Interaction Between High Dose Rifampicine and Efavirenz in Pulmonary Tuberculosis and HIV Co-infection (RIFAVIRENZ)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT01986543|
Recruitment Status : Active, not recruiting
First Posted : November 18, 2013
Last Update Posted : July 11, 2017
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 or disease||Intervention/treatment||Phase|
|Tuberculosis HIV||Drug: drug administration||Phase 2|
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)
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||105 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Interaction Between High Dose Rifampicine and Efavirenz in Pulmonary Tuberculosis and HIV Co-infection|
|Actual Study Start Date :||December 2013|
|Estimated Primary Completion Date :||December 2017|
|Estimated Study Completion Date :||December 2017|
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
- 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 ]
- Efavirenz Cmin; Cmax; Tmax; AUC0-24 [ Time Frame: Week 28 ]
- Pharmacokinetic parameters of R and H (Cmin, Cmax and AUC0-24) [ Time Frame: Week 2 ]
- Pharmacokinetic parameters of R and H (Cmin, Cmax and AUC0-24) [ Time Frame: Week 8 ]
- Mycobacterium tuberculosis culture of sputum [ Time Frame: week 8 ]
- Plasma HIV-1 RNA [ Time Frame: week 28 ]
- Grade 3 and 4 adverse events [ Time Frame: 0-28 weeks ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01986543
|Mbarara Research Base|
|Mbarara PO box 1956, Mbarara, Uganda|
|Principal Investigator:||BONNET Maryline, MD||Epicentre MSF|