Exploring The Potential For High-Dose Rifampicin in Pulmonary Tuberculosis Treatment

Over 10 million people globally are diagnosed with Tuberculosis yearly, and around 1.4 million people die from the disease yearly as well. With the current standardized TB treatment with rifampicin (400mg-600mg/day orally administered) lasting around 6 months, any shortened treatment duration that can maintain effectiveness should be considered. Adult participants in this phase 3 clinical trial with high-dose rifampicin were either designated to a 6-month control regimen, a 4-month regimen of 12000 mg/day (SR1), or a 4-month regimen of 1800 mg/day (SR2). Sputum samples were obtained from participants in each group at timely interludes. As this experiment was technically a noninferiority trial, the primary result analysis was based on whether high-dose rifampicin was not any worse than any current pulmonary TB treatment regimen. In the end, high-dose rifampicin failed the noninferiority trial, as SR1 and SR2 patient response rates were outside of the noninferiority margin (despite showing an advantage over other non-rifampicin TB treatment options).

This study was specifically conducted in low and middle-income regions because multi-resistant TB is more common in these regions. As a result, researchers were compelled that a clinical trial should be conducted in TB rampant areas. SR2 in the end had a slightly higher hazard ratio amongst its participants compared to SR1 and the control group, explaining the slight increase of detected adverse events in SR2 participants. Future iterations of this study could make use of pharmacokinetic assessments (study of drug administration and absorption in patients) and specialized mycobacterial indicator tests to further specialize the testing of rifampicin in higher doses. 

The primary study outcome was positive, as response rates were 93% for the control group, 90% for the SR1 group, and 87% in the SR2 group. However, high-dose rifampicin failed the non-inferiority test of this study, as SR1 and SR2 response rates fell just short of the 8-percentage point noninferiority margin set for this trial. ‌

Author: Abhinav Katyal 

Reference: Jindani A, Atwine D, Grint D, et al. Four-Month High-Dose Rifampicin Regimens for Pulmonary Tuberculosis. NEJM evidence. 2023;2(9). doi:https://doi.org/10.1056/evidoa2300054