| Protocol No: | ECCT/24/10/06 | Date of Protocol: | 21-03-2024 |
| Study Title: | A Phase 2, Randomized, Adaptive, Dose-Ranging, Open-Label Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis (RAD-TB) |
| Study Objectives: | Primary Objectives 1 To compare MGIT liquid culture TTP slope over the first 6 weeks of treatment for each experimental treatment arm to the SOC arm. 2 To compare new Grade 3 or higher adverse events (AEs) (safety) over the first 8 weeks of treatment for each experimental treatment arm to the SOC arm. 1.3 Secondary Objectives 1.To compare time to stable culture conversion by MGIT liquid culture by week 8 for each experimental treatment arm to the SOC arm. 2 To compare MGIT liquid culture TTP slope over the first 8 weeks of treatment for each experimental treatment arm to the SOC arm. 3. To compare new Grade 3 or higher AEs (safety) over 26 weeks of treatment for each experimental treatment arm to the SOC arm. 4.To compare discontinuations of anti-TB drugs for any reason prior to 8 and 26 weeks of treatment for each experimental treatment arm to the SOC arm. 5. To determine the dose- and exposure-response relationships between experimental drug estimated pharmacokinetic (PK) parameters with safety and efficacy. 6. To compare a composite of efficacy and safety outcomes using a risk-benefit approach for each experimental treatment arm to the SOC arm. 7. To compare MGIT liquid culture TTP slope over the first 6 weeks of treatment for Arms 3A-3B and Arms 4A-4B compared to Arm 2. 8 To compare durable cure by 52 weeks after treatment initiation in each experimental treatment arm to the SOC arm. Exploratory Objectives 1 To project a hazard ratio comparing time to stable culture conversion for each experimental treatment arm to the SOC arm. 2 To compare TTP with time to culture conversion outcome measurements. 3 To compare sputum ribosomal synthesis ratio (RS ratio) quantification over the first 8 weeks of treatment and at 26 weeks of treatment for each experimental treatment arm to the SOC arm. 4 To describe the proportion of participants with culture conversion by MGIT liquid culture during the first 8 weeks of treatment in each experimental treatment arm and the SOC arm. 5 To obtain qualitative data on the acceptability of the assigned treatment regimens among people living with TB. 1.4.6 To evaluate whether Mtb-specific T-cell phenotype and function, and transcriptomic signatures, can be used to monitor treatment response. |
| Laymans Summary: | A5409/RAD-TB is an adaptive Phase 2 randomized, controlled, openlabel, dose-ranging, platform protocol to evaluate the safety and efficacy of multidrug regimens for the treatment of adults with drug-susceptible pulmonary tuberculosis (TB). The adaptive design allows for regimens to be added during the trial for efficient testing of new drugs and drug combinations, identified as promising via translational modeling, against the standard of care (SOC) within the same trial infrastructure. |
| Abstract of Study: | A5409/RAD-TB is an adaptive Phase 2 randomized, controlled, openlabel, dose-ranging, platform protocol to evaluate the safety and efficacy of multidrug regimens for the treatment of adults with drug-susceptible pulmonary tuberculosis (TB). The adaptive design allows for regimens to be added during the trial for efficient testing of new drugs and drug combinations, identified as promising via translational modeling, against the standard of care (SOC) within the same trial infrastructure. The protocol will be amended when information becomes suitable from within or outside of the trial indicating that a new regimen is available for testing. Key aspects are the adaptive design (flexibility to add regimens as they are identified as suitable for testing), dose-finding within regimens, and the translational modeling framework. DURATION 52 weeks, inclusive of 8 weeks of experimental study treatment, followed by 18 weeks of SOC treatment. SAMPLE SIZE 45 participants in each experimental treatment arm and at least 90 participants in the SOC arm. POPULATION Participants with Xpert MTB/RIF positive drug-susceptible pulmonary TB, living with and without HIV, aged ≥18 years. STRATIFICATION Randomization will be stratified by Xpert semi-quantitative result and will additionally be balanced by site. REGIMENS Participants will be randomized to SOC (Arm 1) or to an experimental treatment arm, with twice the allocation to Arm 1 as to concurrentlyenrolling experimental treatment arms, as follows: Arm 1 (SOC): isoniazid/rifampicin/pyrazinamide/ethambutol (HRZE) for 8 weeks and then isoniazid (INH)/rifampicin (RIF) for 18 weeks, for a total of 26 weeks of anti-TB treatment, at standard doses. Arm 2: bedaquiline (BDQ) 400 mg for 2 weeks and then 200 mg for 6 weeks + pretomanid (Pa) 200 mg for 8 weeks + linezolid (LZD) 600 mg for 8 weeks, followed by INH/RIF for 18 weeks, for a total of 26 weeks of anti-TB treatment. Arm 3A: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks + Pa 200 mg for 8 weeks + TBI-223 1200 mg for 8 weeks, followed by INH/RIF for 18 weeks, for a total of 26 weeks of anti-TB treatment. Arm 3B: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks + Pa 200 mg for 8 weeks + TBI-223 2400 mg for 8 weeks, followed by INH/RIF for 18 weeks, for a total of 26 weeks of anti-TB treatment. Arm 4A: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks + Pa 200 mg for 8 weeks + sutezolid (SZD) 800 mg for 8 weeks, followed by INH/RIF for 18 weeks, for a total of 26 weeks of anti-TB treatment. Arm 4B: BDQ 400 mg for 2 weeks and then 200 mg for 6 weeks + Pa 200 mg for 8 weeks + SZD 1600 mg for 8 weeks, followed by INH/RIF for 18 weeks, for a total of 26 weeks of anti-TB treatment. |