2R2: Higher Dose Rifampin for 2 Months vs Standard Dose Rifampin for Latent TB.

NCT03988933 | Completed Phase 2 DMC

• 1 other identifier: FND-143350-1
• Study Type: interventional
• Target: 1,368
• Locations: 3 countries
• Sites: 9

Brief 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 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.

Conditions

Latent Tuberculosis

Keywords

Latent Tuberculosis; Rifampin; Short Treatment for Latent Tuberculosis; High dose rifampin

Outcome Measures

Primary Outcomes (2)

• 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).

  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.

  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

  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

  26 months from randomization in all arms.

Study Arms (3)

Intervention Arm 1

EXPERIMENTAL

Two months of daily self-administered rifampin at 20 mg/kg (maximum 1200 mg/day).

Drug: Rifampin double dose

Intervention Arm 2

EXPERIMENTAL

Two months of daily self-administered rifampin at 30 mg/Kg (maximum 1800 mg/day).

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).

Drug: Rifampin standard dose

Interventions

Rifampin double dose DRUG

Double dose of rifampin for 2 months.

Also known as: 2R20

Intervention Arm 1

Rifampin triple dose DRUG

Triple dose of rifampin for 2 months.

Also known as: 2R30

Intervention Arm 2

Rifampin standard dose DRUG

Standard dose of rifampin for 4 months.

Also known as: 4R10

Control Arm

Eligibility Criteria

• Age: 10 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• McGill University Health Centre/Research Institute of the McGill University Health Centre: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (9)

Unviversity of Calgary

Calgary, Alberta, Canada

Location

The Governors of the University of Alberta

Edmonton, Alberta, T6G 2C8, Canada

Location

BCCDC TB clinic

Vancouver, British Columbia, Canada

Location

MUHC

Montreal, Quebec, H4A 3J1, Canada

Location

Universitas Padjadjaran, Klinik Penelitian Tuberculosis (TB research clinic)

Bandung, Indonesia

Location

Hai Ba Trung District Health Center, No. 16B

Hà Nội, Vietnam

Location

Hanoi Lung Hospital

Hà Nội, Vietnam

Location

Nam Tu Liem District Health Center, No. 3

Hà Nội, Vietnam

Location

Phoi Viet TB and Respiratory Diseases Clinic.

Ho Chi Minh City, Vietnam

Location

Related Publications (11)

• 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.

  PMID: 28827417 BACKGROUND

• Boeree 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.

  PMID: 28100438 BACKGROUND

• Dian 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.

  PMID: 30224533 BACKGROUND

• Jindani 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.

  PMID: 27155189 BACKGROUND

• Ruslami 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.

  PMID: 23103177 BACKGROUND

• Ruslami 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.

  PMID: 17452486 BACKGROUND

• Swindells 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.

  PMID: 30865794 BACKGROUND

• Velasquez 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.

  PMID: 29954183 BACKGROUND

• Yunivita 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.

  PMID: 27526979 BACKGROUND

• Ruslami 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.

  PMID: 38552659 DERIVED

• Fregonese 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.

  PMID: 36730240 DERIVED

MeSH Terms

Conditions

Latent Tuberculosis

Interventions

Rifampin

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Dick Menzies

  RI-MUHC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: This is a partially double-blinded trial. Participation in control arm will be open label while participation in the two intervention arms will be double-blinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Investigator at Research Institute of McGill University Health Center

Model Details: 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).

Study Record Dates

• First Submitted: June 13, 2019
• First Posted: June 18, 2019
• Study Start: September 20, 2019
• Primary Completion: January 31, 2023
• Study Completion: December 31, 2024
• Last Updated: April 13, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Protocol and consent form will be available once approval is received from the research ethical board and will remain available.
• Access Criteria: Access criteria will be specified in the plan for data sharing, once available.

Locations

VN (4); CA (4); ID (1)