Study protocol for a duration-randomized clinical trial to determine the optimal length of treatment for multidrug-resistant tuberculosis with a 5-drug regimen: The DRAMATIC trial

Pawandeep Kaur¹, Lelia H Chaisson², Zana Wangari Kiragu¹, Praewpannarai Buddadhumaruk³, Ariana F Austin², Yilan Gao¹, Veronika J Wirtz¹, Robert D Arbeit⁴, Krystle Bliss Fetalvero⁵, Hoa Binh Nguyen⁶, Nhung Viet Nguyen⁷, Huy Ha⁸, Kathleen Eisenach⁹, Nicholas D Walter¹⁰, Carole D Mitnick¹¹, Maria Tarcela S Gler⁵, Ha Phan¹², Payam Nahid¹³, Patrick P J Phillips¹⁴, C Robert Horsburgh¹⁵, Gustavo E Velásquez¹⁶

Affiliations

¹ Department of Global Health, Boston University School of Public Health, Boston, MA, USA.
² UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; UCSF Institute for Global Health Sciences, University of California, San Francisco, San Francisco, California, USA.
³ UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
⁴ Division of Geographic Medicine and Infectious Diseases, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA.
⁵ De La Salle Medical and Health Sciences Institute, Das Mariñas, Philippines.
⁶ National Lung Hospital/National Tuberculosis Control Programme, Ha Noi, Viet Nam.
⁷ University of Medicine and Pharmacy, Vietnam National University, Ha Noi, Viet Nam.
⁸ Hanoi Lung Hospital/National Tuberculosis Control Programme, Ha Noi, Viet Nam; Center for Promotion of Advancement of Society, Ha Noi, Viet Nam.
⁹ TB or NOT TB Consulting, LLC, Little Rock, AR, USA.
¹⁰ Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Consortium for Applied Microbial Metrics, Aurora, CO, USA.
¹¹ Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA; Partners in Health, 800 Boylston Street Suite 300, Boston, MA, USA.; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
¹² Center for Promotion of Advancement of Society, Ha Noi, Viet Nam; Vietnam Tuberculosis Program/University of California, San Francisco Research Collaboration Unit, Ha Noi, Viet Nam.
¹³ UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; UCSF Institute for Global Health Sciences, University of California, San Francisco, San Francisco, California, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
¹⁴ UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
¹⁵ Department of Global Health, Boston University School of Public Health, Boston, MA, USA; Department of Epidemiology and Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
¹⁶ UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, California, USA. Electronic address: gustavo.velasquez@ucsf.edu.

PMID: 40064371
PMCID: PMC12083089 (available on 2026-05-01)
DOI: 10.1016/j.cct.2025.107875

Study protocol for a duration-randomized clinical trial to determine the optimal length of treatment for multidrug-resistant tuberculosis with a 5-drug regimen: The DRAMATIC trial

Pawandeep Kaur et al. Contemp Clin Trials. 2025 May.

. 2025 May:152:107875.

doi: 10.1016/j.cct.2025.107875. Epub 2025 Mar 8.

Authors

Affiliations

¹ Department of Global Health, Boston University School of Public Health, Boston, MA, USA.
² UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; UCSF Institute for Global Health Sciences, University of California, San Francisco, San Francisco, California, USA.
³ UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
⁴ Division of Geographic Medicine and Infectious Diseases, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA.
⁵ De La Salle Medical and Health Sciences Institute, Das Mariñas, Philippines.
⁶ National Lung Hospital/National Tuberculosis Control Programme, Ha Noi, Viet Nam.
⁷ University of Medicine and Pharmacy, Vietnam National University, Ha Noi, Viet Nam.
⁸ Hanoi Lung Hospital/National Tuberculosis Control Programme, Ha Noi, Viet Nam; Center for Promotion of Advancement of Society, Ha Noi, Viet Nam.
⁹ TB or NOT TB Consulting, LLC, Little Rock, AR, USA.
¹⁰ Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Consortium for Applied Microbial Metrics, Aurora, CO, USA.
¹¹ Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA; Partners in Health, 800 Boylston Street Suite 300, Boston, MA, USA.; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
¹² Center for Promotion of Advancement of Society, Ha Noi, Viet Nam; Vietnam Tuberculosis Program/University of California, San Francisco Research Collaboration Unit, Ha Noi, Viet Nam.
¹³ UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; UCSF Institute for Global Health Sciences, University of California, San Francisco, San Francisco, California, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
¹⁴ UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
¹⁵ Department of Global Health, Boston University School of Public Health, Boston, MA, USA; Department of Epidemiology and Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
¹⁶ UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, California, USA; Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, California, USA. Electronic address: gustavo.velasquez@ucsf.edu.

PMID: 40064371
PMCID: PMC12083089 (available on 2026-05-01)
DOI: 10.1016/j.cct.2025.107875

Abstract

Background: Current guidelines for the treatment of multidrug-resistant/rifampin-resistant tuberculosis (MDR/RR-TB) are based on clinical trials evaluating fixed duration regimens. However, when a regimen succeeds, it remains unknown whether a shorter duration could yield the same results. Similarly, if a regimen fails, it is unclear whether extending the treatment could improve outcomes. Trials are needed to assess the relationship between various treatment durations and outcomes.

Methods/design: We designed a duration-randomized trial of treatment for fluoroquinolone-susceptible MDR/RR-TB. The DRAMATIC (Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical) Trial is a multicenter, randomized, partially blinded, four-arm, phase 2 trial that examines an all oral, pyrazinamide-free regimen of bedaquiline, clofazimine, delamanid, linezolid, and levofloxacin, with administration of linezolid only in the initial 16 weeks of treatment. The four trial arms are treatment durations of 16, 24, 32 and 40 weeks. Randomization is stratified by "extensive" or "non-extensive" disease based on baseline smear (or Xpert) and cavitary status. The primary endpoint is relapse-free survival at week 76. The target sample size is 220. Participants are being enrolled in sites in the Philippines and Vietnam. The expected output will be an equation describing the relationship between treatment duration and the proportion of participants with relapse-free survival.

Discussion: This trial aims to demonstrate that a duration-response relationship can be described for the treatment of MDR/RR-TB by a duration-randomized trial.

Keywords: Bedaquiline; Clinical trial; Clofazimine; Delamanid; Duration randomization; Levofloxacin; Linezolid; Multidrug-resistant tuberculosis.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

1. World Health Organization. Global Tuberculosis Report 2024. Geneva; 2024.
1. World Health Organization. WHO consolidated guidelines on tuberculosis Module 4: Treatment - Drug-resistant tuberculosis treatment 2022 update. 2022. - PubMed
1. World Health Organization. Key updates to the treatment of drug-resistant tuberculosis: rapid communication, June 2024. 2024.
1. Li SY, Irwin SM, Converse PJ, Mdluli KE, Lenaerts AJ, Nuermberger EL. Evaluation of moxifloxacin-containing regimens in pathologically distinct murine tuberculosis models. Antimicrob Agents Chemother. 2015. Jul;59(7):4026–30. - PMC - PubMed
1. Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014. Oct 23;371(17):1577–87. - PMC - PubMed

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Study protocol for a duration-randomized clinical trial to determine the optimal length of treatment for multidrug-resistant tuberculosis with a 5-drug regimen: The DRAMATIC trial

Affiliations

Study protocol for a duration-randomized clinical trial to determine the optimal length of treatment for multidrug-resistant tuberculosis with a 5-drug regimen: The DRAMATIC trial

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources