Latent TuberculosisPhase 22R2NCT03988933
2R2: Higher Dose Rifampin for 2 Months vs Standard Dose Rifampin for Latent TB.
A Phase 2 study testing Rifampin double dose, Rifampin triple dose and Rifampin standard dose in people with Latent Tuberculosis, run by McGill University Health Centre/Research Institute of the McGill University Health Centre at 9 sites in 3 countries.
Trial summary
Rationale: Shorter regimens of high dose daily rifampin may be safe, and as effective as the standard rifampin regimen when taken for 4 months to treat latent TB (LTBI). However, there is insufficient evidence on the optimal dose of rifampin that has similar efficacy as the standard 4-month rifampin regimen without… Read more about this study
- Who is it for?
- Ages 10 years and older
- Conditions the study is for
- Latent Tuberculosis
- What is being tested?
- Rifampin double dose, Rifampin triple dose and Rifampin standard dose
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,368 participants
- Where
- 9 sitesin 3 countries
- Study dates
- 20 Sep 2019to 31 Dec 2024
- 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 10 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Adults, and children aged 10 and older who weigh at least 25kg.
- Evidence of latent TB infection: positive tuberculin skin test (5mm or greater or 10mm or greater, based on National guidelines) or positive interferon gamma release assay.
- Eligible to take latent TB treatment according to Canadian guidelines in the Canadian sites, and according to World Health Organization (WHO) guidelines in the international sites (this includes household contacts, other contacts, HIV infected, other causes of immune suppression, fibronodular disease on chest-x ray (CXR), or other indication).
Who cannot join
- Children aged 0-9 and children aged 10 or older who weigh less than 25kg
- Pregnancy
- Baseline AST or ALT that is at least 3 times higher than upper limit of normal
- Baseline Grade 3-4 abnormalities of hematological tests (WBC, platelets or hemoglobin).
- Prior treatment for latent or active TB.
- Rifampin contra-indicated - due to potential drug interactions that are considered too important, or difficult to manage, by health care provider; or due to history of allergy/ hypersensitivity to rifampin, rifabutin or rifapentine.
- Household contacts of index TB patients with confirmed, or suspected rifampin resistant TB.
Trial locations and contacts
9 sites in 3 countries.
9 sites in 3 countries
Canada4 sites
Unviversity of Calgary
Calgary, Alberta
The Governors of the University of Alberta
Edmonton, Alberta, T6G 2C8
MUHC
Montreal, Quebec, H4A 3J1
BCCDC TB clinic
Vancouver, British Columbia
Vietnam4 sites
Hai Ba Trung District Health Center, No. 16B
Hà Nội
Hanoi Lung Hospital
Hà Nội
Nam Tu Liem District Health Center, No. 3
Hà Nội
Phoi Viet TB and Respiratory Diseases Clinic.
Ho Chi Minh City
Indonesia1 site
Universitas Padjadjaran, Klinik Penelitian Tuberculosis (TB research clinic)
Bandung
About this study
Official title: 2R2: Higher Dose Rifampin for 2 Months vs Standard Dose Rifampin for Latent TB: a 3-arm Randomized Trial.
Rationale:
Shorter regimens of high dose daily rifampin may be safe, and as effective as the standard rifampin regimen when taken for 4 months to treat latent TB (LTBI). However, there is insufficient evidence on the optimal dose of rifampin that has similar efficacy as the standard 4-month rifampin regimen without jeopardizing safety or affecting completion rates.
Read more
Objectives:
The general purpose of this study is to determine if rifampin at double or triple the standard dose for 2 months is as safe and effective as the standard dose of rifampin when taken for 4 months to treat latent tuberculosis (TB).
Treatment:
Persons who need treatment for latent TB, will be given rifampin, either at the standard dose (10mg/kg/day) for 4 months (control arm); or at double dose (20mg/kg/day) for 2 months (intervention arm 1); or at triple dose (30mg/kg/day) for 2 months (intervention arm 2).
Design:
This is 1:1:1 randomized, phase 2b, partially blind, controlled trial. The two higher doses (intervention arms) will be administered double-blind: participants and providers will be aware of the duration of their regimen, but they will both remain blinded to the specific dose (i.e. 20 or 30 mg/kg/day) for those randomized to 2-months regimens. All members of the same household of a patient with newly diagnosed active pulmonary TB will be randomized together (i.e. cluster randomized).
Population and setting:
Adults and children aged 10 years and above, who have latent TB infection and are recommended by their doctor to take treatment for latent TB can participate in the study.
The planned number of persons with latent TB to recruit is about 1359 in total (or about 453 for each of the three arms).
The study will take place in 6 sites: four in Canada (Calgary, Edmonton, Montreal and Vancouver), one in Indonesia (Bandung) and one in Viet Nam (1 clinic in Ho Chi Min City and 3 clinics in Ha Noi).
Outcomes:
Primary outcomes are: 1) Treatment completion and 2) Safety (i.e. grade 3-5 adverse events).
Secondary outcomes are: 1) Safety (i.e. grade 1-2 adverse events) and 2) Efficacy (i.e. rates of active TB in the 26 months post-randomization). More information on how outcomes are defined is provided in the detailed description below.
Read the detailed description
Additional information extracted from study protocol is provided below:
Study duration:
The study started in September 2019. Enrollment has started in all study sites and is planned to last until end of 2022. At each site, study will last until 26 months after the last randomization in that site.
Study procedures:
The treatment should be given at the time of randomization; participants will be followed for the duration of treatment (i.e. 2-4 months), and for 2 years after treatments is finished.
Follow up during treatment consists of 3 clinic visits for participants in all arms. At each visit, a pill count and monitoring of possible side effects will be performed.
Follow-up after treatment will consist of contacting participants by phone every 3 months for 2 years, to check for symptoms of active TB.
Outcomes definitions:
Primary outcomes:
- Treatment completion (i.e. comparing how many people in each group completed treatment). Treatment completion is defined as taking at least 80% of the doses in 120% of the allowed time. The number of pills taken will be known by counting the pills dispensed and brought back by participants at each visit while they are on treatment.
- Safety: Grade 3-5 adverse events that result in permanent discontinuation of study drug and are considered probably or possibly related to the study drug by an independent 3-member adjudication panel blinded to study treatment.
Secondary outcomes:
- Safety: grade 1-2 adverse events that result in permanent discontinuation of study drug and are considered probably or possibly related to the study drug by the same independent 3-member adjudication panel.
- Efficacy: comparing rates of active TB in the 26 months post-randomization
Statistical analyses:
There are two planned primary analyses, comparing each of the two intervention arms to the conventional arm: 1) Superiority of treatment completion, using a logistic regression; 2) Non-inferiority of safety, using a Poisson regression to compare the occurrence of the grade 3-5 adverse events. We will use the confidence interval approach, and compare the upper limit of the difference using a margin of 4%.
Given that some exclusion post randomization could occur (for example if drug sensitivity test (DST) results for the index case were not available at the time of randomization but later showed resistance to rifampin- their contacts would not be eligible for the study and would be subsequently be excluded), a modified intention to treat analysis will be used - with these valid post-randomization exclusions. A secondary analysis will be done among patients who completed therapy per protocol.
Other planned secondary analyses are: 1) Non-inferiority of completion. The maximum allowable difference will be 5%, with one-sided significance level; 2) Non-inferiority of grade 1-2 adverse events (in the same way as grade 3-5 adverse events done for primary analysis); 3) Comparison of incidence of active TB per 100 person-years of follow-up, in the 26 months post-randomization. All analyses will include adjustment for clustering by household. In stratified analysis, results will be presented by indication for LTBI treatment. Sensitivity analyses will be conducted where by analysis are stratified by study centre and by country.
Interim Analyses:
There will be at least two interim analyses of study regimen completion and of Grade 3-5 adverse events. The first analysis will be conducted after the first 150 participants have completed therapy, the second after 450 participants have completed therapy or sooner if there are concerns about excess toxicity with either high-dose arm. The Data and Safety Monitoring Board (DSMB) will be responsible to review the two planned interim analyses, as well as any unexpected Grade 4 adverse events, or deaths that could be related to study regimens. Rather than having a formal stopping rule, the decision to stop enrollment, would be made by the DSMB, based on the safety reports received and the results of interim analyses.
- Conditions
- Latent Tuberculosis
- Being tested
- Rifampin double dose, Rifampin triple dose, Rifampin standard dose
- Keywords
- Latent Tuberculosis, Rifampin, Short Treatment for Latent Tuberculosis, High dose rifampin
- Medical subject headings
- Latent Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rifampin double doseDrug
Also called 2R20
Double dose of rifampin for 2 months.
Rifampin triple doseDrug
Also called 2R30
Triple dose of rifampin for 2 months.
Rifampin standard doseDrug
Also called 4R10
Standard dose of rifampin for 4 months.
| Study group | Role | What they receive |
|---|---|---|
| Intervention Arm 1 | Experimental | Two months of daily self-administered rifampin at 20 mg/kg (maximum 1200 mg/day). Receives: Drug: Rifampin double dose |
| Intervention Arm 2 | Experimental | Two months of daily self-administered rifampin at 30 mg/Kg (maximum 1800 mg/day). Receives: Drug: Rifampin triple dose |
| Control Arm | Active comparator | Four months of daily self-administered rifampin at a dose of 10mg per kg per day (maximum 600mg per day). Receives: Drug: Rifampin standard dose |
What is being measured
The primary outcome is the main question the study is designed to answer.
Treatment completion (taking 80% of doses within 120% of allowed time)
Completion will be defined as taking 80% of doses within 120% of allowed time (48 doses within 72 days for the two-month regimens, and 96 doses within 144 days for the 4-month regimen).
Measured: 2 months from randomization for participants in the two intervention arms and 4 months for the control arm.
Safety measured by Grade 3 to 5 adverse events
Grade 3 to 5 adverse events (and Grade 1-2 rash) which result in permanent discontinuation of the study drug, and that are considered probably or possibly related to the study drug by the majority of a three-member independent and blinded Adverse Events panel.
Measured: 2 months plus 2 weeks in the intervention arms; 4 months plus 2 weeks in the control arm.
Secondary outcomes (2)
Safety measured by Grade 1 to 2 adverse events
Grade 1 to 2 adverse events which result in permanent discontinuation of the study drug and are considered probably or possibly related to the study drug by the adverse events panel.
Measured: 2 months plus 2 weeks in the intervention arms; 4 months plus 2 weeks in the control arm.
Efficacy measured during follow-up visits and telephone calls
Active TB - symptoms will be ascertained monthly by direct questioning during treatment phase follow-up visits, and by telephone call every 3 months up to 26 months after randomization.
Measured: 26 months from randomization in all arms.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2019
- Study start20 Sep 2019
- Primary completion31 Jan 2023
- Study completion31 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Latent TuberculosisStudies of the same condition, open and under way.
- More trials run by McGill University Health Centre/Research Institute of the McGill University Health CentreThe 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
- Model description
- Participants will be randomized 1:1:1 to be in control arm or in one of the two intervention arms. Intervention arms: Arm 1: 60 doses daily self-administered rifampin at 20 mg/kg (2R20 - maximum 1200 mg/day). Arm 2: 60 doses daily self-administered rifampin at 30 mg/Kg (2R30) - maximum 1800 mg/day). Comparator: Arm 3 (standard): 120 doses daily self-administered rifampin at 10mg/kg (4R10maximum 600mg per day).
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 1,368 participants (actual)
Sponsor and investigators
- Lead sponsor
- McGill University Health Centre/Research Institute of the McGill University Health Centre
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR)
- Responsible party
- Principal investigator, Dick Menzies, McGill University Health Centre/Research Institute of the McGill University Health Centre
- Investigators
- Dick Menzies, Principal investigator, RI-MUHC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03988933
- Sponsor's protocol ID
- FND-143350-1
- Acronym
- 2R2
- Status last verified
- Apr 2026
- First submitted
- 13 Jun 2019
- Last updated
- 13 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Protocol and consent form will be available for data sharing once approved by research ethical review board. A detailed plan for data sharing of other study documents and/or data is under definition and will be posted during the trial.
Publications
Aarnoutse RE, Kibiki GS, Reither K, Semvua HH, Haraka F, Mtabho CM, Mpagama SG, van den Boogaard J, Sumari-de Boer IM, Magis-Escurra C, Wattenberg M, Logger JGM, Te Brake LHM, Hoelscher M, Gillespie SH, Colbers A, Phillips PPJ, Plemper van Balen G, Boeree MJ; PanACEA Consortium. Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2017 Oct 24;61(11):e01054-17. doi: 10.1128/AAC.01054-17. Print 2017 Nov.
PubMed 28827417Boeree 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 28100438Dian S, Yunivita V, Ganiem AR, Pramaesya T, Chaidir L, Wahyudi K, Achmad TH, Colbers A, Te Brake L, van Crevel R, Ruslami R, Aarnoutse R. Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01014-18. doi: 10.1128/AAC.01014-18. Print 2018 Dec.
PubMed 30224533Jindani A, Borgulya G, de Patino IW, Gonzales T, de Fernandes RA, Shrestha B, Atwine D, Bonnet M, Burgos M, Dubash F, Patel N, Checkley AM, Harrison TS, Mitchison D; International Consortium for Trials of Chemotherapeutic Agents in Tuberculosis, St George's University of London. A randomised Phase II trial to evaluate the toxicity of high-dose rifampicin to treat pulmonary tuberculosis. Int J Tuberc Lung Dis. 2016 Jun;20(6):832-8. doi: 10.5588/ijtld.15.0577.
PubMed 27155189Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, Borm G, Aarnoutse RE, van Crevel R. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013 Jan;13(1):27-35. doi: 10.1016/S1473-3099(12)70264-5. Epub 2012 Oct 25.
PubMed 23103177Ruslami R, Nijland HM, Alisjahbana B, Parwati I, van Crevel R, Aarnoutse RE. Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2007 Jul;51(7):2546-51. doi: 10.1128/AAC.01550-06. Epub 2007 Apr 23.
PubMed 17452486Swindells S, Ramchandani R, Gupta A, Benson CA, Leon-Cruz J, Mwelase N, Jean Juste MA, Lama JR, Valencia J, Omoz-Oarhe A, Supparatpinyo K, Masheto G, Mohapi L, da Silva Escada RO, Mawlana S, Banda P, Severe P, Hakim J, Kanyama C, Langat D, Moran L, Andersen J, Fletcher CV, Nuermberger E, Chaisson RE; BRIEF TB/A5279 Study Team. One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis. N Engl J Med. 2019 Mar 14;380(11):1001-1011. doi: 10.1056/NEJMoa1806808.
PubMed 30865794Velasquez GE, Brooks MB, Coit JM, Pertinez H, Vargas Vasquez D, Sanchez Garavito E, Calderon RI, Jimenez J, Tintaya K, Peloquin CA, Osso E, Tierney DB, Seung KJ, Lecca L, Davies GR, Mitnick CD. Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial. Am J Respir Crit Care Med. 2018 Sep 1;198(5):657-666. doi: 10.1164/rccm.201712-2524OC.
PubMed 29954183Yunivita V, Dian S, Ganiem AR, Hayati E, Hanggono Achmad T, Purnama Dewi A, Teulen M, Meijerhof-Jager P, van Crevel R, Aarnoutse R, Ruslami R. Pharmacokinetics and safety/tolerability of higher oral and intravenous doses of rifampicin in adult tuberculous meningitis patients. Int J Antimicrob Agents. 2016 Oct;48(4):415-21. doi: 10.1016/j.ijantimicag.2016.06.016. Epub 2016 Jul 26.
PubMed 27526979Ruslami R, Fregonese F, Apriani L, Barss L, Bedingfield N, Chiang V, Cook VJ, Fisher D, Flores E, Fox GJ, Johnston J, Lim RK, Long R, Paulsen C, Nguyen TA, Nhung NV, Gibson D, Valiquette C, Benedetti A, Menzies D. High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial. Lancet Respir Med. 2024 Jun;12(6):433-443. doi: 10.1016/S2213-2600(24)00076-6. Epub 2024 Mar 26.
PubMed 38552659Fregonese F, Apriani L, Barss L, Benedetti A, Cook V, Fisher D, Fox GJ, Johnston J, Long R, Nguyen TA, Nguyen VN, Ruslami R, Menzies D. High dose rifampin for 2 months vs standard dose rifampin for 4 months, to treat TB infection: Protocol of a 3-arm randomized trial (2R2). PLoS One. 2023 Feb 2;18(2):e0278087. doi: 10.1371/journal.pone.0278087. eCollection 2023.
PubMed 36730240
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 2R2: Higher Dose Rifampin for 2 Months vs Standard Dose Rifampin for Latent TB: a 3-arm Randomized Trial.
- ClinicalTrials.gov ID
- NCT03988933
- Acronym / sponsor ID
- 2R2 / FND-143350-1
- Conditions
- Latent Tuberculosis
- Keywords
- Latent Tuberculosis, Rifampin, Short Treatment for Latent Tuberculosis, High dose rifampin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,368 participants (actual)
- Lead sponsor
- McGill University Health Centre/Research Institute of the McGill University Health CentreUniversity, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR)
- Study start
- 20 Sep 2019 (actual)
- Primary completion
- 31 Jan 2023 (actual)
- Study completion
- 31 Dec 2024 (actual)
- First posted
- 18 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.
Rationale:
Shorter regimens of high dose daily rifampin may be safe, and as effective as the standard rifampin regimen when taken for 4 months to treat latent TB (LTBI). However, there is insufficient evidence on the optimal dose of rifampin that has similar efficacy as the standard 4-month rifampin regimen without jeopardizing safety or affecting completion rates.
Objectives:
The general purpose of this study is to determine if rifampin at double or triple the standard dose for 2 months is as safe and effective as the standard dose of rifampin when taken for 4 months to treat latent tuberculosis (TB).
Treatment:
Persons who need treatment for latent TB, will be given rifampin, either at the standard dose (10mg/kg/day) for 4 months (control arm); or at double dose (20mg/kg/day) for 2 months (intervention arm 1); or at triple dose (30mg/kg/day) for 2 months (intervention arm 2).
Design:
This is 1:1:1 randomized, phase 2b, partially blind, controlled trial. The two higher doses (intervention arms) will be administered double-blind: participants and providers will be aware of the duration of their regimen, but they will both remain blinded to the specific dose (i.e. 20 or 30 mg/kg/day) for those randomized to 2-months regimens. All members of the same household of a patient with newly diagnosed active pulmonary TB will be randomized together (i.e. cluster randomized).
Population and setting:
Adults and children aged 10 years and above, who have latent TB infection and are recommended by their doctor to take treatment for latent TB can participate in the study.
The planned number of persons with latent TB to recruit is about 1359 in total (or about 453 for each of the three arms).
The study will take place in 6 sites: four in Canada (Calgary, Edmonton, Montreal and Vancouver), one in Indonesia (Bandung) and one in Viet Nam (1 clinic in Ho Chi Min City and 3 clinics in Ha Noi).
Outcomes:
Primary outcomes are: 1) Treatment completion and 2) Safety (i.e. grade 3-5 adverse events).
Secondary outcomes are: 1) Safety (i.e. grade 1-2 adverse events) and 2) Efficacy (i.e. rates of active TB in the 26 months post-randomization). More information on how outcomes are defined is provided in the detailed description below.
Detailed description
Additional information extracted from study protocol is provided below:
Study duration:
The study started in September 2019. Enrollment has started in all study sites and is planned to last until end of 2022. At each site, study will last until 26 months after the last randomization in that site.
Study procedures:
The treatment should be given at the time of randomization; participants will be followed for the duration of treatment (i.e. 2-4 months), and for 2 years after treatments is finished.
Follow up during treatment consists of 3 clinic visits for participants in all arms. At each visit, a pill count and monitoring of possible side effects will be performed.
Follow-up after treatment will consist of contacting participants by phone every 3 months for 2 years, to check for symptoms of active TB.
Outcomes definitions:
Primary outcomes:
- Treatment completion (i.e. comparing how many people in each group completed treatment). Treatment completion is defined as taking at least 80% of the doses in 120% of the allowed time. The number of pills taken will be known by counting the pills dispensed and brought back by participants at each visit while they are on treatment.
- Safety: Grade 3-5 adverse events that result in permanent discontinuation of study drug and are considered probably or possibly related to the study drug by an independent 3-member adjudication panel blinded to study treatment.
Secondary outcomes:
- Safety: grade 1-2 adverse events that result in permanent discontinuation of study drug and are considered probably or possibly related to the study drug by the same independent 3-member adjudication panel.
- Efficacy: comparing rates of active TB in the 26 months post-randomization
Statistical analyses:
There are two planned primary analyses, comparing each of the two intervention arms to the conventional arm: 1) Superiority of treatment completion, using a logistic regression; 2) Non-inferiority of safety, using a Poisson regression to compare the occurrence of the grade 3-5 adverse events. We will use the confidence interval approach, and compare the upper limit of the difference using a margin of 4%.
Given that some exclusion post randomization could occur (for example if drug sensitivity test (DST) results for the index case were not available at the time of randomization but later showed resistance to rifampin- their contacts would not be eligible for the study and would be subsequently be excluded), a modified intention to treat analysis will be used - with these valid post-randomization exclusions. A secondary analysis will be done among patients who completed therapy per protocol.
Other planned secondary analyses are: 1) Non-inferiority of completion. The maximum allowable difference will be 5%, with one-sided significance level; 2) Non-inferiority of grade 1-2 adverse events (in the same way as grade 3-5 adverse events done for primary analysis); 3) Comparison of incidence of active TB per 100 person-years of follow-up, in the 26 months post-randomization. All analyses will include adjustment for clustering by household. In stratified analysis, results will be presented by indication for LTBI treatment. Sensitivity analyses will be conducted where by analysis are stratified by study centre and by country.
Interim Analyses:
There will be at least two interim analyses of study regimen completion and of Grade 3-5 adverse events. The first analysis will be conducted after the first 150 participants have completed therapy, the second after 450 participants have completed therapy or sooner if there are concerns about excess toxicity with either high-dose arm. The Data and Safety Monitoring Board (DSMB) will be responsible to review the two planned interim analyses, as well as any unexpected Grade 4 adverse events, or deaths that could be related to study regimens. Rather than having a formal stopping rule, the decision to stop enrollment, would be made by the DSMB, based on the safety reports received and the results of interim analyses.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
- Model description
- Participants will be randomized 1:1:1 to be in control arm or in one of the two intervention arms. Intervention arms: Arm 1: 60 doses daily self-administered rifampin at 20 mg/kg (2R20 - maximum 1200 mg/day). Arm 2: 60 doses daily self-administered rifampin at 30 mg/Kg (2R30) - maximum 1800 mg/day). Comparator: Arm 3 (standard): 120 doses daily self-administered rifampin at 10mg/kg (4R10maximum 600mg per day).
| Arm | Type | Receives |
|---|---|---|
| Intervention Arm 1 | Experimental | Drug: Rifampin double doseTwo months of daily self-administered rifampin at 20 mg/kg (maximum 1200 mg/day). |
| Intervention Arm 2 | Experimental | Drug: Rifampin triple doseTwo months of daily self-administered rifampin at 30 mg/Kg (maximum 1800 mg/day). |
| Control Arm | Active comparator | Drug: Rifampin standard doseFour months of daily self-administered rifampin at a dose of 10mg per kg per day (maximum 600mg per day). |
Who may qualify
- Ages
- 10 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (3 listed)
- Adults, and children aged 10 and older who weigh at least 25kg.
- Evidence of latent TB infection: positive tuberculin skin test (5mm or greater or 10mm or greater, based on National guidelines) or positive interferon gamma release assay.
- Eligible to take latent TB treatment according to Canadian guidelines in the Canadian sites, and according to World Health Organization (WHO) guidelines in the international sites (this includes household contacts, other contacts, HIV infected, other causes of immune suppression, fibronodular disease on chest-x ray (CXR), or other indication).
Key exclusion criteria (7 listed)
- Children aged 0-9 and children aged 10 or older who weigh less than 25kg
- Pregnancy
- Baseline AST or ALT that is at least 3 times higher than upper limit of normal
- Baseline Grade 3-4 abnormalities of hematological tests (WBC, platelets or hemoglobin).
- Prior treatment for latent or active TB.
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 double doseAlso: 2R20Double dose of rifampin for 2 months. | Drug | Intervention Arm 1 |
| Rifampin triple doseAlso: 2R30Triple dose of rifampin for 2 months. | Drug | Intervention Arm 2 |
| Rifampin standard doseAlso: 4R10Standard dose of rifampin for 4 months. | Drug | Control Arm |
Primary outcome
Treatment completion (taking 80% of doses within 120% of allowed time)
Time frame: 2 months from randomization for participants in the two intervention arms and 4 months for the control arm.
Completion will be defined as taking 80% of doses within 120% of allowed time (48 doses within 72 days for the two-month regimens, and 96 doses within 144 days for the 4-month regimen).
Safety measured by Grade 3 to 5 adverse events
Time frame: 2 months plus 2 weeks in the intervention arms; 4 months plus 2 weeks in the control arm.
Grade 3 to 5 adverse events (and Grade 1-2 rash) which result in permanent discontinuation of the study drug, and that are considered probably or possibly related to the study drug by the majority of a three-member independent and blinded Adverse Events panel.
2 secondary outcomes
Safety measured by Grade 1 to 2 adverse events
Time frame: 2 months plus 2 weeks in the intervention arms; 4 months plus 2 weeks in the control arm.
Efficacy measured during follow-up visits and telephone calls
Time frame: 26 months from randomization in all arms.
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 13 Apr 2026.
- Background: PubMed 28827417Aarnoutse RE, Kibiki GS, Reither K, Semvua HH, Haraka F, Mtabho CM, Mpagama SG, van den Boogaard J, Sumari-de Boer IM, Magis-Escurra C, Wattenberg M, Logger JGM, Te Brake LHM, Hoelscher M, Gillespie SH, Colbers A, Phillips PPJ, Plemper van Balen G, Boeree MJ; PanACEA Consortium. Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2017 Oct 24;61(11):e01054-17. doi: 10.1128/AAC.01054-17. Print 2017 Nov.
- 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 30224533Dian S, Yunivita V, Ganiem AR, Pramaesya T, Chaidir L, Wahyudi K, Achmad TH, Colbers A, Te Brake L, van Crevel R, Ruslami R, Aarnoutse R. Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01014-18. doi: 10.1128/AAC.01014-18. Print 2018 Dec.
- Background: PubMed 27155189Jindani A, Borgulya G, de Patino IW, Gonzales T, de Fernandes RA, Shrestha B, Atwine D, Bonnet M, Burgos M, Dubash F, Patel N, Checkley AM, Harrison TS, Mitchison D; International Consortium for Trials of Chemotherapeutic Agents in Tuberculosis, St George's University of London. A randomised Phase II trial to evaluate the toxicity of high-dose rifampicin to treat pulmonary tuberculosis. Int J Tuberc Lung Dis. 2016 Jun;20(6):832-8. doi: 10.5588/ijtld.15.0577.
- Background: PubMed 23103177Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, Borm G, Aarnoutse RE, van Crevel R. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013 Jan;13(1):27-35. doi: 10.1016/S1473-3099(12)70264-5. Epub 2012 Oct 25.
- Background: PubMed 17452486Ruslami R, Nijland HM, Alisjahbana B, Parwati I, van Crevel R, Aarnoutse RE. Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2007 Jul;51(7):2546-51. doi: 10.1128/AAC.01550-06. Epub 2007 Apr 23.
- Background: PubMed 30865794Swindells S, Ramchandani R, Gupta A, Benson CA, Leon-Cruz J, Mwelase N, Jean Juste MA, Lama JR, Valencia J, Omoz-Oarhe A, Supparatpinyo K, Masheto G, Mohapi L, da Silva Escada RO, Mawlana S, Banda P, Severe P, Hakim J, Kanyama C, Langat D, Moran L, Andersen J, Fletcher CV, Nuermberger E, Chaisson RE; BRIEF TB/A5279 Study Team. One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis. N Engl J Med. 2019 Mar 14;380(11):1001-1011. doi: 10.1056/NEJMoa1806808.
- Background: PubMed 29954183Velasquez GE, Brooks MB, Coit JM, Pertinez H, Vargas Vasquez D, Sanchez Garavito E, Calderon RI, Jimenez J, Tintaya K, Peloquin CA, Osso E, Tierney DB, Seung KJ, Lecca L, Davies GR, Mitnick CD. Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial. Am J Respir Crit Care Med. 2018 Sep 1;198(5):657-666. doi: 10.1164/rccm.201712-2524OC.
- Background: PubMed 27526979Yunivita V, Dian S, Ganiem AR, Hayati E, Hanggono Achmad T, Purnama Dewi A, Teulen M, Meijerhof-Jager P, van Crevel R, Aarnoutse R, Ruslami R. Pharmacokinetics and safety/tolerability of higher oral and intravenous doses of rifampicin in adult tuberculous meningitis patients. Int J Antimicrob Agents. 2016 Oct;48(4):415-21. doi: 10.1016/j.ijantimicag.2016.06.016. Epub 2016 Jul 26.
- Derived from this study: PubMed 38552659Ruslami R, Fregonese F, Apriani L, Barss L, Bedingfield N, Chiang V, Cook VJ, Fisher D, Flores E, Fox GJ, Johnston J, Lim RK, Long R, Paulsen C, Nguyen TA, Nhung NV, Gibson D, Valiquette C, Benedetti A, Menzies D. High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial. Lancet Respir Med. 2024 Jun;12(6):433-443. doi: 10.1016/S2213-2600(24)00076-6. Epub 2024 Mar 26.
- Derived from this study: PubMed 36730240Fregonese F, Apriani L, Barss L, Benedetti A, Cook V, Fisher D, Fox GJ, Johnston J, Long R, Nguyen TA, Nguyen VN, Ruslami R, Menzies D. High dose rifampin for 2 months vs standard dose rifampin for 4 months, to treat TB infection: Protocol of a 3-arm randomized trial (2R2). PLoS One. 2023 Feb 2;18(2):e0278087. doi: 10.1371/journal.pone.0278087. eCollection 2023.
- Individual participant dataSharing planned: Yes. Protocol and consent form will be available for data sharing once approved by research ethical review board. A detailed plan for data sharing of other study documents and/or data is under definition and will be posted during the trial.
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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.
Dick Menzies principal investigator
RI-MUHC
9 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Rifampin double dose, Rifampin triple dose and Rifampin standard dose in people with Latent Tuberculosis, run by McGill University Health Centre/Research Institute of the McGill University Health Centre at 9 sites in 3 countries.
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 3 inclusion and 7 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 13 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in Canada, Vietnam, Indonesia. 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?
Treatment completion (taking 80% of doses within 120% of allowed time) (time frame: 2 months from randomization for participants in the two intervention arms and 4 months for the control arm.). 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 NCT03988933, which also lists 11 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 13 Apr 2026; AzTrials last refreshed its copy on 5 Nov 2026.