Protocol > Research Study
BMJ Open. 2020 October 10; Volume 10 (Issue 10); e036599.; DOI:10.1136/bmjopen-2019-036599
Sweeney S, Gomez G, Kitson N, Sinha A, Yatskevich N, et al.
BMJ Open. 2020 October 10; Volume 10 (Issue 10); e036599.; DOI:10.1136/bmjopen-2019-036599
INTRODUCTION
Current treatment regimens for multidrug-resistant tuberculosis (MDR-TB) are long, poorly tolerated and have poor outcomes. Furthermore, the costs of treating MDR-TB are much greater than those for treating drug-susceptible TB, both for health service and patient-incurred costs. Urgent action is needed to identify short, effective, tolerable and cheaper treatments for people with both quinolone-susceptible and quinolone-resistant MDR-TB. We present the protocol for an economic evaluation (PRACTECAL-EE substudy) alongside an ongoing clinical trial (TB-PRACTECAL) aiming to assess the costs to patients and providers of new regimens, as well as their cost-effectiveness and impact on participant poverty levels. This substudy is based on data from the three countries participating in the main trial.
METHODS AND ANALYSIS
Primary cost data will be collected from the provider and patient perspectives, following economic best practice. We will estimate the probability that new MDR-TB regimens containing bedaquiline, pretomanid and linezolid are cost-effective from a societal perspective as compared with the standard of care for MDR-TB patients in Uzbekistan, South Africa and Belarus. Analysis uses a Markov model populated with primary cost and outcome data collected at each study site. We will also estimate the impact of new regimens on prevalence of catastrophic patient costs due to TB.
ETHICS AND DISSEMINATION
Ethical approval has been obtained from the London School of Hygiene & Tropical Medicine and Médecins Sans Frontières. Local ethical approval will be sought in each study site. The results of the economic evaluation will be shared with the country health authorities and published in a peer-reviewed journal.
Current treatment regimens for multidrug-resistant tuberculosis (MDR-TB) are long, poorly tolerated and have poor outcomes. Furthermore, the costs of treating MDR-TB are much greater than those for treating drug-susceptible TB, both for health service and patient-incurred costs. Urgent action is needed to identify short, effective, tolerable and cheaper treatments for people with both quinolone-susceptible and quinolone-resistant MDR-TB. We present the protocol for an economic evaluation (PRACTECAL-EE substudy) alongside an ongoing clinical trial (TB-PRACTECAL) aiming to assess the costs to patients and providers of new regimens, as well as their cost-effectiveness and impact on participant poverty levels. This substudy is based on data from the three countries participating in the main trial.
METHODS AND ANALYSIS
Primary cost data will be collected from the provider and patient perspectives, following economic best practice. We will estimate the probability that new MDR-TB regimens containing bedaquiline, pretomanid and linezolid are cost-effective from a societal perspective as compared with the standard of care for MDR-TB patients in Uzbekistan, South Africa and Belarus. Analysis uses a Markov model populated with primary cost and outcome data collected at each study site. We will also estimate the impact of new regimens on prevalence of catastrophic patient costs due to TB.
ETHICS AND DISSEMINATION
Ethical approval has been obtained from the London School of Hygiene & Tropical Medicine and Médecins Sans Frontières. Local ethical approval will be sought in each study site. The results of the economic evaluation will be shared with the country health authorities and published in a peer-reviewed journal.
Conference Material > Slide Presentation
Stringer B, Lowton K, Cusinato M, Fielding K, Liverko I, et al.
MSF Scientific Days International 2023. 2023 June 7; DOI:10.57740/by3w-4h53
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 (talk)
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
Conference Material > Poster
Motta I, Cusinato M, Ludman A, Abdrasuliev T, Butabekov I, et al.
MSF Scientific Days International 2023. 2023 June 7; DOI:10.57740/vz2n-4971
Journal Article > LetterFull Text
Clin Infect Dis. 2024 February 29; Online ahead of print; DOI:10.1093/cid/ciad767
Crocker-Buque T, Lachenal N, Narasimooloo C, Abdrasuliev T, Parpieva N, et al.
Clin Infect Dis. 2024 February 29; Online ahead of print; DOI:10.1093/cid/ciad767
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.)
Conference Material > Abstract
Stringer B, Lowton K, Cusinato M, Fielding K, Liverko I, et al.
MSF Scientific Days 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.
Conference Material > Abstract
Berry C, Motta I, Kazounis E, Fielding K, Dodd M, et al.
MSF Scientific Days International 2022. 2022 May 11; DOI:10.57740/8wq5-2b43
INTRODUCTION
Rifamipcin-resistant tuberculosis (RR-TB) affects around 465,000 people each year globally. Current treatment is of 9-20 months’ duration; is toxic and poorly efficacious. TB-PRACTECAL is a multi-arm, 2-stage, randomised controlled, multi-country, non-inferiority trial comparing 24-week regimens to the locally approved standard of care (control). We report TB-PRACTECAL stage 1 and 2 outcomes as well as additional analyses from dropped arms.
METHODS
Participants 15 years and above with pulmonary RR-TB from Uzbekistan, South Africa, and Belarus were included regardless of HIV status or CD4 count. Patients were randomized in a 1:1:1:1 ratio in stage 1 and 1:1 in stage 2. Randomization lists were stratified according to trial site. The BPaL regimen was comprised of bedaquiline 400mg daily for 2 weeks then 200mg three times weekly for 22 weeks, pretomanid 200mg daily for 24 weeks, and linezolid 600mg daily for 16 weeks followed by 300mg daily for 8 weeks. BPaLM additionally contained moxifloxacin 400mg daily and BPaLC contained clofazimine 100mg daily. Treatment was administered daily under observation. Transition to stage 2 occurred after enrolment of 240 participants and BPaLM was found to be the most promising arm. Randomisation continued during transition and all participants continued their allocated regimen and were followed up to 108 weeks. A post-hoc analysis was conducted comparing the three investigational arms to control using the primary efficacy outcome: proportion of patients with unfavourable outcome (death, treatment discontinuation, treatment failure, recurrence, lost to follow-up) at 72 weeks. We also assessed the proportion of patients with grade =3 or serious adverse events (SAE) by 72 weeks and mean change in QT corrected using Fridericia’s formula (QTcF) at week 24.
ETHICS
This study was approved by the Ethics Review Board (ERB) of the London School of Hygiene and Tropical Medicine and the local ERBs in Uzbekistan, Belarus and South Africa; and by the MSF ERB.
RESULTS
In March 2021, TB-PRACTECAL was terminated for efficacy at which point, 552 patients were enrolled. In the modified intention-to-treat population (comprising all randomised patients dispensed study medication at least once, excluding patients who did not have microbiologically-proven RR-TB), 252 patients had reached 72 weeks of follow-up, 44.0% of whom were female and 22.6% were HIV positive. In the modified intention- to-treat population, the percentage of unfavourable outcomes was 48.5% (32/66) for control, 23.3% (14/60) for BPaL, 18.8% (12/64) for BPaLC, and 11.3% (7/62) for BPaLM. There were three recurrences in BPaL, one in BPaLC, and none in BPaLM. Percentage of Grade =3 or SAE were 19.4% (14/72; 16 events), 31.9% (23/72; 32 events) and 21.7% (15/69; 24 events) in BPaLM, BPaLC and BPaL respectively, compared with 58.9% (43/73; 69 events) in the control. Mean change in QTcF at week 24 was 27.0 milliseconds (ms), 40.2 ms, and 23.3 ms in BPaLM, BPaLC, and BPaL respectively; compared with 44.89 ms in the control.
CONCLUSION
24-week all-oral regimens of bedaquiline, pretomanid and tapered-dose linezolid, with and without clofazamine or moxifloxacin are safe and efficacious in the treatment of RR-TB. Trial results show that treatment with BPaLM was more effective and had a better safety profile than the Control. BPaLC and BPaL were also highly effective.
CONFLICTS OF INTEREST
None declared.
Rifamipcin-resistant tuberculosis (RR-TB) affects around 465,000 people each year globally. Current treatment is of 9-20 months’ duration; is toxic and poorly efficacious. TB-PRACTECAL is a multi-arm, 2-stage, randomised controlled, multi-country, non-inferiority trial comparing 24-week regimens to the locally approved standard of care (control). We report TB-PRACTECAL stage 1 and 2 outcomes as well as additional analyses from dropped arms.
METHODS
Participants 15 years and above with pulmonary RR-TB from Uzbekistan, South Africa, and Belarus were included regardless of HIV status or CD4 count. Patients were randomized in a 1:1:1:1 ratio in stage 1 and 1:1 in stage 2. Randomization lists were stratified according to trial site. The BPaL regimen was comprised of bedaquiline 400mg daily for 2 weeks then 200mg three times weekly for 22 weeks, pretomanid 200mg daily for 24 weeks, and linezolid 600mg daily for 16 weeks followed by 300mg daily for 8 weeks. BPaLM additionally contained moxifloxacin 400mg daily and BPaLC contained clofazimine 100mg daily. Treatment was administered daily under observation. Transition to stage 2 occurred after enrolment of 240 participants and BPaLM was found to be the most promising arm. Randomisation continued during transition and all participants continued their allocated regimen and were followed up to 108 weeks. A post-hoc analysis was conducted comparing the three investigational arms to control using the primary efficacy outcome: proportion of patients with unfavourable outcome (death, treatment discontinuation, treatment failure, recurrence, lost to follow-up) at 72 weeks. We also assessed the proportion of patients with grade =3 or serious adverse events (SAE) by 72 weeks and mean change in QT corrected using Fridericia’s formula (QTcF) at week 24.
ETHICS
This study was approved by the Ethics Review Board (ERB) of the London School of Hygiene and Tropical Medicine and the local ERBs in Uzbekistan, Belarus and South Africa; and by the MSF ERB.
RESULTS
In March 2021, TB-PRACTECAL was terminated for efficacy at which point, 552 patients were enrolled. In the modified intention-to-treat population (comprising all randomised patients dispensed study medication at least once, excluding patients who did not have microbiologically-proven RR-TB), 252 patients had reached 72 weeks of follow-up, 44.0% of whom were female and 22.6% were HIV positive. In the modified intention- to-treat population, the percentage of unfavourable outcomes was 48.5% (32/66) for control, 23.3% (14/60) for BPaL, 18.8% (12/64) for BPaLC, and 11.3% (7/62) for BPaLM. There were three recurrences in BPaL, one in BPaLC, and none in BPaLM. Percentage of Grade =3 or SAE were 19.4% (14/72; 16 events), 31.9% (23/72; 32 events) and 21.7% (15/69; 24 events) in BPaLM, BPaLC and BPaL respectively, compared with 58.9% (43/73; 69 events) in the control. Mean change in QTcF at week 24 was 27.0 milliseconds (ms), 40.2 ms, and 23.3 ms in BPaLM, BPaLC, and BPaL respectively; compared with 44.89 ms in the control.
CONCLUSION
24-week all-oral regimens of bedaquiline, pretomanid and tapered-dose linezolid, with and without clofazamine or moxifloxacin are safe and efficacious in the treatment of RR-TB. Trial results show that treatment with BPaLM was more effective and had a better safety profile than the Control. BPaLC and BPaL were also highly effective.
CONFLICTS 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.