The full Phase 2 trial programme for UNITE4TB is now established, encompassing 6 new chemical entities (NCEs) and over 20 novel treatment regimens. The Phase 2B DECISION trial (dose-optimizing the DprE1 inhibitor BTZ-043) has been completed in South Africa and Tanzania; results will be released in Year 5. The multi-arm, multi-stage platform PARADIGM4TB trial, launched in January 2024, will complete recruitment in July 2025 (400 participants at 14 sites in 5 countries on 3 continents) for the first regimen-selection (2B) phase of 10 experimental regimens including BTZ-043 and/or the leucyl-tRNA synthetase inhibitor ganfeborole. Interim analysis in late 2025/early 2026 will select the best regimens for the duration-randomisation (2C) phase.
In parallel, a second regimen-selection (2B) phase will begin in Q3/Q4 2025, adding 4 new regimens and 2 NCEs (quabodepistat and delpazolid). Additional trial sites in Asia, Europe and South America will join this largest TB platform trial ever conducted. One more Phase 2B/C study—Stage 3 of the PanACEA-STEP2C platform trial—is in preparation to assess treatments for isoniazid-monoresistant and extensively (including bedaquiline)-resistant TB; enrolment will begin in Q3/Q4 2025.
The Phase 2A programme is progressing. ENABLE, a dose-selection study for the transcription regulator alpibectir plus ethionamide, was initiated in Year 4; >60% of participants were recruited by July 2025. SYNERGY, an innovative two-stage evaluation of the diarylquinolone TBAJ-587 in 8-week combinations with four other NCEs, will start in 2026.
Tools to improve trial conduct are advancing. Pharmacokinetic assays for BTZ-043 and ganfeborole are complete, while assays for quabodepistat and alpibectir/ethionamide are ongoing. Epidemiological cut-off values for BTZ-043 and ganfeborole have been defined, with future experiments planned for other drugs. Sample collection and analyses for PK-PD and host/bacterial biomarkers continue across trials. Digital Adherence Technology (Wisepill boxes and AARDEX software) is being rolled out across PARADIGM4TB and will be implemented in SYNERGY. Machine Learning/AI evaluations using TB-PACTS datasets have identified multi-factorial models predicting outcomes including recurrence post-treatment.
The C-Path Data Archive, which houses the Data Collaboration Platform, was user-tested and updated in November 2024. The Data Management Plan was revised, and procedures for safe and sustainable data access are being finalised.
The Community Advisory Group, Ethics Advisory Board and Scientific Advisory Board meet regularly, attend annual meetings, and have reviewed four trial protocols (SYNERGY pending). Communication and dissemination efforts have produced 19 scientific papers, 302 dissemination activities (targeting policymakers, funders and national TB programmes), and 12 poster/conference presentations. Capacity-building has included 12 webinars, 3 seminars for healthcare professionals and 7 educational articles (22 training materials total). The Young Investigators Group has expanded its activities, and the consortium has co-organised 4 webinars and an Interactive Education session for healthcare professionals.
