Abstract
INTRODUCTION: Preclinical and clinical study data show that combining bedaquiline (B or BDQ), moxifloxacin (M), and pyrazinamide (Z), known as BMZ, has potent antimicrobial activity that might shorten treatment duration for drug-susceptible pulmonary tuberculosis. METHODS/DESIGN: We describe the design of Tuberculosis Trials Consortium (TBTC) Study 38/CRUSH-TB (NCT05766267), an open-label multicenter international randomized controlled phase 2C trial that compares two four-month regimens, BMZ plus rifabutin (Rb) (2BMZRb/2BMRb) or BMZ plus delamanid (D or DLM) (2BMZD/2BMD), with standard 6-months isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE). All drugs are administered seven days per week, under direct observation, at least five days per week. A total of 288 participants, aged ≥12 years, newly diagnosed with sputum smear-positive or Xpert MTB/RIF (Ultra)-positive drug-susceptible pulmonary tuberculosis, will be randomized 1:1:1 to receive BMZRb, BMZD, or HRZE. Participants are followed until 78 weeks post-randomization, or until the last enrolled participant completes 52 weeks post-randomization, whichever comes first. The primary endpoint is time to sputum culture negative in liquid media. Secondary endpoints include sustained cure, safety, and additional mycobacteriology and pharmacokinetic and pharmacodynamic outcomes. This trial has an adaptive design, wherein new arms can be added. DISCUSSION: This trial tests the hypothesis whether four-month BMZ-based regimens with Rb or D can shorten time to culture negativity while being safe and tolerable for participants. The study design is adaptive, allowing for additional study arms as new drugs become available. Findings from this trial might have important implications for clinically managing drug-susceptible pulmonary tuberculosis at individual and programmatic levels. Trial registration IND Number: 158058. IND Sponsor: U.S. Centers for Disease Control and Prevention. CLINICALTRIALS: govIdentifier:NCT05766267. Registered 13 March 2023, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05766267.