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
Stringer B, Lowton K, Cusinato M, Fielding K, Liverko I, et al.
MSF Scientific Day International 2023. 2023 June 7; DOI:10.57740/by3w-4h53
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 > LetterFull Text
Clin Infect Dis. 2024 August 15; Volume 79 (Issue 2); 569-570.; DOI:10.1093/cid/ciad767
Crocker-Buque T, Lachenal N, Narasimooloo C, Abdrasuliev T, Parpieva N, et al.
Clin Infect Dis. 2024 August 15; Volume 79 (Issue 2); 569-570.; DOI:10.1093/cid/ciad767
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
Stringer B, Lowton K, Cusinato M, Fielding K, Liverko I, et al.
MSF Scientific Day International 2023. 2023 June 7; DOI:10.57740/0589-cg13
INTRODUCTION
The TB-PRACTECAL study trialed a shorter, more tolerable regimen of oral drugs than standard of care (SoC) – which can last for up to 20 months and involve both injectables and up to 20 tablets a day. In this sub-study, PRACTECAL-PRO, we measured and explored trial participant quality of life, experiences, and perspectives on treatment, to understand outcomes more fully. Both studies were conducted in Uzbekistan, South Africa, and Belarus.
METHODS
We conducted a mixed-methods evaluation using quality of life (QoL) surveys and in-depth interviews. Participants in investigational and SoC arms completed the Short Form 12 (SF-12) and St George’s Respiratory Questionnaire (SGRQ) at four timepoints (baseline, 12, 24, and 48 weeks). Healthy age- and sex-matched volunteers were surveyed at a single timepoint to establish locally relevant controls. Participants from investigational arms were purposively sampled for in-depth interviews to describe qualitatively patient satisfaction and experience with the investigational arm trial, including factors enabling toleration or rejection of a novel treatment by patients.
ETHICS
This study was approved by the MSF Ethics Review Board and by the ethics review committees of the Ministry of Health of the Republic of Uzbekistan; the Republican Scientific and Practical Centre for Pulmonology and Tuberculosis, Belarus; the regulatory authority of the Ministry of Health of the Republic of Belarus and Pharma Ethics Independent Ethics Committee, South Africa.
RESULTS
Overall, of 137 trial participants 28.5% (39) and 71.5% (98) were randomised to the SoC arm and one of three investigational arms, respectively. Statistically significant univariate scores by arm were observed at week 48 for SGRQ Impact domain (median -3.8, 95% confidence interval (CI), -5.7 to 0.0) and at week 24 for SF-12 physical component score (median 3.1, 95%CI 0.2 to 6.7). Longitudinal analysis showed that the proportional reduction in SGRQ scores per month was higher in the investigational group compared to the SoC for all domains and the total score. For both the SGRQ and SF-12, baseline scores indicated worse quality of life for the trial participant group (that is, investigational arms and SoC together) than for the healthy control group. Qualitative analysis showed early treatment satisfaction was a useful predictor of better adherence. Treatment acceptability was linked to participants’ support networks and their experience of counselling and clinical advice. Tolerability of the regimen helped reassure patients and household members on efficacy and value of the treatment. Participants reported that early improvement helped them return to productive lives sooner, with the potential to address social determinants with financial protection schemes for a shorter investment period. Patient perspectives around residual burden of disease can help inform clinicians about ongoing care.
CONCLUSION
All PRACTECAL-PRO participants reported worse generic and disease-specific QoL at baseline, compared to an age and sex-matched healthy control group. Participants taking a novel shortened oral regimens demonstrated both a quicker improvement in their respiratory disease-specific QoL over 48 weeks than those receiving SoC, and an improvement that exceeded the SGRQ’s minimum clinically important difference. In-depth interviews give insights suggesting investment toward patient-sensitive and socially responsive treatment and care. For interviewees, the supportive care experienced was as important as their satisfaction and tolerability of the novel drug regimen. Patient perspectives are an essential component of assessing clinical trial outcomes.
CONFLCITS OF INTEREST
None declared.
The TB-PRACTECAL study trialed a shorter, more tolerable regimen of oral drugs than standard of care (SoC) – which can last for up to 20 months and involve both injectables and up to 20 tablets a day. In this sub-study, PRACTECAL-PRO, we measured and explored trial participant quality of life, experiences, and perspectives on treatment, to understand outcomes more fully. Both studies were conducted in Uzbekistan, South Africa, and Belarus.
METHODS
We conducted a mixed-methods evaluation using quality of life (QoL) surveys and in-depth interviews. Participants in investigational and SoC arms completed the Short Form 12 (SF-12) and St George’s Respiratory Questionnaire (SGRQ) at four timepoints (baseline, 12, 24, and 48 weeks). Healthy age- and sex-matched volunteers were surveyed at a single timepoint to establish locally relevant controls. Participants from investigational arms were purposively sampled for in-depth interviews to describe qualitatively patient satisfaction and experience with the investigational arm trial, including factors enabling toleration or rejection of a novel treatment by patients.
ETHICS
This study was approved by the MSF Ethics Review Board and by the ethics review committees of the Ministry of Health of the Republic of Uzbekistan; the Republican Scientific and Practical Centre for Pulmonology and Tuberculosis, Belarus; the regulatory authority of the Ministry of Health of the Republic of Belarus and Pharma Ethics Independent Ethics Committee, South Africa.
RESULTS
Overall, of 137 trial participants 28.5% (39) and 71.5% (98) were randomised to the SoC arm and one of three investigational arms, respectively. Statistically significant univariate scores by arm were observed at week 48 for SGRQ Impact domain (median -3.8, 95% confidence interval (CI), -5.7 to 0.0) and at week 24 for SF-12 physical component score (median 3.1, 95%CI 0.2 to 6.7). Longitudinal analysis showed that the proportional reduction in SGRQ scores per month was higher in the investigational group compared to the SoC for all domains and the total score. For both the SGRQ and SF-12, baseline scores indicated worse quality of life for the trial participant group (that is, investigational arms and SoC together) than for the healthy control group. Qualitative analysis showed early treatment satisfaction was a useful predictor of better adherence. Treatment acceptability was linked to participants’ support networks and their experience of counselling and clinical advice. Tolerability of the regimen helped reassure patients and household members on efficacy and value of the treatment. Participants reported that early improvement helped them return to productive lives sooner, with the potential to address social determinants with financial protection schemes for a shorter investment period. Patient perspectives around residual burden of disease can help inform clinicians about ongoing care.
CONCLUSION
All PRACTECAL-PRO participants reported worse generic and disease-specific QoL at baseline, compared to an age and sex-matched healthy control group. Participants taking a novel shortened oral regimens demonstrated both a quicker improvement in their respiratory disease-specific QoL over 48 weeks than those receiving SoC, and an improvement that exceeded the SGRQ’s minimum clinically important difference. In-depth interviews give insights suggesting investment toward patient-sensitive and socially responsive treatment and care. For interviewees, the supportive care experienced was as important as their satisfaction and tolerability of the novel drug regimen. Patient perspectives are an essential component of assessing clinical trial outcomes.
CONFLCITS OF INTEREST
None declared.
Journal Article > ResearchFull Text
Lancet Respir Med. 2024 February 1; Volume 12 (Issue 2); 117-128.; DOI:10.1016/S2213-2600(23)00389-2
Nyang'wa BT, Berry C, Kazounis E, Motta I, Parpieva N, et al.
Lancet Respir Med. 2024 February 1; Volume 12 (Issue 2); 117-128.; DOI:10.1016/S2213-2600(23)00389-2
BACKGROUND
Around 500,000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis.
METHODS
This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete.
FINDINGS
Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related.
INTERPRETATION
The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis.
Around 500,000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis.
METHODS
This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete.
FINDINGS
Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related.
INTERPRETATION
The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis.