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

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.'