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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. 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. 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%). 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.).

Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months. Among 2516 participants who had undergone randomization, 2343 had a culture positive for that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group. The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

Monotherapy with lefamulin, a novel, pleuromutilin antibiotic with intravenous and oral formulation options, was noninferior to moxifloxacin for efficacy and generally safe and well tolerated for community-acquired bacterial pneumonia (CABP). Lefamulin’s spectrum of activity targets bacteria that cause CABP. Abstract Background Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP. Methods In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5–10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%). Results There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference −2.9%, 95% confidence interval [CI] g −8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference −2.6%, 95% CI −8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference −2.5%, 95% CI −8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin. Conclusions Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated. Clinical Trials Registration NCT02559310.

Globally, there are more than 500,000 new infections with drug-resistant tuberculosis each year. In this trial involving patients with rifampin-resistant tuberculosis, a shorter, more intense course of treatment (9 to 11 months) was found to be noninferior to a standard 20-month regimen.

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.

In a phase 1 clinical study, coadministration of the adsorbent-based DAV132 product together with the fluoroquinolone antibiotic moxifloxacin, while not affecting the plasma concentrations of the antibiotic, reduced by >99% exposure of the intestinal microbiota to the moxifloxacin. Abstract Background Antibiotics are life-saving drugs but severely affect the gut microbiome with short-term consequences including diarrhea and selection of antibiotic-resistant bacteria. Long-term links to allergy and obesity are also suggested. We devised a product, DAV132, and previously showed its ability to deliver a powerful adsorbent, activated charcoal, in the late ileum of human volunteers. Methods We performed a randomized controlled trial in 28 human volunteers treated with a 5-day clinical regimen of the fluoroquinolone antibiotic moxifloxacin in 2 parallel groups, with or without DAV132 coadministration. Two control goups of 8 volunteers each receiving DAV132 alone, or a nonactive substitute, were added. Results The coadministration of DAV132 decreased free moxifloxacin fecal concentrations by 99%, while plasmatic levels were unaffected. Shotgun quantitative metagenomics showed that the richness and composition of the intestinal microbiota were largely preserved in subjects co-treated with DAV132 in addition to moxifloxacin. No adverse effect was observed. In addition, DAV132 efficiently adsorbed a wide range of clinically relevant antibiotics ex vivo. Conclusions DAV132 was highly effective to protect the gut microbiome of moxifloxacin-treated healthy volunteers and may constitute a clinical breakthrough by preventing adverse health consequences of a wide range of antibiotic treatments. Clinical Trials Registration NCT02176005.

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.

The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed. Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17–3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4–8) on 4 months of BPaMZ and 11 weeks (6–12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3–7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. TB Alliance.

This phase I thorough QTc, double‐blind, randomized, placebo‐ and positive‐controlled, parallel group, multiple‐dose study evaluated avacopan's effect on cardiac repolarization using concentration‐QTc (C‐QTc) as the primary analysis. Avacopan 30 mg b.i.d. (therapeutic dose) was administered orally on days 1 through 7 followed by avacopan 100 mg b.i.d. (supratherapeutic dose) on days 8 through 14 in 29 healthy participants. Moxifloxacin 400 mg and placebo were administered on days 1 and 15 in a nested crossover design for assay sensitivity in separate cohorts to 28 participants. Time‐matched plasma concentrations and up to 10 replicate ECGs were obtained on prespecified days at baseline and postdose on days 1, 7, 14, and 15. The mean change from baseline on QTcF for avacopan (−5.5 to 3.5 ms) was similar to placebo (−6.9 to 1.4 ms) across days 1, 7, and 14. The mean effect on ΔΔQTcF (90% CI) was estimated as 1.5 ms (−0.17 to 3.09) and 0.8 ms (−2.41 to 4.05) for 30 and 100 mg avacopan b.i.d. treatments, respectively. Based on the C‐QTc analysis, avacopan's effect on ΔΔQTcF >10 ms can be excluded within the observed plasma concentration range of up to ~1220 and ~335 ng/mL for avacopan and active major metabolite, M1, respectively. The estimated population slopes showed a shallow relationship, which was not statistically significant. There was no clinically meaningful effect of avacopan on heart rate or cardiac conduction (PR and QRS intervals). Avacopan appeared to be generally well tolerated in this study population.

International organisations, scientists and the tuberculosis (TB) community have been advocating for a shorter, safer treatment for drug-susceptible (DS)-TB with equal or better efficacy than current regimens. A promising approach to achieve this is the combination of dose-optimised repurposed drugs. The RML-TB trial is a phase IIb, randomised, non-inferiority, controlled, open-label, multicentre clinical trial. It compares an experimental regimen (optimised-dose rifampicin (R) at 30mg/kg/day, moxifloxacin 600mg/day and linezolid (L) 600 mg/day) with the standard fixed-dose combination regimen of R, isoniazid, pyrazinamide and ethambutol. In the experimental arm, L is administered at 600 mg two times per day for 2 weeks, then once daily for 6 weeks. The primary efficacy outcome is the proportion of patients with negative culture at 8 weeks. Sputum samples will be collected at screening visit, randomisation visit and 1 week, 2 weeks, 4 weeks, 6 weeks and 8 weeks post randomisation. The primary safety outcome is the incidence of grade 3-4 adverse events or a change in treatment regimen within 8 weeks. Safety assessment will be done using the Common Terminology Criteria for Adverse Events classification version 5. Participants must be at least 18 years old, with smear-positive, DS pulmonary TB. Exclusion criteria include corrected QT interval (QTc) prolongation, HIV positive status, severely impaired blood counts or the use of QTc-prolonging drugs. The study will enrol 120 patients (60 per arm) over a 2.5-year period across 13 TB units in Spain. The study was approved by the ethics committee from Vall d'Hebron University Hospital on the meeting held on 18 March 2022 and The Spanish Drug Agency. Patients will provide informed consent and can withdraw from the trial at any time without giving any reason. This decision will not affect their medical care. Data collection is minimal, and analysis will be blinded. Personal data will be restricted to principal investigators or authorised personnel. Results will be shared via the European Union Drug Regulating Authorities Clinical Trials Database (EUDRACT) website and published in an open-source medical journal, guiding future TB clinical trials and treatment development. EUDRACT number: 2021-001626-22. CTIS: 2023-509075-17-00.