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. 2025 May 7;25(1):674.
doi: 10.1186/s12879-025-11068-1.

Non-inferiority stepped wedge cluster randomized controlled trial on all-oral shorter regimens for rifampicin resistant/multidrug-resistant TB in Pakistan - a study protocol

Nida Khan  1 , Muhammad Ahmar Khan  2 , Naila Muzaffar  2 , Ahmad Ismail  2 , Abdul Ghafoor  3 , Jonathon R Campbell  4   5   6 , Gwenaelle Le Coroller  7 , Zia Un Nisa  2 , Corinne Simone Merle  8 , Muhammad Amir Khan  2
Affiliations

Non-inferiority stepped wedge cluster randomized controlled trial on all-oral shorter regimens for rifampicin resistant/multidrug-resistant TB in Pakistan - a study protocol

Nida Khan et al. BMC Infect Dis. .

Abstract

Introduction: Pakistan has one of the largest burdens of rifampicin-resistant/ multidrug-resistant TB according to the global estimates. Novel all oral treatment regimens containing new antibiotics with reduced treatment duration are available. World Health Organization guidelines recommend the use of shorter all-oral regimens under operational research. To guide recommendations, we will compare two all-oral, short (≤ 11 months) regimens for the outcomes of efficacy, safety, cost, and health-related quality of life under programmatic conditions in Pakistan.

Methods: This is a stepped wedge, cluster randomized controlled trial with economic evaluation and health related quality of life sub-studies. Modified all-oral 9-month regimen will be sequentially rolled-out compared with the standard all-oral 11-month regimen at 12 sites in Punjab, Islamabad and Azad Jammu and Kashmir region, Pakistan. A total of 400 eligible participants will be enrolled in both study arms. The primary outcome is difference in efficacy as measured by the proportion of patients with treatment success without recurrence at 12 months after the end of treatment between regimens using a non-inferiority design with a margin of 12%. The intention to treat analysis principle will be employed and a marginal mean model with Poisson generalized estimation equations, and a log-link will be used to assess the relative risk. The economic evaluation will be carried out from the healthcare providers perspective; linear mixed models will be used to estimate differences in costs between arms. Health related quality of life will be measured with the EQ-5D-3L quality of life questionnaire at four time points during the study period. The impact will be assessed by calculating the changes for each participant between time points. Ethical approval for this study has been obtained from national bioethics committee, Pakistan (Ref: No.4-87/NBC-491/20/48).

Discussion: The study's findings will be disseminated to physicians, program implementers, scientific audiences, and policymakers on both a national and international level via reports, presentations, and scientific publications.

Trial registration: ISRCTN registry. ISRCTN17334530, 'retrospectively registered' on 8th February 2021. 'Clinical trial number: not applicable.'

Keywords: All-oral; Cluster randomized controlled trial; Economic evaluation; Health related quality of life; Non-inferiority; Rifampicin-resistant/multidrug-resistant TB; Safety; Short regimen; Stepped wedge; Treatment efficacy.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The research protocols were submitted for approval by National Bioethics Committee, Pakistan and ethical approval for conducting this study was received (Ref: No.4–87/NBC-491/20/48). Protection of patient confidentiality is essential, and the study will follow the principles of the 2018 Declaration of Helsinki. Informed written consent will be obtained from patients or a guardian in the case of minors, as defined by local legal requirements. Those who do not consent to participate in this research will receive treatment as per national guidelines. Consent for publication: This is a study protocol, does not require consent to publish, Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Transition period from control to intervention arm
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