Phase 2C clinical trial of novel short-course regimens for the treatment of pulmonary tuberculosis: TBTC study 38/CRUSH-TB design

Ekaterina V. Kurbatova, Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: ies3@cdc.gov.
Kelly E. Dooley, Vanderbilt University Medical Center, Nashville, TN, USA.
Wendy Carr, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Jason E. Stout, Duke University, Durham, NC, USA.
Eric L. Nuermberger, Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA.
Patrick P. Phillips, UCSF Center for Tuberculosis, University of California, San Francisco, CA, USA.
Nigel A. Scott, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Caryn M. Upton, TASK Applied Science Brooklyn Chest Hospital, Cape Town, South Africa.
Elisa Ignatius, Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA.
Michelle Haas, Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, USA.
Nicholas D. Walter, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Rita M. Traxler, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Nicole E. Brown, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Rosanna Boyd, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Kia E. Bryant, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Meredith G. Dixon, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Rada Savic, UCSF Center for Tuberculosis, University of California, San Francisco, CA, USA.
Christie Eichberg, Medical University of South Carolina, Department of Medicine, Division of Infectious Disease, Charleston, SC, USA.
Anneke Hesseling, Department of Paediatrics and Child Health, Desmond Tutu Tuberculosis Centre, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
Charles Bark, Tuberculosis Research Unit, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Debra A. Benator, Veterans Affairs Medical Center and the George Washington University, Washington, DC, USA; The George Washington University, Washington, DC, USA.
Grace Muzanyi, Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.
Nicholas S. Twycross, Division of Pulmonology and Department of Medicine, University of Cape Town Lung Institute, Cape Town, South Africa.
Greg J. Fox, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
Samuel Pierre, GHESKIO, Port-au-Prince, Haiti.
Joseph Burzynski, Bureau of Tuberculosis Control, New York City Department of Health and Mental Hygiene, Queens, NY, USA.
Daniel W. Fitzgerald, Weill Cornell Medicine Center for Global Health, New York, NY, USA.

Document Type

Journal Article

Publication Date

9-5-2025

Journal

Contemporary clinical trials

Volume

158

DOI

10.1016/j.cct.2025.108075

Keywords

Bedaquiline; Delamanid; Randomized clinical trial; Rifabutin; TB; Tuberculosis

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.

Department

Medicine

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