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.
Journal Article > ReviewFull Text
Clin Infect Dis. 2024 March 20; Volume 78 (Issue 3); 730-741.; DOI:10.1093/cid/ciad653
Hasan T, Medcalf E, Nyang'wa BT, Egizi E, Berry C, et al.
Clin Infect Dis. 2024 March 20; Volume 78 (Issue 3); 730-741.; DOI:10.1093/cid/ciad653
BACKGROUND
Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials.
METHODS
A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid.
RESULTS
Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3–4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid.
CONCLUSIONS
Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.
Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials.
METHODS
A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid.
RESULTS
Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3–4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid.
CONCLUSIONS
Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.
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.
Journal Article > ResearchFull Text
Clin Infect Dis. 2023 October 24; Online ahead of print; ciad653.; DOI:10.1093/cid/ciad653
Hasan T, Medcalf E, Nyang'wa BT, Egizi E, Berry C, et al.
Clin Infect Dis. 2023 October 24; Online ahead of print; ciad653.; DOI:10.1093/cid/ciad653
BACKGROUND
Effectiveness, safety, tolerability and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel six-month oral regimens that include bedaquiline (B), pretomanid (Pa), linezolid (L) with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multi-drug resistant tuberculosis/rifampicin resistant (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently-completed clinical trials.
METHODS
A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid.
RESULTS
Data from three clinical trials investigating eight unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200mg of linezolid, 68/195 (35%) experienced a Grade 3-4 adverse event vs 89/396 (22%) of patients receiving BPaL-containing regimens containing 600mg of linezolid.
CONCLUSIONS
Regimens containing BPaL were relatively well-tolerated when they included a daily linezolid dose of 600mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.
Effectiveness, safety, tolerability and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel six-month oral regimens that include bedaquiline (B), pretomanid (Pa), linezolid (L) with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multi-drug resistant tuberculosis/rifampicin resistant (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently-completed clinical trials.
METHODS
A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid.
RESULTS
Data from three clinical trials investigating eight unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200mg of linezolid, 68/195 (35%) experienced a Grade 3-4 adverse event vs 89/396 (22%) of patients receiving BPaL-containing regimens containing 600mg of linezolid.
CONCLUSIONS
Regimens containing BPaL were relatively well-tolerated when they included a daily linezolid dose of 600mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.
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
PLOS Glob Public Health. 2022 December 7; Volume 2 (Issue 12); e0001337.; DOI:10.1371/journal.pgph.0001337
Sweeney S, Berry C, Kazounis E, Motta I, Vassall A, et al.
PLOS Glob Public Health. 2022 December 7; Volume 2 (Issue 12); e0001337.; DOI:10.1371/journal.pgph.0001337
Current options for treating tuberculosis (TB) that is resistant to rifampicin (RR-TB) are few, and regimens are often long and poorly tolerated. Following recent evidence from the TB-PRACTECAL trial countries are considering programmatic uptake of 6-month, all-oral treatment regimens. We used a Markov model to estimate the incremental cost-effectiveness of three regimens containing bedaquiline, pretomanid and linezolid (BPaL) with and without moxifloxacin (BPaLM) or clofazimine (BPaLC) compared with the current mix of long and short standard of care (SOC) regimens to treat RR-TB from the provider perspective in India, Georgia, Philippines, and South Africa. We estimated total costs (2019 USD) and disability-adjusted life years (DALYs) over a 20-year time horizon. Costs and DALYs were discounted at 3% in the base case. Parameter uncertainty was tested with univariate and probabilistic sensitivity analysis. We found that all three regimens would improve health outcomes and reduce costs compared with the current programmatic mix of long and short SOC regimens in all four countries. BPaL was the most cost-saving regimen in all countries, saving $112-$1,173 per person. BPaLM was the preferred regimen at a willingness to pay per DALY of 0.5 GDP per capita in all settings. Our findings indicate BPaL-based regimens are likely to be cost-saving and more effective than the current standard of care in a range of settings. Countries should consider programmatic uptake of BPaL-based regimens.
Journal Article > Pre-Print
medRxiv. 2022 November 10; DOI:10.1101/2022.11.08.22282060
Sweeney S, Berry C, Kazounis E, Motta I, Vassall A, et al.
medRxiv. 2022 November 10; DOI:10.1101/2022.11.08.22282060
INTRODUCTION
Current options for treating tuberculosis (TB) that is resistant to rifampicin (RR-TB) are few, and regimens are often long and poorly tolerated. Following recent evidence from the TB-PRACTECAL trial countries are considering programmatic uptake of 6-month, all-oral treatment regimens.
METHODS
We used a Markov model to estimate the incremental cost-effectiveness of three regimens containing bedaquiline, pretomanid and linezolid (BPaL) with and without moxifloxacin (BPaLM) or clofazimine (BPaLC) compared with the current mix of long and short standard of care (SOC) regimens to treat RR-TB from the provider perspective in India, Georgia, Philippines, and South Africa. We estimated total costs (2019 USD) and disability-adjusted life years (DALYs) over a 20-year time horizon. Costs and DALYs were discounted at 3% in the base case. Parameter uncertainty was tested with univariate and probabilistic sensitivity analysis.
RESULTS
We found that all three regimens would improve health outcomes and reduce costs compared with the current programmatic mix of long and short SOC regimens in all four countries. BPaL was the most cost-saving regimen in all countries, saving $112-$1,173 per person. BPaLM was the preferred regimen at a willingness to pay per DALY of 0.5 GDP per capita in all settings.
CONCLUSIONS
Our findings indicate BPaL-based regimens are likely to be cost-saving and more effective than the current standard of care in a range of settings. Countries should consider programmatic uptake of BPaL-based regimens.
Current options for treating tuberculosis (TB) that is resistant to rifampicin (RR-TB) are few, and regimens are often long and poorly tolerated. Following recent evidence from the TB-PRACTECAL trial countries are considering programmatic uptake of 6-month, all-oral treatment regimens.
METHODS
We used a Markov model to estimate the incremental cost-effectiveness of three regimens containing bedaquiline, pretomanid and linezolid (BPaL) with and without moxifloxacin (BPaLM) or clofazimine (BPaLC) compared with the current mix of long and short standard of care (SOC) regimens to treat RR-TB from the provider perspective in India, Georgia, Philippines, and South Africa. We estimated total costs (2019 USD) and disability-adjusted life years (DALYs) over a 20-year time horizon. Costs and DALYs were discounted at 3% in the base case. Parameter uncertainty was tested with univariate and probabilistic sensitivity analysis.
RESULTS
We found that all three regimens would improve health outcomes and reduce costs compared with the current programmatic mix of long and short SOC regimens in all four countries. BPaL was the most cost-saving regimen in all countries, saving $112-$1,173 per person. BPaLM was the preferred regimen at a willingness to pay per DALY of 0.5 GDP per capita in all settings.
CONCLUSIONS
Our findings indicate BPaL-based regimens are likely to be cost-saving and more effective than the current standard of care in a range of settings. Countries should consider programmatic uptake of BPaL-based regimens.
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
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 > 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.