ABSTRACT
Background: Globally 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
Subject(s)
HIV Infections , Tuberculosis, Multidrug-Resistant , Tuberculosis , COVID-19ABSTRACT
Background Since the emergence of the COVID-19 pandemic, substantial concern has surrounded its impact among the Rohingya refugees living in the Kutupalong-Balukhali refugee camps in Bangladesh. Early modeling work projected a massive outbreak was likely after an introduction of the SARS-CoV-2 virus into the camps. Despite this, only 317 laboratory-confirmed cases and 10 deaths were reported through October 2020. While these official numbers portray a situation where the virus has been largely controlled, other sources contradict this, suggesting the low reported numbers to be a result of limited care seeking and testing, highlighting a population not willing to seek care or be tested. SARS-CoV-2 seroprevalence estimates from similar a timeframe in India (57%) and Bangladesh (74%) further sow doubt that transmission had been controlled. Here we explore multiple data sources to understand the plausibility of a much larger SARS-CoV-2 outbreak among the Rohingya refugees. Methods We used a mixed approach to analyze SARS-CoV-2 transmission using multiple available datasets. Using data from reported testing, cases, and deaths from the World Health Organization (WHO) and from WHO's Emergency Warning, Alert, and Response System, we characterized the probabilities of care seeking, testing, and being positive if tested. Unofficial death data, including reported pre-death symptoms, come from a community-based mortality survey conducted by the International Organization for Migration (IOM),) in addition to community health worker reported deaths. We developed a probabilistic inference framework, drawing on these data sources, to explore three scenarios of what might have happened among the Rohingya refugees. Results Among the 144 survey-identified deaths, 48 were consistent with suspected COVID-19. These deaths were consistent with viral exposures during Ramadan, a period of increased social contacts, and coincided with a spike in reported cases and testing positivity in June 2020. The age profile of suspected COVID-19 deaths mirrored that expected. Through the probability framework, we find that under each scenario, a substantial outbreak likely occurred, though the cumulative size and timing vary considerably. In conjunction with the reported and suspected deaths, the data suggest a large outbreak could have occurred early during spring 2020. Furthermore, while many mild and asymptomatic infections likely occurred, death data analyzed suggest there may have been significant unreported mortality. Conclusions With the high population density, inability to home isolate adequately, and limited personal protective equipment, infection prevention and control in the Rohingya population is extremely challenging. Despite the low reported numbers of cases and deaths, our results suggest an early large-scale outbreak is consistent with multiple sources of data, particularly when accounting for limited care seeking behavior and low infection severity among this young population. While the currently available data do not allow us to estimate the precise incidence, these results indicate substantial unrecognized SARS-CoV-2 transmission may have occurred in these camps. However, until serological testing provides more conclusive evidence, we are only able to speculate about the extent of transmission among the Rohingya.