TuberculosisPhase 2SAEFRIFNCT03982277
Safety and Efficacy of High Dose Rifampicin in Tuberculosis (TB)-HIV Co-infected Patients on Efavirenz- or Dolutegravir-based Antiretroviral Therapy
A Phase 2 study testing Rifampin 300 Mg Oral Capsule in people with Tuberculosis, run by Makerere University at 1 site in Uganda.
Trial summary
Higher doses of rifampicin has been associated with a faster drop in bacterial load over time, and shorter treatment regimens with high dose rifampicin are being proposed. Sub-therapeutic rifampicin concentrations are common in TB patients and have been demonstrated in several studies carried out among patients with… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis
- What is being tested?
- Rifampin 300 Mg Oral Capsule
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 130 participants
- Where
- 1 siteUganda
- Study dates
- 30 Apr 2019to 23 Jul 2021
- 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
- Evidence of a personally signed and dated informed consent document.
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
- Age of ≥18 years
- Confirmed HIV-1 infection
- Already started on EFV-based or DTG-based ART or planned to start on ART
- Diagnosed with tuberculosis and due to initiate rifampicin-containing therapy
Who cannot join
- Rifampicin resistant TB identified by baseline Xpert Mycobacterium Tuberculous (MTB)/ Rifampicin (RIF)
- Pregnant women or women planning to get pregnant during TB treatment
- Women of reproductive age on DTG who decline the use of effective contraception methods (in particular: intrauterine device or condoms)
- Decompensated liver disease and/or aminotransferases >5x upper limit of normal (ULN)
- Glomerular filtration rate < 50 ml/min
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized, Four-arm Open Label Phase Two-b Clinical Trial to Evaluate the Pharmacokinetics, Safety/Tolerability and Efficacy of High Dose Rifampicin in TB-HIV Co-infected Patients on Efavirenz- or Dolutegravir-based Antiretroviral Therapy
Higher doses of rifampicin has been associated with a faster drop in bacterial load over time, and shorter treatment regimens with high dose rifampicin are being proposed. Sub-therapeutic rifampicin concentrations are common in TB patients and have been demonstrated in several studies carried out among patients with tuberculosis receiving the standard dose (10mg/kg) of rifampicin. Insufficient exposure to isoniazid and rifampicin, which are the cornerstones of TB treatment, has been associated with drug resistance, treatment failure and delayed bacterial clearance from sputum. Evidence has indicated that the current dose of rifampicin (10mg/kg) is inadequate for many patients. Several studies have suggested that dose escalation (to 20-35mg/kg) is safe, and that higher doses (35mg/kg) may accelerate clearance of TB bacteria from the sputum of infected individuals and achievement of target concentrations.15,16 However, these studies have almost entirely been conducted among HIV negative TB patients, or TB-HIV co-infected patients without severe immunosuppression who are not yet receiving antiretroviral therapy (ART). TB-HIV co-infected patients on multiple additional drugs, including ART, are at increased risk of drug-drug interactions and drug related toxicities, including hepatotoxicity. Increasing the dose of rifampicin is a promising approach; however, there is paucity of data on the safety of higher doses of rifampicin in HIV infected patients on ART, and almost no information on the enzyme induction effect of high dose rifampicin on Efavirenz (EFV) and Dolutegravir (DTG). In this study, the investigators will not only evaluate for the enzyme induction effect of 35mg/kg of rifampicin on the most widely used first-line antiretrovirals, but will also look at the safety of these combinations in a population in which there is still scarce safety data. The aim of this study is to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz and dolutegravir in TB-HIV co-infected patients.
Read the detailed description
The investigators will enroll 120 TB-HIV co-infected patients initiating TB treatment. Participants will be randomized to either high dose (35mg/kg) or standard dose (10mg/kg) rifampicin in addition to either dolutegravir (DTG) or efavirenz (EFV), for those who are antiretroviral therapy (ART) naïve. Patients who are already on ART will remain on their current ART regimen. The randomization groups (30 participants in each arm) include:Arm One A: R35mg/kg Isoniazid/Ethambutol/Pyrazinamide (HEZ) + DTG, Arm One B: R10mg/kg HEZ + DTG (Control 1), Arm Two A: R35mg/kg HEZ + EFV, Arm Two B: R10mg/kg HEZ + EFV (Control 2).
High dose rifampicin will be administered for the first 8 weeks (intensive phase) of TB treatment. All other anti-TB drugs will be administered at the standard dose using fixed-dose combinations (FDC). All participants will receive standard dose rifampicin during the continuation phase (weeks 9 -24). Pharmacokinetic (PK) blood sampling will be performed after 6 weeks (±2 weeks) of TB treatment. PK sampling will occur pre-dose and at 1, 2, 4 and 8 hours after observed dose for rifampicin and DTG concentrations and approximately 12-14 hours post-dose for EFV (to measure mid-dose interval (MDI) concentration). The EFV MDI and rifampicin pre-dose samples will be collected concurrently in the EFV arms. Safety laboratory tests including liver and renal function tests will be measured every two weeks or when patients present with symptoms suggestive of toxicity. In participants with culture positive TB at baseline, sputum cultures will be performed after 8 weeks of anti-TB treatment.
The investigators will use population pharmacokinetic modelling to determine the rifampicin and DTG exposure in each arm. Using these models the investigators will evaluate for drug-drug interactions between ART and the standard and high dose of rifampicin. Investigators will compare the mid-dose concentrations of EFV and trough concentrations of DTG in each intervention and control arm using Wilcoxon rank-sum test. The investigators will also compare the proportion of participants with grade 3 or 4 adverse events in each arm using the chi-squared test. Investigators will compare the proportion of participants who are sputum culture negative after 8 weeks of treatment among those in the high dose and standard dose arms using the chi-squared test.
- Conditions
- Tuberculosis
- Being tested
- Rifampin 300 Mg Oral Capsule
- Keywords
- High dose rifampicin, TB/HIV co-infected persons, safety, pharmacokinetics, efficacy
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rifampin 300 Mg Oral CapsuleDrug
High dose rifampicin at 35mg/kg
| Study group | Role | What they receive |
|---|---|---|
| High dose Rifampin + DTG | Experimental | High dose Rifampicin (35mg/kg ) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Dolutegravir based ART regimen Receives: Drug: Rifampin 300 Mg Oral Capsule |
| Standard dose Rifampin + DTG | No intervention | Standard dose rifampicin (10mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Dolutegravir based ART regimen |
| High dose Rifampin + EFV | Experimental | High dose rifampicin (35mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Efavirenz based ART regimen Receives: Drug: Rifampin 300 Mg Oral Capsule |
| Standard dose Rifampin + EFV | No intervention | Standard dose rifampicin (10mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Efavirenz based ART regimen |
What is being measured
The primary outcome is the main question the study is designed to answer.
Measures of model predicted exposure/pharmacokinetic (PK) parameters
Area under the concentration-time curve over 24 hours (AUC(0-24h)) of DTG, EFV and rifampicin, by rifampicin dose (10 vs. 35 mg/kg rifampicin)
Measured: 6 (+/-2) weeks from ART initiation
Pharmacokinetics of high dose rifampicin on DTG and EFV
Maximum concentrations (Cmax), trough concentrations) of DTG, EFV and rifampicin, by rifampicin dose (10 vs. 35 mg/kg rifampicin)
Measured: 6 (+/-2) weeks from ART initiation
Secondary outcomes (2)
Safety of high dose rifampicin
Grade 3 or 4 laboratory or clinical adverse events, according to the National Institutes of Health Division of AIDS toxicity tables (DAIDS).
Measured: up to 24 weeks
Efficacy of high dose rifampicin
Negative sputum cultures
Measured: 8 weeks after TB treatment initiation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jun 2019
- Study start30 Apr 2019
- Primary completion16 Mar 2021
- Study completion23 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (18)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- 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
- 130 participants (actual)
Sponsor and investigators
- Lead sponsor
- Makerere University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Christine Sekaggya-Wiltshire, MBChB, PhD, Principal investigator, Infectious Diseases Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03982277
- Sponsor's protocol ID
- ST/224/219
- Acronym
- SAEFRIF
- Status last verified
- Mar 2022
- First submitted
- 30 May 2019
- Last updated
- 23 Mar 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual patient data (IPD) will made available to other researchers for further analysis or met-analysis following direct request to the sponsor (Infectious Diseases Institute).
Publications
Milstein M, Lecca L, Peloquin C, Mitchison D, Seung K, Pagano M, Coleman D, Osso E, Coit J, Vargas Vasquez DE, Sanchez Garavito E, Calderon R, Contreras C, Davies G, Mitnick CD. Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial. BMC Infect Dis. 2016 Aug 27;16(1):453. doi: 10.1186/s12879-016-1790-x.
PubMed 27567500Diacon AH, Patientia RF, Venter A, van Helden PD, Smith PJ, McIlleron H, Maritz JS, Donald PR. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob Agents Chemother. 2007 Aug;51(8):2994-6. doi: 10.1128/AAC.01474-06. Epub 2007 May 21.
PubMed 17517849Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis. 2000 Sep;4(9):796-806.
PubMed 10985648Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, Kibiki GS, Churchyard G, Sanne I, Ntinginya NE, Minja LT, Hunt RD, Charalambous S, Hanekom M, Semvua HH, Mpagama SG, Manyama C, Mtafya B, Reither K, Wallis RS, Venter A, Narunsky K, Mekota A, Henne S, Colbers A, van Balen GP, Gillespie SH, Phillips PPJ, Hoelscher M; PanACEA consortium. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017 Jan;17(1):39-49. doi: 10.1016/S1473-3099(16)30274-2. Epub 2016 Oct 26.
PubMed 28100438Sekaggya-Wiltshire C, von Braun A, Lamorde M, Ledergerber B, Buzibye A, Henning L, Musaazi J, Gutteck U, Denti P, de Kock M, Jetter A, Byakika-Kibwika P, Eberhard N, Matovu J, Joloba M, Muller D, Manabe YC, Kamya MR, Corti N, Kambugu A, Castelnuovo B, Fehr JS. Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations. Clin Infect Dis. 2018 Aug 16;67(5):708-716. doi: 10.1093/cid/ciy179.
PubMed 29514175Park JS, Lee JY, Lee YJ, Kim SJ, Cho YJ, Yoon HI, Lee CT, Song J, Lee JH. Serum Levels of Antituberculosis Drugs and Their Effect on Tuberculosis Treatment Outcome. Antimicrob Agents Chemother. 2015 Oct 12;60(1):92-8. doi: 10.1128/AAC.00693-15. Print 2016 Jan.
PubMed 26459901Burhan E, Ruesen C, Ruslami R, Ginanjar A, Mangunnegoro H, Ascobat P, Donders R, van Crevel R, Aarnoutse R. Isoniazid, rifampin, and pyrazinamide plasma concentrations in relation to treatment response in Indonesian pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2013 Aug;57(8):3614-9. doi: 10.1128/AAC.02468-12. Epub 2013 May 20.
PubMed 23689725Peloquin CA, Nitta AT, Burman WJ, Brudney KF, Miranda-Massari JR, McGuinness ME, Berning SE, Gerena GT. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother. 1996 Sep;30(9):919-25. doi: 10.1177/106002809603000901.
PubMed 8876848Sekaggya-Wiltshire C, von Braun A, Scherrer AU, Manabe YC, Buzibye A, Muller D, Ledergerber B, Gutteck U, Corti N, Kambugu A, Byakika-Kibwika P, Lamorde M, Castelnuovo B, Fehr J, Kamya MR. Anti-TB drug concentrations and drug-associated toxicities among TB/HIV-coinfected patients. J Antimicrob Chemother. 2017 Apr 1;72(4):1172-1177. doi: 10.1093/jac/dkw534.
PubMed 28108678Sloan D. Pharmacokinetic Variability in TB Therapy: Associations with HIV and Effect on Outcome. Paper presented at: Conference on Retroviruses and Opportunistic Infections2014.
Chang KC, Leung CC, Yew WW, Kam KM, Yip CW, Ma CH, Tam CM, Leung EC, Law WS, Leung WM. Peak plasma rifampicin level in tuberculosis patients with slow culture conversion. Eur J Clin Microbiol Infect Dis. 2008 Jun;27(6):467-72. doi: 10.1007/s10096-007-0454-6. Epub 2008 Jan 24.
PubMed 18214560van Ingen J, Aarnoutse RE, Donald PR, Diacon AH, Dawson R, Plemper van Balen G, Gillespie SH, Boeree MJ. Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment? Clin Infect Dis. 2011 May;52(9):e194-9. doi: 10.1093/cid/cir184.
PubMed 21467012Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, Phillips PP, Gillespie SH, McHugh TD, Hoelscher M, Heinrich N, Rehal S, van Soolingen D, van Ingen J, Magis-Escurra C, Burger D, Plemper van Balen G, Aarnoutse RE; PanACEA Consortium. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015 May 1;191(9):1058-65. doi: 10.1164/rccm.201407-1264OC.
PubMed 25654354Peloquin CA, Velasquez GE, Lecca L, Calderon RI, Coit J, Milstein M, Osso E, Jimenez J, Tintaya K, Sanchez Garavito E, Vargas Vasquez D, Mitnick CD, Davies G. Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis. Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00038-17. doi: 10.1128/AAC.00038-17. Print 2017 Aug.
PubMed 28559269Schutz C, Ismail Z, Proxenos CJ, Marais S, Burton R, Kenyon C, Maartens G, Wilkinson RJ, Meintjes G. Burden of antituberculosis and antiretroviral drug-induced liver injury at a secondary hospital in South Africa. S Afr Med J. 2012 Mar 2;102(6):506-11. doi: 10.7196/samj.5650.
PubMed 22668951
Study at a glance
From the registry record, last updated by the sponsor on 23 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Four-arm Open Label Phase Two-b Clinical Trial to Evaluate the Pharmacokinetics, Safety/Tolerability and Efficacy of High Dose Rifampicin in TB-HIV Co-infected Patients on Efavirenz- or Dolutegravir-based Antiretroviral Therapy
- ClinicalTrials.gov ID
- NCT03982277
- Acronym / sponsor ID
- SAEFRIF / ST/224/219
- Conditions
- Tuberculosis
- Keywords
- High dose rifampicin, TB/HIV co-infected persons, safety, pharmacokinetics, efficacy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 130 participants (actual)
- Lead sponsor
- Makerere UniversityUniversity, hospital or other
- Study start
- 30 Apr 2019 (actual)
- Primary completion
- 16 Mar 2021 (actual)
- Study completion
- 23 Jul 2021 (actual)
- First posted
- 11 Jun 2019 (actual)
- 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.
Higher doses of rifampicin has been associated with a faster drop in bacterial load over time, and shorter treatment regimens with high dose rifampicin are being proposed. Sub-therapeutic rifampicin concentrations are common in TB patients and have been demonstrated in several studies carried out among patients with tuberculosis receiving the standard dose (10mg/kg) of rifampicin. Insufficient exposure to isoniazid and rifampicin, which are the cornerstones of TB treatment, has been associated with drug resistance, treatment failure and delayed bacterial clearance from sputum. Evidence has indicated that the current dose of rifampicin (10mg/kg) is inadequate for many patients. Several studies have suggested that dose escalation (to 20-35mg/kg) is safe, and that higher doses (35mg/kg) may accelerate clearance of TB bacteria from the sputum of infected individuals and achievement of target concentrations.15,16 However, these studies have almost entirely been conducted among HIV negative TB patients, or TB-HIV co-infected patients without severe immunosuppression who are not yet receiving antiretroviral therapy (ART). TB-HIV co-infected patients on multiple additional drugs, including ART, are at increased risk of drug-drug interactions and drug related toxicities, including hepatotoxicity. Increasing the dose of rifampicin is a promising approach; however, there is paucity of data on the safety of higher doses of rifampicin in HIV infected patients on ART, and almost no information on the enzyme induction effect of high dose rifampicin on Efavirenz (EFV) and Dolutegravir (DTG). In this study, the investigators will not only evaluate for the enzyme induction effect of 35mg/kg of rifampicin on the most widely used first-line antiretrovirals, but will also look at the safety of these combinations in a population in which there is still scarce safety data. The aim of this study is to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz and dolutegravir in TB-HIV co-infected patients.
Detailed description
The investigators will enroll 120 TB-HIV co-infected patients initiating TB treatment. Participants will be randomized to either high dose (35mg/kg) or standard dose (10mg/kg) rifampicin in addition to either dolutegravir (DTG) or efavirenz (EFV), for those who are antiretroviral therapy (ART) naïve. Patients who are already on ART will remain on their current ART regimen. The randomization groups (30 participants in each arm) include:Arm One A: R35mg/kg Isoniazid/Ethambutol/Pyrazinamide (HEZ) + DTG, Arm One B: R10mg/kg HEZ + DTG (Control 1), Arm Two A: R35mg/kg HEZ + EFV, Arm Two B: R10mg/kg HEZ + EFV (Control 2).
High dose rifampicin will be administered for the first 8 weeks (intensive phase) of TB treatment. All other anti-TB drugs will be administered at the standard dose using fixed-dose combinations (FDC). All participants will receive standard dose rifampicin during the continuation phase (weeks 9 -24). Pharmacokinetic (PK) blood sampling will be performed after 6 weeks (±2 weeks) of TB treatment. PK sampling will occur pre-dose and at 1, 2, 4 and 8 hours after observed dose for rifampicin and DTG concentrations and approximately 12-14 hours post-dose for EFV (to measure mid-dose interval (MDI) concentration). The EFV MDI and rifampicin pre-dose samples will be collected concurrently in the EFV arms. Safety laboratory tests including liver and renal function tests will be measured every two weeks or when patients present with symptoms suggestive of toxicity. In participants with culture positive TB at baseline, sputum cultures will be performed after 8 weeks of anti-TB treatment.
The investigators will use population pharmacokinetic modelling to determine the rifampicin and DTG exposure in each arm. Using these models the investigators will evaluate for drug-drug interactions between ART and the standard and high dose of rifampicin. Investigators will compare the mid-dose concentrations of EFV and trough concentrations of DTG in each intervention and control arm using Wilcoxon rank-sum test. The investigators will also compare the proportion of participants with grade 3 or 4 adverse events in each arm using the chi-squared test. Investigators will compare the proportion of participants who are sputum culture negative after 8 weeks of treatment among those in the high dose and standard dose arms using the chi-squared test.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| High dose Rifampin + DTG | Experimental | Drug: Rifampin 300 Mg Oral CapsuleHigh dose Rifampicin (35mg/kg ) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Dolutegravir based ART regimen |
| Standard dose Rifampin + DTG | No intervention | –Standard dose rifampicin (10mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Dolutegravir based ART regimen |
| High dose Rifampin + EFV | Experimental | Drug: Rifampin 300 Mg Oral CapsuleHigh dose rifampicin (35mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Efavirenz based ART regimen |
| Standard dose Rifampin + EFV | No intervention | –Standard dose rifampicin (10mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Efavirenz based ART regimen |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Evidence of a personally signed and dated informed consent document.
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
- Age of ≥18 years
- Confirmed HIV-1 infection
- Already started on EFV-based or DTG-based ART or planned to start on ART
Key exclusion criteria (5 listed)
- Rifampicin resistant TB identified by baseline Xpert Mycobacterium Tuberculous (MTB)/ Rifampicin (RIF)
- Pregnant women or women planning to get pregnant during TB treatment
- Women of reproductive age on DTG who decline the use of effective contraception methods (in particular: intrauterine device or condoms)
- Decompensated liver disease and/or aminotransferases >5x upper limit of normal (ULN)
- Glomerular filtration rate < 50 ml/min
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 |
|---|---|---|
| Rifampin 300 Mg Oral CapsuleHigh dose rifampicin at 35mg/kg | Drug | High dose Rifampin + DTG, High dose Rifampin + EFV |
Primary outcome
Measures of model predicted exposure/pharmacokinetic (PK) parameters
Time frame: 6 (+/-2) weeks from ART initiation
Area under the concentration-time curve over 24 hours (AUC(0-24h)) of DTG, EFV and rifampicin, by rifampicin dose (10 vs. 35 mg/kg rifampicin)
Pharmacokinetics of high dose rifampicin on DTG and EFV
Time frame: 6 (+/-2) weeks from ART initiation
Maximum concentrations (Cmax), trough concentrations) of DTG, EFV and rifampicin, by rifampicin dose (10 vs. 35 mg/kg rifampicin)
2 secondary outcomes
Safety of high dose rifampicin
Time frame: up to 24 weeks
Efficacy of high dose rifampicin
Time frame: 8 weeks after TB treatment initiation
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Mar 2023.
- Background: PubMed 27567500Milstein M, Lecca L, Peloquin C, Mitchison D, Seung K, Pagano M, Coleman D, Osso E, Coit J, Vargas Vasquez DE, Sanchez Garavito E, Calderon R, Contreras C, Davies G, Mitnick CD. Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial. BMC Infect Dis. 2016 Aug 27;16(1):453. doi: 10.1186/s12879-016-1790-x.
- Background: PubMed 17517849Diacon AH, Patientia RF, Venter A, van Helden PD, Smith PJ, McIlleron H, Maritz JS, Donald PR. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob Agents Chemother. 2007 Aug;51(8):2994-6. doi: 10.1128/AAC.01474-06. Epub 2007 May 21.
- Background: PubMed 10985648Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis. 2000 Sep;4(9):796-806.
- Background: PubMed 28100438Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, Kibiki GS, Churchyard G, Sanne I, Ntinginya NE, Minja LT, Hunt RD, Charalambous S, Hanekom M, Semvua HH, Mpagama SG, Manyama C, Mtafya B, Reither K, Wallis RS, Venter A, Narunsky K, Mekota A, Henne S, Colbers A, van Balen GP, Gillespie SH, Phillips PPJ, Hoelscher M; PanACEA consortium. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017 Jan;17(1):39-49. doi: 10.1016/S1473-3099(16)30274-2. Epub 2016 Oct 26.
- Background: PubMed 29514175Sekaggya-Wiltshire C, von Braun A, Lamorde M, Ledergerber B, Buzibye A, Henning L, Musaazi J, Gutteck U, Denti P, de Kock M, Jetter A, Byakika-Kibwika P, Eberhard N, Matovu J, Joloba M, Muller D, Manabe YC, Kamya MR, Corti N, Kambugu A, Castelnuovo B, Fehr JS. Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations. Clin Infect Dis. 2018 Aug 16;67(5):708-716. doi: 10.1093/cid/ciy179.
- Background: PubMed 26459901Park JS, Lee JY, Lee YJ, Kim SJ, Cho YJ, Yoon HI, Lee CT, Song J, Lee JH. Serum Levels of Antituberculosis Drugs and Their Effect on Tuberculosis Treatment Outcome. Antimicrob Agents Chemother. 2015 Oct 12;60(1):92-8. doi: 10.1128/AAC.00693-15. Print 2016 Jan.
- Background: PubMed 23689725Burhan E, Ruesen C, Ruslami R, Ginanjar A, Mangunnegoro H, Ascobat P, Donders R, van Crevel R, Aarnoutse R. Isoniazid, rifampin, and pyrazinamide plasma concentrations in relation to treatment response in Indonesian pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2013 Aug;57(8):3614-9. doi: 10.1128/AAC.02468-12. Epub 2013 May 20.
- Background: PubMed 8876848Peloquin CA, Nitta AT, Burman WJ, Brudney KF, Miranda-Massari JR, McGuinness ME, Berning SE, Gerena GT. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother. 1996 Sep;30(9):919-25. doi: 10.1177/106002809603000901.
- Background: PubMed 28108678Sekaggya-Wiltshire C, von Braun A, Scherrer AU, Manabe YC, Buzibye A, Muller D, Ledergerber B, Gutteck U, Corti N, Kambugu A, Byakika-Kibwika P, Lamorde M, Castelnuovo B, Fehr J, Kamya MR. Anti-TB drug concentrations and drug-associated toxicities among TB/HIV-coinfected patients. J Antimicrob Chemother. 2017 Apr 1;72(4):1172-1177. doi: 10.1093/jac/dkw534.
- BackgroundSloan D. Pharmacokinetic Variability in TB Therapy: Associations with HIV and Effect on Outcome. Paper presented at: Conference on Retroviruses and Opportunistic Infections2014.
- Background: PubMed 18214560Chang KC, Leung CC, Yew WW, Kam KM, Yip CW, Ma CH, Tam CM, Leung EC, Law WS, Leung WM. Peak plasma rifampicin level in tuberculosis patients with slow culture conversion. Eur J Clin Microbiol Infect Dis. 2008 Jun;27(6):467-72. doi: 10.1007/s10096-007-0454-6. Epub 2008 Jan 24.
- Background: PubMed 21467012van Ingen J, Aarnoutse RE, Donald PR, Diacon AH, Dawson R, Plemper van Balen G, Gillespie SH, Boeree MJ. Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment? Clin Infect Dis. 2011 May;52(9):e194-9. doi: 10.1093/cid/cir184.
- Published manuscript for resultsLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Individual patient data (IPD) will made available to other researchers for further analysis or met-analysis following direct request to the sponsor (Infectious Diseases Institute).
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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.
Christine Sekaggya-Wiltshire, MBChB, PhD principal investigator
Infectious Diseases Institute
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 Rifampin 300 Mg Oral Capsule in people with Tuberculosis, run by Makerere University 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 6 inclusion and 5 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: finished, as of the sponsor's last update on 23 Mar 2023. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Measures of model predicted exposure/pharmacokinetic (PK) parameters (time frame: 6 (+/-2) weeks from ART initiation). 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?
On the ClinicalTrials.gov record for NCT03982277, which also lists 18 linked publications.
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 23 Mar 2023.