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 are available on head-to-head comparison between 10 mg/kg and 25/35 mg/kg rifampicin in treating pulmonary tuberculosis during study initiation.

Methods: A multicentric, phase IIb randomized trial recruited 333 new culture-positive, drug-sensitive adult patients with pulmonary tuberculosis 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 (AEs) and time-to-culture conversion in liquid media, assessed by division of AIDS system for grading the severity of adverse events division of AIDS criteria and Kaplan-Meier methods.

Results: In a modified intention-to-treat population of 323 patients (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 the 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 = .039), hyperbilirubinemia (P = .031), clinical jaundice (P = .032), and treatment interruption (P = .039). Eighteen serious AEs and 6 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. Because 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.

Keywords: efficacy; high-dose; rifampicin; safety; time-to-culture-conversion.

Graphical abstract

https://tidbitapp.io/tidbits/safety-and-efficacy-of-25-mg-and-35-mg-versus-10-mg-rifampicin-in-pulmonary-tb-a-randomised-trial/

Figure 1.

Randomization, and analysis of study participants. CP, continuous phase; E, ethambutol; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; H/INH, isoniazid; IP, intensive phase; LFU, lost to follow-up; LJ, Lowenstein-Jensen; MDR, multidrug resistant; MGIT BACTEC mycobacterial growth indicator tube 960; m-ITT, modified intention-to-treat; NTM, nontuberculous mycobacteria, R, rifampicin; R10 (2R₁₀ Isoniazid, Ethambutol, Pyrizinamide [HEZ]₇/4 Isoniazid, Rifampicin, Ethambutol [HRE]₇), 2 months of rifampicin 10 mg/kg and HEZ given orally daily (intensive phase [IP]) followed by HRE given orally daily for 4 months (CP); R25 (2R₂₅HEZ₇/4HRE₇), 2 months of rifampicin 25 mg/kg and HEZ given orally daily (IP) followed by HRE given orally daily for 4 months (CP); R35 (2R₃₅HEZ₇/4HRE₇), 2 months of rifampicin 35 mg/kg and HEZ given orally daily (IP) followed by HRE given orally daily for 4 months (CP); Rx, treatment; Z, pyrazinamide.

Figure 2.

Grade 3 or 4 hepatic adverse events. The number of cases with hepatotoxicity (grade 3/4 liver enzymes, whichever is the higher grade), or grade 3/4 hyperbilirubinemia, or clinical jaundice or treatment interruption, between control arm (R10) and experimental arms (R25 or R35) were compared for significant differences. Trend test P value comparing R10 vs R25 and R10 vs R35 arms indicated in the diagram. P ≤ .05 is considered statistically significant.

Figure 3.

Kaplan-Meier curves for time-to-culture conversion. A, Time-to-culture conversion in liquid media-MGIT. B, Time-to-culture conversion on solid media Löwenstein-Jensen. Survival function estimated by the Kaplan-Meier method. Censoring is indicated by vertical marks. The number of patients at risk at different time points during intensive and continuation phase of treatment is presented in the graph. Solid vertical line refers to the week 8 time point (cutoff in primary analysis). Dashed vertical line refers to the week 12 time point (cutoff in post hoc analysis). Kaplan-Meier curves displaying the estimated survival probability for 3 different arms of patients after treatment given for 180 d. MGIT, Mycobacteria Growth Indicator Tube.