Tb-practecal: Study Protocol for a Randomised, Controlled, Open-label, Phase II-III Trial to Evaluate the Safety and Efficacy of Regimens Containing Bedaquiline and Pretomanid for the Treatment of Adult Patients With Pulmonary Multidrug Resistant Tuberculosis

BackgroundGlobally rifampicin-resistant tuberculosis disease affects around 460 000 people each year. Current recommended regimens are 9-24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis. MethodsTB-PRACTECAL is an open-label, randomised, controlled, phase II/III non-inferiority trial evaluating the safety and efficacy of 24 week regimens containing bedaquiline and pretomanid to treat rifampicin resistant tuberculosis. Conducted in Uzbekistan, South Africa and Belarus, patients aged 15 and above with rifampicin resistant pulmonary tuberculosis and requiring a new course of therapy are eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients are randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also include moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment is administered under direct observation for 24 weeks in investigational arms and 36 to 96 weeks in the standard of care arm. The second stage of the study is equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome is the percentage of unfavourable outcomes at 72 weeks post randomisation. This is a composite of early treatment discontinuation, treatment failure, recurrence, lost to follow up and death. The study is conducted in accordance with ICH-GCP and full ethical approval was obtained from Médecins sans Frontières ethical review board, London School of Hygiene and Tropical Medicine ethical review board as well as ERBs and regulatory authorities at each site. DiscussionTB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel regimens that are effective and safe to patients quicker. The trial took a patient-centred approach, adapting to best practice guidelines throughout recruitment. The implementation faced significant challenges from the COVID-19 pandemic. The trial was terminated early for efficacy on the advice of the DSMB and will report on data collected up to end of recruitment and additionally, the planned final analysis at 72 weeks after end of recruitment. Trial registrationClinicaltrials.gov registration number NCT02589782