Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2016 March 1; Volume 20 (Issue 3); 290-294.; DOI:10.5588/ijtld.15.0490
Furin J, Alirol E, Allen E, Fielding K, Merle CS, et al.
Int J Tuberc Lung Dis. 2016 March 1; Volume 20 (Issue 3); 290-294.; DOI:10.5588/ijtld.15.0490
Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.
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.
Journal Article > ResearchFull Text
Int J Tuberc Lung Dis. 2013 December 17; Volume 17 (Issue 12); 1518-1523.; DOI:10.5588/ijtld.13.0238
Russell GK, Merle CS, Cooke GS, Casas EDT, da Fonseca M, et al.
Int J Tuberc Lung Dis. 2013 December 17; Volume 17 (Issue 12); 1518-1523.; DOI:10.5588/ijtld.13.0238
SETTING
Achieving the World Health Organization (WHO) target of zero paediatric tuberculosis (TB) deaths will require an understanding of the underlying risk factors for mortality.
OBJECTIVE
To identify risk factors for mortality and assess the impact of human immunodeficiency virus (HIV) testing during anti-tuberculosis treatment in children in 13 TB-HIV programmes run by Médecins Sans Frontières.
DESIGN
In a retrospective cohort study, we recorded mortality and analysed risk factors using descriptive statistics and logistic regression. Diagnosis was based on WHO algorithm and smear microscopy.
RESULTS
A total of 2451 children (mean age 5.2 years, SD 3.9) were treated for TB. Half (51.0%) lived in Asia, the remainder in sub-Saharan Africa; 56.0% had pulmonary TB; 6.4% were diagnosed using smear microscopy; 211 (8.6%) died. Of 1513 children tested for HIV, 935 (61.8%) were positive; 120 (12.8%) died compared with 30/578 (5.2%) HIV-negative children. Risk factors included being HIV-positive (OR 2.6, 95%CI 1.6–4.2), age <5 years (1.7, 95%CI 1.2–2.5) and having tuberculous meningitis (2.6, 95%CI 1.0–6.8). Risk was higher in African children of unknown HIV status than in those who were confirmed HIV-negative (1.9, 95%CI 1.1–3.3).
CONCLUSIONS
Strategies to eliminate childhood TB deaths should include addressing the high-risk groups identified in this study, enhanced TB prevention, universal HIV testing and the development of a rapid diagnostic test.
Achieving the World Health Organization (WHO) target of zero paediatric tuberculosis (TB) deaths will require an understanding of the underlying risk factors for mortality.
OBJECTIVE
To identify risk factors for mortality and assess the impact of human immunodeficiency virus (HIV) testing during anti-tuberculosis treatment in children in 13 TB-HIV programmes run by Médecins Sans Frontières.
DESIGN
In a retrospective cohort study, we recorded mortality and analysed risk factors using descriptive statistics and logistic regression. Diagnosis was based on WHO algorithm and smear microscopy.
RESULTS
A total of 2451 children (mean age 5.2 years, SD 3.9) were treated for TB. Half (51.0%) lived in Asia, the remainder in sub-Saharan Africa; 56.0% had pulmonary TB; 6.4% were diagnosed using smear microscopy; 211 (8.6%) died. Of 1513 children tested for HIV, 935 (61.8%) were positive; 120 (12.8%) died compared with 30/578 (5.2%) HIV-negative children. Risk factors included being HIV-positive (OR 2.6, 95%CI 1.6–4.2), age <5 years (1.7, 95%CI 1.2–2.5) and having tuberculous meningitis (2.6, 95%CI 1.0–6.8). Risk was higher in African children of unknown HIV status than in those who were confirmed HIV-negative (1.9, 95%CI 1.1–3.3).
CONCLUSIONS
Strategies to eliminate childhood TB deaths should include addressing the high-risk groups identified in this study, enhanced TB prevention, universal HIV testing and the development of a rapid diagnostic test.