ƽÌØÎå²»ÖÐ

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 and safety as the standard 4-month rifampin regimen.

Objectives: The primary objectives were to determine if 2 months daily rifampin at double or triple the standard dose is non-inferior for safety, and superior for completion as the standard dose of rifampin when taken for 4 months to treat latent tuberculosis (TB). Secondary objectives were to compare drug exposures (from pharmacokinetic studies) and health system costs.

Design: Phase 2b, partially blind, three-arms (1:1:1) randomized controlled trial. Reference intervention: Rifampin at 10mg/kg/day for 4 months. Experimental interventions: rifampin at 20mg/kg/day (double) for 2 months in intervention arm 1; or, 30mg/kg/day (triple) for 2 months in intervention arm 2. Participants and providers were aware of the duration of the regimen, but were blinded to the specific dose (i.e. 20 or 30 mg/kg/day) for those randomized to 2-months high-dose regimens. All members of the same household were randomized together (i.e. cluster randomized).

Population and setting: Eligible participants were adults and children aged 10 years and older (with weight of at least 25kg) with a positive test for TB infection (TST or IGRA) and recommended to take treatment for TB infection. The study was conducted at sites in Calgary, Edmonton, Montreal, and Vancouver (Canada), Bandung (Indonesia) and Ho Chi Min City and Ha Noi (Vietnam). Enrolment of 1368 participants (about 1/3 from each each country) was completed in September 2022.

Study procedures: Treatment started at randomization. Follow up during treatment consisted of three clinic visits (at 2, 4 and 8 weeks in high dose arms and at 4, 8 and 16 weeks in standard arm). At each visit, pill counts and monitoring of possible side effects was performed. At 2 weeks (for participants in the experimental arms) and at 4 weeks visit (for all participants) blood samples were taken for monitoring of hematologic and liver toxicity and for pharmacokinetic sub-study. After treatment was stopped or completed, participants were contacted by phone every 3 months to check for symptoms of active TB, until 26 months after randomization.

Primary outcomes: 1) Grade 1-2 rash/allergy or 3-5 adverse events of all types that resulted in permanent discontinuation of study drug and were considered probably or possibly related to the study drug by an independent 3-member adjudication panel blinded to study treatment. 2) Treatment completion (defined as taking at least 80% of the intended doses in 120% of the allowed time).

Secondary outcomes: 1) Grade 1-2 adverse events that resulted in permanent discontinuation of study drug and were considered probably or possibly related to the study drug by the same panel. 2) Drug exposure – based on C_max and AUC_0-24h from pharmacokinetic studies; 3) Health system costs; 4) Efficacy in TB prevention, comparing incidence of TB disease, as judged by an independent and blinded panel, during 26 months post-randomization.

CRFs

SOPs

Protocol

Click hereÌýfor project protocol.