Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis: A Randomized Controlled Trial.
Velásquez GE, Brooks MB, Coit JM, Pertinez H, Vargas Vásquez D, Sánchez Garavito E, Calderón RI, Jiménez J, Tintaya K, Peloquin CA, Osso E, Tierney DB, Seung KJ, Lecca L, Davies GR, Mitnick CD.
Am J Respir Crit Care Med. 2018 Jun 29. doi: 10.1164/rccm.201712-2524OC. [Epub ahead of print] PMID: 29954183
OBJECTIVES: To assess the differences across three daily oral doses of rifampin in change in elimination rate of Mycobacterium tuberculosis in sputum and frequency of rifampin-related adverse events.
METHODS: blinded, randomized, controlled Phase II clinical trial of 180 adults with new smear-positive pulmonary tuberculosis, susceptible to isoniazid and rifampin. We randomized 1:1:1 to 10, 15, and 20 mg/kg/day of rifampin during the intensive phase. We report the primary efficacy and safety endpoints: change in elimination rate of M. tuberculosis log10 colony forming units and frequency of grade 2 or higher rifampin-related adverse events. We report efficacy by treatment arm and by primary (AUC/MIC) and secondary (AUC) pharmacokinetic exposure.
MAIN RESULTS: Each 5 mg/kg/day increase in rifampin dose resulted in differences of -0.011 (95%CI, -0.025 - +0.002;P=0.230) and -0.022 (95%CI, -0.046 - -0.002;P=0.022) log10 colony forming units/mL/day in the modified intention-to-treat and per-protocol analyses, respectively. Elimination rate in the per-protocol population increased significantly with rifampin AUC0-6 (P=0.011) but not with AUC0-6/MIC99.9 (P=0.053). Grade 2 or higher rifampin-related adverse events occurred with similar frequency across the three treatment arms: 26(43.3%), 31(51.7%), and 23(38.3%) participants had at least one event (P=0.7092) up to 4 weeks after the intensive phase. Treatment failed or disease recurred in 11(6.1%) participants.
CONCLUSIONS: Findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01408914.