Safety and Efficacy of 25 mg/kg and 35 mg/kg vs 10 mg/kg Rifampicin in Pulmonary TB: A Phase IIb Randomized Controlled Trial

Abstract

Background Globally no trial data available on head-to-head comparison between 10 and 25/35 mg/kg rifampicin in treating pulmonary tuberculosis (PTB) during study initiation. Methods A multi-centric, phase-IIb randomized trial recruited 333 new culture-positive, drug-sensitive adult PTB patients, to compare safety and efficacy of high-dose rifampicin (R25/R35), against conventional dose (R10) given daily for 8-weeks followed by standard doses for 16-weeks. Main outcomes were treatment-emergent grade 3/4 adverse events (AE) and time-to-culture conversion in liquid media, assessed by DAIDS criteria and Kaplan-Meier methods. Results In modified intention-to-treat population of 323 (R10-105/R25-112/R35-106), grade 3/4 AEs were reported in 34 patients [R10-9.5% (10/105), R25-9.8% (11/112), R35-12.3% (13/106)] during intensive phase. Among 23 patients [R10-3.8% (4/105), R25-6.3% (7/112), R35-11.3% (12/106)] with grade 3/4 hepatotoxicity, 15 [R10-1.9% (2/105), R25-3.6% (4/112), R35-8.5% (9/106)] had grade 3/4 hyperbilirubinemia and 9 patients [R10-1.0% (1/105), R25-0.9% (1/112), R35-6.6% (7/106)] developed clinical jaundice. Significant differences observed only between R10 and R35 with hepatotoxicity (p = 0.039), hyperbilirubinemia (p = 0.031), clinical jaundice (p = 0.032), and treatment interruption (p = 0.039). Eighteen serious AEs and six deaths (R10-3/R25-1/R35-2) occurred during study period. Time-to-stable culture conversion in liquid media was faster in R25 [adjusted hazard ratio 1.71, 95% confidence interval (CI) 1.26-2.31; (solid: 1.97, 95%CI, 1.46-2.67)] and R35 [1.81, 95%CI, 1.33-2.48; (solid: 2.24, 95%CI, 1.64-3.06)], than R10 [34 vs 44 days]. R25 had no failure/relapse. Conclusions Hepatotoxicity, clinical jaundice and treatment interruptions occurred significantly higher with R35 than R10. Since R25 was comparably safe as R10 and also highly efficacious than R10, it may be considered for implementation. Clinical Trials Registration CTRI/2017/12/010951