Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial

Abstract

Background Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. Methods endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. Discussion The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. Trial registration ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Nine-month, all-oral regimens for rifampin-resistant tuberculosis

“…endTB is an international, multicenter, open-label Phase III, non-inferiority clinical trial conducted by the endTB consortium (Médecins Sans Frontières [MSF], Partners In Health [PIH], and Interactive Research and Development [IRD]). Full design (Figure S1) and implementation details are published 8 . The study was approved by institutional review/ethics boards at Harvard Medical School (HMS), IRD, Institute of Tropical Medicine (ITM), MSF, and at each participating site.…”

“…). Full design (Figure S1) and implementation details are published 8 . The study was approved by institutional review/ethics boards at Harvard Medical School (HMS), IRD, Institute of Tropical Medicine (ITM), MSF, and at each participating site.…”

“…The trial excluded persons with baseline: pregnancy; elevated liver enzymes; uncorrectable electrolyte disorders; QT interval corrected by the Fridericia formula (QTcF) ≥450 msec or other cardiac risk factors for arrhythmia; resistance or prior exposure (≥30 days) to bedaquiline, delamanid, clofazimine, or linezolid; and ≥15 days treatment with any second-line anti-tuberculosis drug during the current TB episode. 8 The Supplement details baseline eligibility criteria and retention in the study of participants who became pregnant.…”

Diagnosis and treatment of tuberculosis in adults with HIV

“…[34] Although the BPaL regimen has shown a high success rate in treating patients with XDR-TB in South Africa, its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. [35][36][37] More controlled studies are still needed to prove whether BPaL is safer and more effective than other anti-TB regimens. Ongoing clinical trials, such as endTB and TB PRACTECAL, are expected to provide high-quality and direct evidence for short-duration and all-oral drug-resistant regimens.…”

Establishment and application of a method of tagged-amplicon deep sequencing for low-abundance drug resistance in HIV-1

“…Once the virus develops drug resistance, the viral load will continue to increase, leading to the failure of ART treatment ( Tachbele et al, 2021 ). If the problem of HIV-1 drug resistance cannot be effectively controlled, it may lead to the widespread of drug-resistant viruses and the emergence of multidrug-resistant ( Guglielmetti et al, 2021 ).…”