all patients will receive 16 weeks of H+R with R at 10mg/Kg/day and EFV at 600mg/day. Treatment will be observed at home by a domiciliary treatment monitor (DTM). Patients will be followed during 28 weeks after starting TB treatment: weekly visit during first 8 weeks and then every 4 weeks.

Pk sampling for EFV, R and H will be at w2 (Pk1), w8 (Pk2) and w28 (Pk3). Liver function test and full blood count will be measured after 2, 4 and 8 weeks; sputum culture for TB at baseline and w8; HIV-1 RNA at baseline, w4, w12 and w24 and CD4 count at baseline and w24.

Eligibility criteria: > 18 years old; previously untreated pulmonary TB; Xpert confirming Mtb susceptible to R; body weight >45Kg; CD4 between 50 and 250cells/mm3; Karnofsky score >80%; ALAT/biluribin <5xULN; no grade 4 clinical/biological sign; no pregnancy + barrier contraception; agree to participate and sign a consent form.

Randomisation block, 1:1:1. Sample size: 28 patients to show that the reduction of AUC of EFV with R20mg/Kg vs no R is not greater to 30%, with 20% expected reduction. Same number per study arm and 20% increase for patients' withdrawals or lost to follow-up resulting in a total of 105 patients.

Site: Mbarara (Uganda)

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged of 18 years or more
  • Diagnosis of new pulmonary tuberculosis confirmed by a XpertMTB/RIF test
  • Positive HIV antibody test, naïve of ART with CD4 cell count between 50 and 250cells/mm3
  • For women of childbearing age, to have a negative urine test for pregnancy on the day of enrolment and to accept to take a barrier contraception during the period of the trial
  • Participants well enough to receive ambulatory treatment
  • Weight > 45Kg
  • Home address readily accessible
  • Participants providing informed consent to participate in the trial

Exclusion Criteria:

  • Rifampicin drug resistance based on the XpertMTB/RIF result confirmed by the GenotypeMTBDRplus assay
  • Concomitant opportunistic infection requiring additional infectious medication
  • Karnofsky score <80%
  • ALAT or bilirubin > 5.0 x ULN (hepatitis grade 3 or 4)
  • Haemoglobin < 7.5g/dL (grade 3 or 4)
  • Grade 4 clinical sign or biological result according to the ANRS for grading the intensity of adverse events
  • Patient not able to give his informed consent or is unlikely or unable to cooperate with sampling procedures
  • Patient suffering of psychiatric illness, which may prevent follow-up according to the protocol
  • Patients receiving or requiring medications that may interfere with study drugs
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01986543

Contacts
Contact: ATWINE Daniel, MD 00256 793328410 atwine.daniel@epicentre.msf.org
Contact: BONNET Maryline, MD 0041 22 8498940 maryline.bonnet@geneva.msf.org

Locations
Uganda
Mbarara Research Base Recruiting
Mbarara PO box 1956, Mbarara, Uganda
Contact: ATWINE Daniel, MD    00256 793328410    atwine.daniel@epicentre.msf.org   
Principal Investigator: Maryline Bonnet, MD         
Sponsors and Collaborators
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
  More Information

No publications provided

Responsible Party: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier: NCT01986543     History of Changes
Other Study ID Numbers: ANRS 12292 RIFAVIRENZ
Study First Received: November 12, 2013
Last Updated: April 1, 2014
Health Authority: Uganda: National Council for Science and Technology

Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):
Pharmacokinetic

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Coinfection
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Infection
Virus Diseases
Parasitic Diseases
Efavirenz
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 31, 2014