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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.

Based on results from preclinical and clinical studies, a five-drug combination of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine was identified with treatment shortening potential for drug-susceptible tuberculosis; the Clo-Fast trial aimed to determine the efficacy and safety of this regimen. We compared 3 months of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine, administered with a clofazimine loading dose, to the standard 6 month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol in drug-susceptible tuberculosis. Clo-Fast was a phase 2c open-label trial recruiting participants at six sites in five countries. Participants aged 18 years or older with pulmonary tuberculosis who were sputum smear positive for acid-fast bacilli or molecular tuberculosis assay positive (with Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid) were eligible for enrolment. Individuals with HIV infection with a CD4+ cell count ≥100 cells per mm3 could participate. Participants were randomly assigned in a 2:1 ratio (group 1: group 2) or a 2:1:1 ratio (group 1: group 2: group 3), depending on consent to participate in the intensive pharmacokinetic visits required in group 3, using a central web-based system with permuted blocks. The group 1 regimen included 8 weeks of rifapentine–isoniazid–pyrazinamide–ethambutol–clofazimine, with a 2-week 300 mg clofazimine loading dose, followed by 5 weeks of rifapentine–isoniazid–pyrazinamide–clofazimine (13 weeks total). The group 2 control regimen included 8 weeks of isoniazid–rifampicin–pyrazinamide–ethambutol followed by 18 weeks of rifampicin–isoniazid. Group 3 was identical to group 1 over the first 4 weeks of treatment, except that the regimen was administered without a clofazimine loading dose (100 mg daily); after 4 weeks of group 3 treatment, participants transitioned to local standard of care to complete treatment. Group 3 was designed to assess the effect of a 2-week loading dose on clofazimine pharmacokinetics. Randomisation was stratified by HIV status and advanced disease on chest radiograph. The primary efficacy endpoint was time to sputum culture-negative status by 12 weeks. The primary safety endpoint was the proportion of participants experiencing any grade 3 or worse adverse event over 65 weeks. The key secondary endpoint was unfavourable clinical or bacteriological outcomes by week 65. The efficacy analysis population contained participants assigned to groups 1 and 2 who were not late exclusions (no positive culture at screening, entry, or week 1, or if rifampicin resistance or isoniazid resistance was detected at screening or entry); the safety analysis population contained all randomly assigned participants who took at least one dose of treatment. The trial was registered with ClinicalTrials.gov ID: NCT04311502. 104 participants were randomly assigned to group 1 (n=58), group 2 (n=31), and group 3 (n=15). 82 (79%) were male and 74 (71%) had radiographically advanced disease; 30 (29%) were people with HIV. The trial was stopped early for lack of clinical efficacy. For the primary efficacy outcome, 49 (89%) of 55 group 1 participants and 28 (90%) of 31 group 2 participants had stable sputum culture conversion by week 12 (adjusted hazard ratio 1·21 [90% CI 0·82–1·79]; p=0·2089). Adverse events grade 3 or worse occurred in 26 (45%) of 58 group 1 participants and five (16%) of 31 group 2 participants (difference 30%, 90% CI 14–45; p=0·002). The cumulative probability of a week 65 unfavourable outcome was 52% (95% CI 37–69) in group 1 versus 27% (14–50) in group 2 (p=0·049). Although the trial was stopped early, we found that a 3-month regimen containing clofazimine and rifapentine had 12-week culture conversion rates that did not differ statistically from the standard of care. The regimen was associated with an unacceptably high proportion of participants with unfavourable composite clinical outcomes and grade 3 or worse adverse events. US National Institutes of Health Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) and the National Institute of Allergy and Infectious Diseases.

With the unprecedented scale and scope of the COVID-19 vaccination response, many countries used digital systems to capture vaccine administration data. Data backlogs, a build-up of information captured via paper forms not yet entered into digital systems, were common across countries. This study aimed to identify the root causes of COVID-19 vaccination data backlogs in the Democratic Republic of the Congo, Kenya, Senegal and Tanzania based on primary (interviews and observations at vaccine delivery sites) and secondary data. Root causes of data backlogs were related to technology (system slowdowns, insufficient devices and limited system functionality), infrastructure (lack of reliable internet and data bundles), processes (incongruence between paper and digital tools, separate data collection and entry, lack of integration with routine immunization and lack of standard operating procedures) and people (staff shortages, large workloads and non-payment of staff). Recommendations to inform digital and data systems include: (i) use a country-led, coordinated, iterative approach for system design and introduction, (ii) start with a minimum viable product and (iii) proactively address the needs of the health workforce. As the COVID-19 global emergency ends, these findings can help inform broader health system strengthening efforts to improve effectiveness, resilience and pandemic preparedness. Abrégé Face à l’ampleur et à la portée sans précédent de la campagne vaccinale contre la COVID-19, de nombreux pays ont utilisé des systèmes numériques pour recueillir des données sur l’administration du vaccin. Tous les pays ont connu des retards de données, soit une accumulation d’informations recueillies au moyen de formulaires papier qui n’avaient pas encore été saisies dans les systèmes numériques. Cette étude vise à cerner les causes premières de ces retards de données sur la vaccination contre la COVID-19 en République démocratique du Congo, au Kenya, au Sénégal et en Tanzanie sur la base de données primaires (entretiens et observations sur les sites d’administration du vaccin) et secondaires. Les causes premières des retards de données étaient liées à la technologie (ralentissements des systèmes, insuffisance des appareils et fonctionnalité limitée des systèmes), à l’infrastructure (absence de forfaits de données et de liaison Internet fiables), aux processus (incompatibilité entre les outils papier et numériques, collecte et saisie séparées des données, manque d’intégration avec les vaccinations de routine et absence de procédures opérationnelles normalisées) et au personnel (manque d’effectifs, charges de travail importantes et non-paiement du personnel). Les recommandations pour informer les systèmes numériques et de données comprennent: (i) utiliser une approche itérative, coordonnée et dirigée par les pays pour la conception et la mise en place des systèmes, (ii) commencer par un produit minimum viable et (iii) répondre aux besoins du personnel de santé en amont des problèmes. La crise mondiale liée à la COVID-19 touchant à sa fin, ces résultats sont susceptibles d’éclairer les efforts de renforcement des systèmes de santé dans leur ensemble visant à améliorer l’efficacité, la résilience et la préparation aux pandémies. Resumen Ante la escala y el alcance sin precedentes de la vacunación como respuesta a la COVID-19, muchos países utilizaron sistemas digitales para registrar datos sobre la administración de las vacunas. En todos los países era común que la información recabada a través de formularios en papel se acumulara sin ingresarse en los sistemas digitales. El objetivo de este estudio consistió en identificar las causas fundamentales de la acumulación de datos sin procesar sobre la vacunación contra la COVID-19 en la República Democrática del Congo, Kenia, Senegal y Tanzania a partir de datos primarios (entrevistas y observaciones en los sitios de vacunación) y secundarios. Las causas fundamentales de esa acumulación estaban relacionadas con la tecnología (desaceleraciones del sistema, dispositivos insuficientes y funcionalidad limitada del sistema), la infraestructura (falta de conexión confiable a Internet y paquetes de datos), los procesos (incongruencia entre las herramientas en papel y las digitales, recopilación e ingreso de datos por separado, falta de integración con la inmunización de rutina y falta de procedimientos operativos estándar) y las personas (escasez de personal, grandes cargas de trabajo y falta de pago del personal). Las siguientes son algunas recomendaciones para los sistemas digitales y de datos: (i) utilizar un enfoque iterativo, coordinado y dirigido por el país para el diseño y la introducción del sistema, (ii) comenzar con un producto mínimo viable y (iii) atender de manera proactiva las necesidades del personal de la salud. Ahora que está terminando la emergencia mundial de COVID-19, estos hallazgos pueden servir de base a esfuerzos más amplios de fortalecimiento del sistema de salud dirigidos a mejorar la efectividad, la resiliencia y la preparación para pandemias.