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Published on: April 9, 2012
Rifapentine dosing for drug-susceptible tuberculosis: stage 1 of a seamless phase 2/3 randomized clinical trial
Yang Li1, Lingyun Song1, Zhen Feng1
1Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Objectives:
To evaluate the safety and efficacy across rifapentine doses ranging from 10 to 20 mg/kg for pulmonary drug-susceptible tuberculosis population.
Methods:
The stage 1 of this seamless phase 2/3 randomized controlled trial recruited enrolled adults with drug-susceptible tuberculosis at 16 sites in China between 1 February 2023 and 29 September 2024 (NCT05401071). Participants were randomly divided (1:1:1:1) to receive one of three 4-month regimens containing rifapentine 10, 15, or 20 mg/kg daily plus isoniazid, moxifloxacin, and pyrazinamide, or a standard 6-month regimen consisting of isoniazid, rifampicin, pyrazinamide, and ethambutol. In the stage 1, the primary endpoint was the incidence of permanent regimen discontinuation for safety reasons by week 8. Key secondary endpoints included culture conversion before week 8, adverse events during treatment, and favourable outcomes at the end of treatment.
Results:
A total of 400 participants underwent randomization in stage 1. The incidences of primary endpoint were 9.3% (9/97), 8.9% (9/101), and 14.6% (14/96) in the rifapentine 10, 15, and 20 mg/kg groups, and 3.0% (3/99) in the control group, respectively. Culture conversion before week 8 occurred in 73.8% (45/61), 84.8% (56/66), and 87.9% (51/58) of participants in the rifapentine 10, 15, and 20 mg/kg groups, and 78.0% (46/59) in the control group. Favourable outcomes at the end of treatment were similar across the groups: 81.4% (79/97) in the control group, 80.9% in the rifapentine 10 mg/kg group (relative risk [RR], 0.99; 95% CI, 0.87-1.14), 87.1% in the rifapentine 15 mg/kg group (RR, 1.07; 95% CI, 0.95-1.21), and 82.6% in the rifapentine 20 mg/kg group (RR, 1.01; 95% CI, 0.89-1.16).
Conclusions:
Both rifapentine 15 and 20 mg/kg yielded higher culture conversion rates. However, safety-related discontinuation, particularly in the 20 mg/kg group, was more frequent, highlighting the need for careful benefit-risk assessment and enhanced safety monitoring.
Insights
Rifapentine at 15 and 20 mg/kg improved culture conversion rates for drug-susceptible tuberculosis (DS-TB) treatment. However, higher doses increased safety discontinuations, necessitating careful risk-benefit evaluation for this DS-TB therapy.
Area of Science:
- Clinical Medicine
- Infectious Diseases
- Pharmacology
Background:
- Pulmonary drug-susceptible tuberculosis (DS-TB) remains a significant global health challenge.
- Optimizing treatment regimens for DS-TB is crucial for improving patient outcomes and reducing transmission.
- Rifapentine, a long-acting rifamycin, offers potential for shorter TB treatment durations.
Purpose of the Study:
- To evaluate the safety and efficacy of different rifapentine dosages (10, 15, and 20 mg/kg) in adults with DS-TB.
- To compare novel rifapentine-based 4-month regimens against a standard 6-month regimen.
- To assess key endpoints including treatment discontinuation, culture conversion, and overall treatment success.
Main Methods:
- A seamless phase 2/3 randomized controlled trial involving 400 adults with DS-TB in China.
- Participants received daily rifapentine (10, 15, or 20 mg/kg) plus standard TB drugs or a standard 6-month regimen.
- Primary endpoint: permanent regimen discontinuation for safety reasons by week 8. Secondary endpoints: early culture conversion and favorable treatment outcomes.
Main Results:
- Higher rifapentine doses (15 and 20 mg/kg) showed increased culture conversion rates compared to the control group.
- Incidence of safety-related discontinuation was higher in the rifapentine 20 mg/kg group (14.6%) versus the control group (3.0%).
- Favorable treatment outcomes were similar across all rifapentine dose groups and the control group.
Conclusions:
- Rifapentine at 15 and 20 mg/kg demonstrated improved early microbiological response in DS-TB patients.
- The 20 mg/kg rifapentine dose was associated with a higher rate of safety-related discontinuations.
- Careful benefit-risk assessment and enhanced safety monitoring are essential when considering higher rifapentine doses for DS-TB treatment.
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