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Quabodepistat (formerly OPC-167832) showed potent activity in preclinical studies and in the first stage of an early bactericidal activity study in adults with smear-positive, drug-susceptible pulmonary tuberculosis. Stage 2 of this study was designed to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both versus rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy for 14 days. Stage 2 of this open-label, active-controlled, randomised, parallel-group study was conducted at two research sites in South Africa in adults (aged 18–64 years) with drug-susceptible pulmonary tuberculosis. Eligible participants had a BMI of 16–32 kg/m2 and the ability to produce an adequate volume of sputum (≥10 mL overnight) and were excluded if they had drug-resistant tuberculosis or previous treatment for Mycobacterium tuberculosis within the past 3 years. Participants were centrally randomly assigned via interactive web response technology system, with no stratification, into four treatment groups in a ratio of 14:14:14:4 (quabodepistat 30 mg plus delamanid 300 mg, quabodepistat 30 mg plus bedaquiline 400 mg, or quabodepistat 30 mg plus delamanid 300 mg plus bedaquiline 400 mg orally once daily for 14 days, or rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy [control] according to local standard of care for 20 days). The primary outcomes were safety and tolerability during and after 14 days of treatment in all participants who received any study medication and pharmacokinetics at day 1 and day 14 in participants in the quabodepistat groups with adequate data for deriving pharmacokinetics parameters. The main secondary outcome was bactericidal activity from baseline to day 14 in all eligible participants who were quantitatively culture-positive at baseline. The study was not powered for formal statistical hypothesis testing; therefore, data were summarised by treatment group with descriptive statistics. This study is registered with ClinicalTrials.gov (NCT03678688) and is closed to new participants. 98 participants were screened for entry into stage 2 of the trial between Feb 1, 2021, and Jan 27, 2022, of whom 46 were randomly assigned (14 to each quabodepistat group, 4 to the control group) and 44 received at least one dose of study medication (one patient excluded from the quabodepistat plus delamanid and quabodepistat plus bedaquiline groups). 32 (73%) of 44 participants had at least one treatment-emergent adverse event. Most events (30/32 [94%]) were mild or moderate; the most common treatment-emergent adverse events (≥2 participants; not related to study drugs) were headache (4/44 [9%]), dizziness (3/44 [7%]), abdominal pain (2/44 [5%]), pruritus (2/44 [5%]), and nausea (2/44 [5%]). Two serious adverse events were reported in two participants in the quabodepistat and bedaquiline cohort (anal abscess [n=1], pneumothorax [n=1]); both were deemed not related to study drug. Quabodepistat exposure was minimally affected by coadministration of delamanid or bedaquiline, with lower exposure in the quabodepistat and bedaquiline cohorts (maximum plasma concentration for quabodepistat plus delamanid 208 ng/mL [SD 61; n=11]; quabodepistat plus bedaquiline 175 ng/mL [31; n=10]; quabodepistat plus delamanid plus bedaquiline 183 ng/mL [52; n=11]). Maximum quabodepistat concentrations were achieved approximately 3 h after administration in all combinations. Mean elimination half-life was shorter in combinations with bedaquiline than without bedaquiline (12·3–14·5 h vs 15·2 h). Mean changes from baseline to day 14 of sputum log10 colony-forming units per mL were −2·73 (SD 1·51) for quabodepistat plus delamanid plus bedaquiline (n=12) and −2·71 (SD 0·92) for control (n=19); mean change was −2·17 (SD 1·83) in the quabodepistat plus delamanid cohort (n=11) and −1·97 (SD 1·29) in the quabodepistat plus bedaquiline cohort (n=11). In this 14-day trial, quabodepistat plus delamanid plus bedaquiline, a novel three-drug combination, appeared to be safe, well tolerated, and provided robust early bactericidal activity in adults with drug-susceptible pulmonary tuberculosis. Further evaluation is warranted. Otsuka Pharmaceutical Development & Commercialization and the Bill & Melinda Gates Foundation.

Linezolid plays a crucial role in the first-line treatment of drug-resistant tuberculosis globally. Its prolonged use can lead to neurological and haematological toxicity, highlighting the need for safer oxazolidinones. Delpazolid, a novel oxazolidinone, might be safer. We aimed to evaluate the safety and efficacy of delpazolid and identify an optimal dose. PanACEA-DECODE-01 was a prospective, randomised, open-label, phase 2b, multicentre, dose-finding trial done in five tuberculosis trial sites in Tanzania and South Africa. Adults aged 18–65 years, who weighed 40–90 kg, and had newly diagnosed, smear positive pulmonary tuberculosis were randomly assigned (1:1:1:1:1) through centralised allocation, using a probabilistic minimisation algorithm to receive no delpazolid (D0), delpazolid 400 mg once daily (D400), delpazolid 800 mg once daily (D800), delpazolid 1200 mg once daily (D1200), or delpazolid 800 mg twice daily (D800BD), all administered orally for 16 weeks with follow-up to week 52. All participants received bedaquiline (400 mg orally once daily for the first 14 days, then 200 mg orally thrice weekly), delamanid (100 mg orally twice daily), and moxifloxacin (400 mg orally once daily). Randomisation was stratified based on bacterial load in sputum as measured by GeneXpert cycle threshold (<16 vs ≥16), site, and HIV status. The primary efficacy objective was to establish an exposure–response model with the primary endpoint, measured in the modified intention-to-treat population, of change in mycobacterial load measured by time to positivity using the liquid culture mycobacterial growth indicator tube system. A secondary outcome was the time on treatment to sustained conversion to negative sputum culture in liquid media. The primary safety outcome was the occurrence of oxazolidinone class toxicities defined as peripheral or optical neuropathy, incident leukopenia, anaemia or thrombocytopenia, or adverse events in line with tyramine pressor response, all of grade 2 or higher, possibly, probably or definitely related to delpazolid. This study was registered with ClinicalTrials.gov, NCT04550832. Between Oct 28, 2021, and Aug 31, 2022, 156 individuals were screened for eligibility, 76 of whom were enrolled and randomly assigned to D0 (n=15), D400 (n=15), D800 (n=15), D1200 (n=16), or D800BD (n=15). 60 (79%) of 76 participants were male and 16 (21%) were female. Population pharmacokinetic–pharmacodynamic modelling suggests maximal microbiological activity at a daily total exposure of delpazolid (area under the concentration curve from 0 h to 24 h [AUC0–24]) of 50 mg/L per h; close to the median exposure observed after a 1200 mg dose. This maximal effect was estimated at a 38% (95% CI 4–83; p=0·025) faster decline in bacterial load compared with no delpazolid. In the secondary time-to-event analysis, there was no significant difference in time to culture conversion between treatment arms or exposure tertile. When all delpazolid-containing groups were combined, the hazard ratio for the time to sustained culture conversion to negative, comparing all delpazolid-containing groups with the group without delpazolid was 1·53 (95% CI 0·84–2·76). Two drug-related serious adverse events (one gastritis and one anaemia) occurred in the D800BD group, with high individual AUC0–24. Apart from the anaemia and one event of brief, moderate neutropenia observed at only one visit in the D800 group not in line with the characteristics of oxazolidinone class toxicity, no oxazolidinone class toxicities occurred. The pharmacokinetic–pharmacodynamic modelling results suggest that delpazolid adds efficacy on top of bedaquiline, delamanid, and moxifloxacin; and that a dose of 1200 mg once daily would result in exposures with maximum efficacy. That dose was shown to be safe, raising hope that linezolid toxicities could be averted in long-term treatment. Delpazolid is a promising drug for future tuberculosis treatment regimens and could be widely usable if safety and efficacy are confirmed in larger trials. LigaChem Biosciences, EDCTP2 programme supported by the EU; German Ministry for Education and Research; German Center for Infection Research; Swiss State Secretariat for Education, Research and Innovation; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.

WHO recommends a 2-month optimal duration for new drug regimens for rifampicin-susceptible tuberculosis. We aimed to investigate the efficacy and safety of the 8-week regimens that were assessed as part of the TRUNCATE management strategy of the TRUNCATE-TB trial. TRUNCATE-TB was a multi-arm, multi-stage, open-label, randomised controlled trial in which participants aged 18–65 years with rifampicin-susceptible pulmonary tuberculosis were randomly assigned via a web-based system, using permuted blocks, to 24-week standard treatment (rifampicin, isoniazid, pyrazinamide, and ethambutol) or the TRUNCATE management strategy comprising initial 8-week treatment, then post-treatment monitoring and re-treatment where needed. The four 8-week regimens comprised five drugs, modified from standard treatment: high-dose rifampicin and linezolid, or high-dose rifampicin and clofazimine, or bedaquiline and linezolid, all given with isoniazid, pyrazinamide, and ethambutol; and rifapentine, linezolid, and levofloxacin, given with isoniazid and pyrazinamide. Here, we report the efficacy (proportion with unfavourable outcome; and difference from standard treatment, assessed via Bayesian methods) and safety of the 8-week regimens, assessed in the intention-to-treat population. This prespecified exploratory analysis is distinct from the previously reported 96-week outcome of the strategy in which the regimens were deployed. This trial is registered with ClinicalTrials.gov (NCT03474198). Between March 21, 2018, and March 26, 2020, 675 participants (674 in the intention-to-treat population) were enrolled and randomly assigned to the standard treatment group or one of the four 8-week regimen groups. Two 8-week regimens progressed to full enrolment. An unfavourable outcome (mainly relapse) occurred in seven (4%) of 181 participants on standard treatment; 46 (25%) of 184 on the high-dose rifampicin and linezolid-containing regimen (adjusted difference 21·0%, 95% Bayesian credible interval [BCI] 14·3–28·1); and 26 (14%) of 189 on the bedaquiline and linezolid-containing regimen (adjusted difference 9·3% [4·3–14·9]). Grade 3–4 adverse events occurred in 24 (14%) of 181 participants on standard treatment, 20 (11%) of 184 on the rifampicin-linezolid regimen, and 22 (12%) of 189 on the bedaquiline-linezolid regimen. Efficacy was worse with 8-week regimens, although the difference from standard treatment varied between regimens. Even the best 8-week regimen (bedaquiline-linezolid) should only be used as part of a management strategy involving post-treatment monitoring and re-treatment if necessary. Singapore National Medical Research Council; UK Department of Health and Social Care; UK Foreign, Commonwealth, and Development Office; UK Medical Research Council; Wellcome Trust; and UK Research and Innovation Medical Research Council.

Background We concurrently developed a prospective study to assess clinical outcomes among patients receiving 9-month bedaquiline (BDQ)-containing regimens, aiming to provide valuable data on the use of this short-course regimen in China. Methods This open-label, randomized, controlled, multicenter, non-inferiority trial was conducted at sixteen hospitals, and enrolled participants aged 18 years and older with pulmonary rifampicin/multidrug tuberculosis. Participants were randomly assigned, in a 1:1 ratio. Individuals within the standard-regimen group received 6 months of BDQ, linezolid, levofloxacin, clofazimine, and cycloserine plus 12 months of levofloxacin, and any three potentially effective drugs from clofazimine, cycloserine pyrazinamide, ethambutol and protionamide, whereas individuals within shorter-regimen group received 9 months of BDQ, linezolid, levofloxacin, clofazimine and cycloserine. The primary outcome was the percentage of participants with a composite unfavorable outcome (treatment failure, death, treatment discontinuation, or loss to follow-up) by the end of the treatment course after randomization in the modified intention-to-treat population. The noninferiority margin was 10%. This trial was registered with www.chictr.org.cn , ChiCTR2000029012. Results Between Jan 1, 2020, and Dec 31, 2023, 264 were screened and randomly assigned, 132 of 264 participants were assigned to the standard-regimen group and 132 were assigned to the shorter-regimen. Thirty-three (12.55%) of 264 participants were excluded from the modified intention-to-treat analysis. As a result, 231 participants were included in the modified intention-to-treat analysis (116 in the standard-regimen group and 115 in the shorter-regimen group).In the modified intention-to-treat population, unfavorable outcomes were reported in 19 (16.5%) of 115 participants for whom the outcome was assessable in the shorter-regimen group and 26 (22.4%) of 116 participants in the standard care group (risk difference 5.9 percentage points (97.5% CI − 5.8 to 17.5)). One death was reported in the standard-regimen group. The incidence of QTcF prolongation in the shorter-regimen group (22.6%, 26/115) was similar to the standard-regimen group (24.1%, 28/116). Conclusions The 9-month, all-oral regimen is safe and efficacious for the treatment of pulmonary rifampicin/multidrug-resistant tuberculosis. The high incidence of QTc prolongation associated with the use of BDQ highlights the urgent need of routine electrocardiogram monitoring under treatment with BDQ-containing regimens in the Chinese population.

Linezolid is a key component globally in first-line therapy for drug-resistant tuberculosis but has considerable toxicity. New and safer alternative oxazolidinones are needed. Sutezolid is one such promising alternative. We aimed to evaluate preliminary efficacy and safety of sutezolid and to identify an optimal dose. PanACEA-SUDOCU-01 was a prospective, open-label, randomised, phase 2b dose-finding study in four tuberculosis trial sites in Tanzania and South Africa. Adults aged 18–65 years with newly diagnosed, drug-sensitive, smear-positive tuberculosis were enrolled and randomly assigned (1:1:1:1:1) by a probabilistic minimisation algorithm using a web-based interface, stratified by site, sex, and HIV status, to receive no sutezolid (U0), sutezolid 600 mg once daily (U600), sutezolid 1200 mg once daily (U1200), sutezolid 600 mg twice daily (U600BD), or sutezolid 800 mg twice daily (U800BD), all administered orally for 12 weeks followed by standard therapy for 6 months. All participants received oral bedaquiline (400 mg once daily for 14 days followed by 200 mg thrice weekly), oral delamanid (100 mg twice daily), and oral moxifloxacin (400 mg once daily). For the primary endpoint, measured in the modified intention-to-treat population, sputum samples were taken weekly to measure the change in bacterial load measured by time to positivity using the mycobacterial growth indicator tube system. Safety was assessed through weekly electrocardiography, safety blood tests, vision testing, and physical and neurological examinations. Intensive pharmacokinetic measurements were done on day 14 to determine exposure to sutezolid, bedaquiline, delamanid, and moxifloxacin. This trial is registered with ClinicalTrials.gov (NCT03959566). Between May 20, 2021, and Feb 17, 2022, 186 individuals were screened for eligibility, 75 of whom were enrolled and randomly assigned to U0 (n=16), U600 (n=15), U1200 (n=14), U600BD (n=15), or U800BD (n=15). 56 (75%) participants were male and 19 (25%) were female. The final pharmacokinetic–pharmacodynamic model showed a benefit of sutezolid, with an increase in time to positivity slope steepness of 16·7% (95% CI 0·7–35·0) at the maximum concentration typical for the 1200 mg dose, compared with no sutezolid exposure. A maximum effect of sutezolid exposure was not observed within the investigated dose range. Six (8%) participants (one in the U600 group, two in the U600BD group, one in the U800BD group, and two retrospectively identified in the U600 group) had an increase in a QT interval using Fridericia correction greater than 60 ms from baseline. Two (3%) participants in the U600BD group had grade 4 adverse events, one each of neutropenia and hepatotoxicity, but they were not deemed associated with the use of sutezolid by the investigators. No neuropathy was reported. Sutezolid, combined with bedaquiline, delamanid, and moxifloxacin, was shown to be efficacious and added activity to the background drug combination, although we cannot make a final dose recommendation yet. This study provides valuable information for the selection of sutezolid doses for future studies, and described no oxazolidinone class toxicities at the doses used. EDCTP2 programme funded by the EU; German Ministry for Education and Research; German Center for Infection Research; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.

Background The standard of care (SOC) treatment for drug-susceptible pulmonary tuberculosis (DS-TB) consists of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). New treatment regimen options for DS-TB are needed as HRZE is long in duration (6 months), associated with frequent adverse events, unforgiving of adherence lapses, and complicated by rifamycin-based drug-drug interactions. The recent resurgence of TB drug development, particularly in the context of drug-resistant TB, offers promise for additional regimens for persons with DS-TB, provided they are sufficiently effective and well-tolerated. We spotlight wave 1 of the RAD-TB platform trial (ACTG A5409, NCT06192160) that will investigate new chemical entities for the treatment of DS-TB. Methods In wave 1 of the RAD-TB platform, adult participants initiating treatment for DS-TB will be randomized to SOC (HRZE, Arm 1) or one of five experimental arms for the 8-week intensive phase. The experimental treatment arms will consist of a bedaquiline and pretomanid backbone (BPa) in combination with one of three oxazolidinones. Arm 2 will study linezolid (BPaL) at a dose of 600 mg daily, Arms 3A and 3B will study TBI-223 at 1200 mg and 2400 mg daily, respectively, and Arms 4A and 4B will study sutezolid at 800 mg and 1600 mg daily, respectively. The primary efficacy objective is to compare sputum culture time to positivity (TTP) slope over the first 6 weeks of treatment for each experimental treatment arm to SOC. The primary safety objective is to compare new Grade 3 or higher adverse events over the first 8 weeks of treatment for each experimental treatment arm to SOC. After the intensive phase, all participants will receive the standard isoniazid and rifampicin (HR) continuation phase for 18 weeks. Participants will be followed for 52 weeks after TB treatment initiation to assess long-term outcomes. Discussion Wave 1 of the RAD-TB platform aims to identify the optimal oxazolidinone(s), with regard to both efficacy and safety, to combine with the BPa backbone for the treatment of DS-TB. Subsequent waves of this platform trial may add a fourth drug to the regimen, study new diarylquinolines to substitute for bedaquiline, or study novel agents from other TB drug classes. Trials registration ClinicalTrials.gov NCT06192160 . Registered on January 5, 2024.

Some anti‐mycobacterial drugs are known to cause QT interval prolongation, potentially leading to life‐threatening ventricular arrhythmia. However, the highest leprosy and tuberculosis burden occurs in settings where electrocardiographic monitoring is challenging. The feasibility and accuracy of alternative strategies, such as the use of automated measurements or a mobile electrocardiogram (mECG) device, have not been evaluated in this context. As part of the phase II randomized controlled BE‐PEOPLE trial evaluating the safety of bedaquiline‐enhanced post‐exposure prophylaxis (bedaquiline and rifampicin, BE‐PEP, versus rifampicin, SDR‐PEP) for leprosy, all participants had corrected QT intervals (QTc) measured at baseline and on the day after receiving post‐exposure prophylaxis. The accuracy of mECG measurements as well as automated 12L‐ECG measurements was evaluated. In total, 635 mECGs from 323 participants were recorded, of which 616 (97%) were of sufficient quality for QTc measurement. Mean manually read QTc on 12L‐ECG and mECG were 394 ± 19 and 385 ± 18 ms, respectively (p < 0.001), with a strong correlation (r = 0.793). The mean absolute QTc difference between both modalities was 11 ± 10 ms. Mean manual and automated 12L‐ECG QTc were 394 ± 19 and 409 ± 19 ms, respectively (n = 636; p < 0.001), corresponding to moderate agreement (r = 0.655). The use of a mECG device for QT interval monitoring was feasible and yielded a median absolute QTc error of 8 ms. Automated QTc measurements were less accurate, yielding longer QTc intervals.

Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture. Subjects were randomly assigned to receive two single 400 mg doses of bedaquiline, alone, and, after a 4 week washout period, in combination with steady-state daily dosing of either rifabutin 300 mg or rifampin 600 mg. Blood samples were collected prior to dosing and at multiple time points subsequently, to measure plasma drug concentrations and bactericidal activity in ex vivo M tuberculosis-infected whole blood cultures (WBA). Single oral doses of bedaquiline produced readily detectable WBA ex vivo, reaching a maximal effect of -0.28 log/day, with negative values indicating bacterial killing. Plasma concentrations of 355 ng/ml were sufficient for intracellular mycobacteriostasis. Combined dosing with rifampin or rifabutin produced maximal effects of -0.91 and -0.79 log/d, respectively. However, the activity of the rifabutin combination was sustained throughout the dosing interval, thereby producing a greater cumulative or total effect. At low drug concentrations, rifabutin plus bedaquiline yielded greater mycobactericidal activity than the sum of their separate effects. Neither drug metabolites nor cellular drug accumulation could account for this observation. The combination of rifabutin plus bedaquiline produces sustained intracellular mycobactericidal activity that is greater than the sum of their individual effects. Further studies of the treatment-shortening potential of this combination are warranted.

Treatment options for highly drug-resistant tuberculosis are limited. In this study in South Africa, a new agent, pretomanid, was combined with bedaquiline and linezolid for a 26-week course to treat extensively drug-resistant and complicated multidrug-resistant pulmonary TB. Although there were toxic effects, 90% of patients had favorable outcomes.

Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa. We retrospectively analysed a cohort of all patients who received 6–12 months of oral bedaquiline and delamanid in combination (400 mg bedaquiline once per day for 2 weeks, then 200 mg bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment. Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5–40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment. Use of the bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials. Médecins Sans Frontières (MSF).