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

Latent Tuberculosis Clinical Trial

— 2R2  

Official title:

2R2: Higher Dose Rifampin for 2 Months vs Standard Dose Rifampin for Latent TB: a 3-arm Randomized Trial.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03988933
• Other study ID #: FND-143350-1
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 20, 2019
• Est. completion date: December 2024

Study information

• Verified date: April 2024
• Source: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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.

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:

1. 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.

2. 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:

1. 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.

2. 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1368
• Est. completion date: December 2024
• Est. primary completion date: January 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years and older

Eligibility

Inclusion Criteria:

• 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).

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Latent Tuberculosis
• Tuberculosis

Intervention

Drug:
• Rifampin double dose
Double dose of rifampin for 2 months.
• Rifampin triple dose
Triple dose of rifampin for 2 months.
• Rifampin standard dose
Standard dose of rifampin for 4 months.

Locations

Country	Name	City	State
Canada	Unviversity of Calgary	Calgary	Alberta
Canada	The Governors of the University of Alberta	Edmonton	Alberta
Canada	MUHC	Montreal	Quebec
Canada	BCCDC TB clinic	Vancouver	British Columbia
Indonesia	Universitas Padjadjaran, Klinik Penelitian Tuberculosis (TB research clinic)	Bandung
Vietnam	Hai Ba Trung District Health Center, No. 16B	Hà N?i
Vietnam	Hanoi Lung Hospital	Hà N?i
Vietnam	Nam Tu Liem District Health Center, No. 3	Hà N?i
Vietnam	Phoi Viet TB and Respiratory Diseases Clinic.	Ho Chi Minh City

Sponsors (2)

Lead Sponsor	Collaborator
McGill University Health Centre/Research Institute of the McGill University Health Centre	Canadian Institutes of Health Research (CIHR)

Countries where clinical trial is conducted

Canada,  Indonesia,  Vietnam, 

References & Publications (9)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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	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.	2 months plus 2 weeks in the intervention arms; 4 months plus 2 weeks in the control arm.
Secondary	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.	26 months from randomization in all arms.