Journal Article > ResearchFull Text
Trials. 2021 December 4; Volume 22; 881 .; DOI:10.1186/s13063-021-05850-0
Wharton-Smith A, Horter SCB, Douch E, Gray NSB, James N, et al.
Trials. 2021 December 4; Volume 22; 881 .; DOI:10.1186/s13063-021-05850-0
BACKGROUND
Addressing the global burden of multidrug-resistant tuberculosis (MDR-TB) requires identification of shorter, less toxic treatment regimens. Médecins Sans Frontières (MSF) is currently conducting a phase II/III randomised controlled clinical trial, to find more effective, shorter and tolerable treatments for people with MDR-TB. Recruitment to the trial in Uzbekistan has been slower than expected; we aimed to study patient and health worker experiences of the trial, examining potential factors perceived to impede and facilitate trial recruitment, as well as general perceptions of clinical research in this context.
METHODS
We conducted a qualitative study using maximum variation, purposive sampling of participants. We carried out in-depth interviews (IDIs) and focus group discussions (FGDs) guided by semi-structured topic guides. In December 2019 and January 2020, 26 interviews were conducted with patients, Ministry of Health (MoH) and MSF staff and trial health workers, to explore challenges and barriers to patient recruitment as well as perceptions of the trial and research in general. Preliminary findings from the interviews informed three subsequent focus group discussions held with patients, nurses and counsellors. Focus groups adopted a person-centred design, brainstorming potential solutions to problems and barriers. Interviews and FGDs were audio recorded, translated and transcribed verbatim. Thematic analysis, drawing on constant comparison, was used to analyse the data.
RESULTS
Health system contexts may compete with new approaches especially when legislative health regulations or policy around treatment is ingrained in staff beliefs, perceptions and practice, which can undermine clinical trial recruitment. Trust plays a significant role in how patients engage with the trial. Decision-making processes are dynamic and associated with relationship to diagnosis, assimilation of information, previous knowledge or experience and influence of peers and close relations.
CONCLUSIONS
This qualitative analysis highlights ways in which insights developed together with patients and healthcare workers might inform approaches towards improved recruitment into trials, with the overall objective of delivering evidence for better treatments.
Addressing the global burden of multidrug-resistant tuberculosis (MDR-TB) requires identification of shorter, less toxic treatment regimens. Médecins Sans Frontières (MSF) is currently conducting a phase II/III randomised controlled clinical trial, to find more effective, shorter and tolerable treatments for people with MDR-TB. Recruitment to the trial in Uzbekistan has been slower than expected; we aimed to study patient and health worker experiences of the trial, examining potential factors perceived to impede and facilitate trial recruitment, as well as general perceptions of clinical research in this context.
METHODS
We conducted a qualitative study using maximum variation, purposive sampling of participants. We carried out in-depth interviews (IDIs) and focus group discussions (FGDs) guided by semi-structured topic guides. In December 2019 and January 2020, 26 interviews were conducted with patients, Ministry of Health (MoH) and MSF staff and trial health workers, to explore challenges and barriers to patient recruitment as well as perceptions of the trial and research in general. Preliminary findings from the interviews informed three subsequent focus group discussions held with patients, nurses and counsellors. Focus groups adopted a person-centred design, brainstorming potential solutions to problems and barriers. Interviews and FGDs were audio recorded, translated and transcribed verbatim. Thematic analysis, drawing on constant comparison, was used to analyse the data.
RESULTS
Health system contexts may compete with new approaches especially when legislative health regulations or policy around treatment is ingrained in staff beliefs, perceptions and practice, which can undermine clinical trial recruitment. Trust plays a significant role in how patients engage with the trial. Decision-making processes are dynamic and associated with relationship to diagnosis, assimilation of information, previous knowledge or experience and influence of peers and close relations.
CONCLUSIONS
This qualitative analysis highlights ways in which insights developed together with patients and healthcare workers might inform approaches towards improved recruitment into trials, with the overall objective of delivering evidence for better treatments.
Conference Material > Abstract
Gotham D, Martin M, Barber M, Kazounis E, Batts C, et al.
MSF Scientific Day International 2024. 2024 May 16; DOI:10.57740/aMphKRQ
INTRODUCTION
Clinical trials are a cornerstone of medical innovation. Nonetheless, little information on the cost of conducting clinical trials is available, especially for clinical trials in the global south. This lack of data and transparency hinders the creation of reliable cost estimates and adequate funding of clinical trials in resource- limited settings. Following the recent adoption of the Médecins Sans Frontières (MSF) Clinical Trial Transparency Policy, we present a detailed cost report for TB-PRACTECAL.
METHODS
TB-PRACTECAL was an open-label, phase 2–3, multicentre randomised trial of all-oral regimens for the treatment of drug- resistant tuberculosis. Trial planning began in 2013 and work on publications continued into 2023. The trial took place in six sites across Belarus, South Africa, and Uzbekistan, and enrolled 552 patients. We analysed accounting data for the TB-PRACTECAL project, comprehensively including different costs, presented into 27 categories, by site, and by year, and at the per-patient level.
RESULTS
Total costs for TB-PRACTECAL were €33.9 million, of which 26% were at central level (costs incurred by the UK clinical trial team including trial planning, management, quality assurance, and analysis of results), while 72% were at the trial site level (across all six sites) and 2% were uncategorisable. At trial sites, the largest cost category was staff (43%), followed by external diagnostic services (11%), medicines (9%), other medical consumables (7%), external non-medical services (6%), and transport and travel (6%). Among medicines, the costliest were bedaquiline (46% of medicine costs), linezolid (16%), imipenem/ cilastatin (10%), and delamanid (9%). The mean cost per patient enrolled was €61,460 across the whole trial (including trial management overhead). When only site-level costs were considered, per-patient costs ranged between €19,998 and €45,942 across the six sites.
CONCLUSION
The costs of TB-PRACTECAL were similar to previously reported estimates for comparable clinical trials. However, TB- PRACTECAL included additional costs that would not typically be incurred in a commercial trial, such as investments in clinical research infrastructure and purchase of investigative medical products. To our knowledge, this is the first time MSF, or any other entity, published and analysed the disaggregated costs of a specific clinical trial. These data could help generate reliable predictions for future clinical trials and support planning and involvement, particularly in low-resource settings. Additionally, this study highlights the role of clinical trial cost disclosure in supporting both practical and policy discussions around the development of a more equitable system of biomedical R&D and fairer medicine pricing. Additionally, we developed a financial reporting template to facilitate future reporting of clinical trial cost by MSF and other entities investing in research.
Clinical trials are a cornerstone of medical innovation. Nonetheless, little information on the cost of conducting clinical trials is available, especially for clinical trials in the global south. This lack of data and transparency hinders the creation of reliable cost estimates and adequate funding of clinical trials in resource- limited settings. Following the recent adoption of the Médecins Sans Frontières (MSF) Clinical Trial Transparency Policy, we present a detailed cost report for TB-PRACTECAL.
METHODS
TB-PRACTECAL was an open-label, phase 2–3, multicentre randomised trial of all-oral regimens for the treatment of drug- resistant tuberculosis. Trial planning began in 2013 and work on publications continued into 2023. The trial took place in six sites across Belarus, South Africa, and Uzbekistan, and enrolled 552 patients. We analysed accounting data for the TB-PRACTECAL project, comprehensively including different costs, presented into 27 categories, by site, and by year, and at the per-patient level.
RESULTS
Total costs for TB-PRACTECAL were €33.9 million, of which 26% were at central level (costs incurred by the UK clinical trial team including trial planning, management, quality assurance, and analysis of results), while 72% were at the trial site level (across all six sites) and 2% were uncategorisable. At trial sites, the largest cost category was staff (43%), followed by external diagnostic services (11%), medicines (9%), other medical consumables (7%), external non-medical services (6%), and transport and travel (6%). Among medicines, the costliest were bedaquiline (46% of medicine costs), linezolid (16%), imipenem/ cilastatin (10%), and delamanid (9%). The mean cost per patient enrolled was €61,460 across the whole trial (including trial management overhead). When only site-level costs were considered, per-patient costs ranged between €19,998 and €45,942 across the six sites.
CONCLUSION
The costs of TB-PRACTECAL were similar to previously reported estimates for comparable clinical trials. However, TB- PRACTECAL included additional costs that would not typically be incurred in a commercial trial, such as investments in clinical research infrastructure and purchase of investigative medical products. To our knowledge, this is the first time MSF, or any other entity, published and analysed the disaggregated costs of a specific clinical trial. These data could help generate reliable predictions for future clinical trials and support planning and involvement, particularly in low-resource settings. Additionally, this study highlights the role of clinical trial cost disclosure in supporting both practical and policy discussions around the development of a more equitable system of biomedical R&D and fairer medicine pricing. Additionally, we developed a financial reporting template to facilitate future reporting of clinical trial cost by MSF and other entities investing in research.
Conference Material > Poster
Motta I, Cusinato M, Ludman A, Abdrasuliev T, Butabekov I, et al.
MSF Scientific Day International 2023. 2023 June 7; DOI:10.57740/vz2n-4971
Conference Material > Slide Presentation
Nyang'wa BT, Berry C, Motta I, Kazounis E
MSF Scientific Days International 2021: Research. 2021 May 19
Conference Material > Slide Presentation
Berry C, Motta I, Kazounis E, Fielding K, Dodd M, et al.
MSF Scientific Days International 2022. 2022 May 11; DOI:10.57740/v9ye-0032
Conference Material > Video
Berry C, Motta I, Kazounis E, Fielding K, Dodd M, et al.
MSF Scientific Days International 2022. 2022 June 7; DOI:10.57740/atfr-ws57
Journal Article > ResearchFull Text
N Engl J Med. 2022 December 22; Volume 387 (Issue 25); 2331-2343.; DOI:10.1056/NEJMoa2117166
Nyang'wa BT, Berry C, Kazounis E, Motta I, Parpieva N, et al.
N Engl J Med. 2022 December 22; Volume 387 (Issue 25); 2331-2343.; DOI:10.1056/NEJMoa2117166
BACKGROUND
In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed.
METHODS
We conducted an open-label, phase 2–3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points.
RESULTS
Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%).
CONCLUSIONS
In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782. opens in new tab.)
In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed.
METHODS
We conducted an open-label, phase 2–3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points.
RESULTS
Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%).
CONCLUSIONS
In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782. opens in new tab.)
Journal Article > ResearchFull Text
Antimicrob Agents Chemother. 2024 June 6; Volume 68 (Issue 7); e0053624.; DOI:10.1128/aac.00536-24
Motta I, Cusinato M, Ludman AJ, Lachenal N, Dodd M, et al.
Antimicrob Agents Chemother. 2024 June 6; Volume 68 (Issue 7); e0053624.; DOI:10.1128/aac.00536-24
Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25–21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies.
Conference Material > Abstract
Lachenal N, Hewison CCH, Berry C, Mitnick CD, Ahmed SM, et al.
MSF Scientific Days International 2022. 2022 May 11; DOI:10.57740/hs0k-1941
INTRODUCTION
Drug-resistant tuberculosis (DR-TB) carries significant morbidity and mortality risk. Care of DR-TB in pregnancy is even more challenging. A recent meta-analysis examining the impact of DR-TB on pregnancy outcomes found a higher than expected rate of maternal death, pregnancy loss, and a significant prevalence of low-birthweight infants. Anti-tubercular drugs such as bedaquiline and clofazimine have long half-lives and the impact of in-utero exposure is largely unknown. There is little information to help women, their family members, and clinicians make informed decisions about DR-TB treatment during pregnancy.
METHODS
Data on pregnancy outcomes were systematically collected as part of a pharmacovigilance programme supporting a clinical trial (TB-PRACTECAL; N=552) and a prospective cohort (endTB; N=2,906). We present the birth outcomes as reported to investigators by participants.
ETHICS
The endTB and TB-PRACTECAL studies were both approved by the local ethics committees in all recruiting countries and by the MSF Ethics Review Board. endTB was approved by the Partners Healthcare Human Research Committee, Boston, USA, and TB-PRACTECAL was approved by the London School of Hygiene and Tropical Medicine Ethics Committee, UK.
RESULTS
Between 01 April 2015 and 31 December 2021, 58 pregnancies in 53 women were notified from 10 different countries, predominantly Uzbekistan (14), Kazakhstan (13) and Pakistan (9). In 13 cases, pregnancy occurred after completion of tuberculosis treatment. Patients became pregnant a median of 260.5 (range, 0-727) days from treatment start; five women were 5-32 weeks pregnant at treatment start. There were no maternal deaths. 17.0% (9/53) of mothers changed or interrupted treatment during pregnancy. Treatment outcome was successful in 97.3% (36/37) of others in endTB and 100% (7/7) of mothers who completed follow-up in TB-PRACTECAL. Pregnancy outcome was known in 52 cases: 20 elective abortions, three miscarriages and 30 live births (one twin pregnancy). There were no stillbirths. Of the 30 live births, 29 occurred in mothers ever exposed to bedaquiline, 16 to clofazimine, 11 to a second-line injectable, 10 to pretomanid, and 7 to delamanid. Birth weight was known in 24/30 (80.0%) babies. Median weight was 3,015 (range, 1,270 to 4,200) grams. Two babies were born prematurely at 30 and 31 weeks. Low birthweight was reported in seven (29.2%; 7/24) babies. One low-birthweight baby died within four months of birth from complications unrelated to tuberculosis. One baby was treated for DR-TB. There were no reported birth malformations.
CONCLUSION
These results support evidence that effective DR-TB treatments may improve maternal outcomes and prevent perinatal transmission. How these perinatal outcomes compare to other cohorts not affected by TB in these settings or exposed to different TB treatments needs exploration. The factors contributing to low birthweight in babies born to mothers with DR-TB requires further research. A global registry is urgently needed to assist parents and clinicians with decision-making.
CONFLICTS OF INTEREST
The endTB project was funded by UNITAID (Geneva, Switzerland). Provision of delamanid within the endTB project was partially funded through a donation from Otsuka Company (Kyoto, Japan).
Drug-resistant tuberculosis (DR-TB) carries significant morbidity and mortality risk. Care of DR-TB in pregnancy is even more challenging. A recent meta-analysis examining the impact of DR-TB on pregnancy outcomes found a higher than expected rate of maternal death, pregnancy loss, and a significant prevalence of low-birthweight infants. Anti-tubercular drugs such as bedaquiline and clofazimine have long half-lives and the impact of in-utero exposure is largely unknown. There is little information to help women, their family members, and clinicians make informed decisions about DR-TB treatment during pregnancy.
METHODS
Data on pregnancy outcomes were systematically collected as part of a pharmacovigilance programme supporting a clinical trial (TB-PRACTECAL; N=552) and a prospective cohort (endTB; N=2,906). We present the birth outcomes as reported to investigators by participants.
ETHICS
The endTB and TB-PRACTECAL studies were both approved by the local ethics committees in all recruiting countries and by the MSF Ethics Review Board. endTB was approved by the Partners Healthcare Human Research Committee, Boston, USA, and TB-PRACTECAL was approved by the London School of Hygiene and Tropical Medicine Ethics Committee, UK.
RESULTS
Between 01 April 2015 and 31 December 2021, 58 pregnancies in 53 women were notified from 10 different countries, predominantly Uzbekistan (14), Kazakhstan (13) and Pakistan (9). In 13 cases, pregnancy occurred after completion of tuberculosis treatment. Patients became pregnant a median of 260.5 (range, 0-727) days from treatment start; five women were 5-32 weeks pregnant at treatment start. There were no maternal deaths. 17.0% (9/53) of mothers changed or interrupted treatment during pregnancy. Treatment outcome was successful in 97.3% (36/37) of others in endTB and 100% (7/7) of mothers who completed follow-up in TB-PRACTECAL. Pregnancy outcome was known in 52 cases: 20 elective abortions, three miscarriages and 30 live births (one twin pregnancy). There were no stillbirths. Of the 30 live births, 29 occurred in mothers ever exposed to bedaquiline, 16 to clofazimine, 11 to a second-line injectable, 10 to pretomanid, and 7 to delamanid. Birth weight was known in 24/30 (80.0%) babies. Median weight was 3,015 (range, 1,270 to 4,200) grams. Two babies were born prematurely at 30 and 31 weeks. Low birthweight was reported in seven (29.2%; 7/24) babies. One low-birthweight baby died within four months of birth from complications unrelated to tuberculosis. One baby was treated for DR-TB. There were no reported birth malformations.
CONCLUSION
These results support evidence that effective DR-TB treatments may improve maternal outcomes and prevent perinatal transmission. How these perinatal outcomes compare to other cohorts not affected by TB in these settings or exposed to different TB treatments needs exploration. The factors contributing to low birthweight in babies born to mothers with DR-TB requires further research. A global registry is urgently needed to assist parents and clinicians with decision-making.
CONFLICTS OF INTEREST
The endTB project was funded by UNITAID (Geneva, Switzerland). Provision of delamanid within the endTB project was partially funded through a donation from Otsuka Company (Kyoto, Japan).
Journal Article > ResearchFull Text
Trials. 2022 June 13; Volume 23 (Issue 1); 484.; DOI:10.1186/s13063-022-06331-8
Berry C, du Cros PAK, Fielding K, Gajewski S, Kazounis E, et al.
Trials. 2022 June 13; Volume 23 (Issue 1); 484.; DOI:10.1186/s13063-022-06331-8
BACKGROUND
Globally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently 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.
METHODS
TB-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 were eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients were randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also included moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment was 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 was equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome was the percentage of unfavourable outcomes at 72 weeks post-randomisation. This was a composite of early treatment discontinuation, treatment failure, recurrence, lost-to-follow-up and death. The study is being 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.
DISCUSSION
TB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel treatments 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 the end of recruitment and, additionally, the planned final analysis at 72 weeks after the end of recruitment.
Globally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently 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.
METHODS
TB-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 were eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients were randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also included moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment was 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 was equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome was the percentage of unfavourable outcomes at 72 weeks post-randomisation. This was a composite of early treatment discontinuation, treatment failure, recurrence, lost-to-follow-up and death. The study is being 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.
DISCUSSION
TB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel treatments 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 the end of recruitment and, additionally, the planned final analysis at 72 weeks after the end of recruitment.