TuberculosisPhase 2RIFAVIRENZNCT01986543
Interaction Between High Dose Rifampicine and Efavirenz in Pulmonary Tuberculosis and HIV Co-infection
A Phase 2 study testing drug administration in people with Tuberculosis and HIV, run by ANRS, Emerging Infectious Diseases at 1 site in Uganda.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis, HIV
- What is being tested?
- drug administration
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 105 participants
- Where
- 1 siteUganda
- Study dates
- Dec 2013to Dec 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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)
- Conditions
- Tuberculosis, HIV
- Being tested
- drug administration
- Keywords
- Pharmacokinetic
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
drug administrationDrug
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | 8 weeks R20mg/Kg + HZE and efavirenz 600mg Receives: Drug: drug administration |
| Arm 2 | Experimental | 8 weeks R20mg/Kg + HZE and efavirenz 800mg Receives: Drug: drug administration |
| Standard arm | Active comparator | 8 weeks R10mg/Kg + HZE and efavirenz 600mg Receives: Drug: drug administration |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: Week 8
Efavirenz Cmin; Cmax; Tmax; AUC0-24
Measured: Week 28
Secondary outcomes (5)
Pharmacokinetic parameters of R and H (Cmin, Cmax and AUC0-24)
Measured: Week 2
Pharmacokinetic parameters of R and H (Cmin, Cmax and AUC0-24)
Measured: Week 8
Mycobacterium tuberculosis culture of sputum
Measured: week 8
Plasma HIV-1 RNA
Measured: week 28
Grade 3 and 4 adverse events
Measured: 0-28 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2013 (estimated)
- Study startDec 2013
- Primary completionDec 2017 (estimated)
- Study completionDec 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by ANRS, Emerging Infectious DiseasesThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 105 participants (estimated)
Sponsor and investigators
- Lead sponsor
- ANRS, Emerging Infectious Diseases
- Sponsor type
- Other government
- Responsible party
- Sponsor
- Investigators
- BONNET Maryline, MD, Principal investigator, Epicentre MSF
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01986543
- Sponsor's protocol ID
- ANRS 12292 RIFAVIRENZ
- Acronym
- RIFAVIRENZ
- Status last verified
- Jul 2017
- First submitted
- 12 Nov 2013
- Last updated
- 11 Jul 2017
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 11 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Interaction Between High Dose Rifampicine and Efavirenz in Pulmonary Tuberculosis and HIV Co-infection
- ClinicalTrials.gov ID
- NCT01986543
- Acronym / sponsor ID
- RIFAVIRENZ / ANRS 12292 RIFAVIRENZ
- Conditions
- Tuberculosis, HIV
- Keywords
- Pharmacokinetic
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 105 participants (estimated)
- Lead sponsor
- ANRS, Emerging Infectious DiseasesOther government
- Study start
- Dec 2013 (actual)
- Primary completion
- Dec 2017 (estimated)
- Study completion
- Dec 2017 (estimated)
- First posted
- 18 Nov 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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)
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Drug: drug administration8 weeks R20mg/Kg + HZE and efavirenz 600mg |
| Arm 2 | Experimental | Drug: drug administration8 weeks R20mg/Kg + HZE and efavirenz 800mg |
| Standard arm | Active comparator | Drug: drug administration8 weeks R10mg/Kg + HZE and efavirenz 600mg |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (9 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| drug administration | Drug | Arm 1, Arm 2, Standard arm |
Primary outcome
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
5 secondary outcomes
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
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jul 2017.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
BONNET Maryline, MD principal investigator
Epicentre MSF
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing drug administration in people with Tuberculosis and HIV, run by ANRS, Emerging Infectious Diseases at 1 site in Uganda.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 11 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Uganda. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jul 2017.