Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine to Treat MDR-TB

Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis that is resistant to at least isoniazid and rifampicin, the two most important drugs in treating TB. In 2017, approximately 558,000 new people were estimated to have developed MDR-TB, and 8.5% of the cases had extensively drug-resistant tuberculosis (XDR-TB).(1) Current WHO-endorsed MDR-TB treatment regimens take 9-20 months to complete and are associated with substantial toxicity, including deafness from injectable agents, hepatitis from pyrazinamide and severe neuropathy from linezolid. Given the long duration and toxicities of MDR-TB regimens, it is perhaps not surprising that WHO reports that only 25% of patients with MDR-TB are enrolled into WHO-endorsed treatment regimens. Thus, there is an urgent need for shorter, less toxic treatments for MDR-TB. This proposal will determine the efficacy, safety, tolerability and optimal duration of a novel, all oral MDR-TB treatment regimen while addressing three major challenges with innovations that have the potential to transform future trials.

The proposed DRAMATIC (Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical) Trial is a multicenter, randomized, partially blinded, four-arm, phase 2 trial that will examine an injectable- and pyrazinamide-sparing regimen of bedaquiline, delamanid, levofloxacin, linezolid, and clofazimine. The DRAMATIC regimen limits the administration of linezolid to the initial 8 weeks of treatment, the window before linezolid-related neuropathy occurs. Animal and human studies provide evidence for the potential efficacy of this 5-drug regimen, but the optimal duration of treatment remains uncertain.(2-4)

Primary Objectives:

1. Describe the relationship between the duration of the experimental regimen and the proportion of participants with sustained cure at 76 weeks after randomization without treatment failure or relapse. 2. Describe the relationship between baseline prognostic risk strata and sustained cure at 76 weeks after randomization without treatment failure or relapse. 3. Evaluate the association between novel biologic markers and sustained cure at 76 weeks after randomization without treatment failure or relapse.

Secondary Objectives: 4. Identify the shortest duration of the study regimen that has acceptable safety and efficacy for a Phase 3 clinical trial of the DRAMATIC regimen for treatment of MDR-TB. 5. Describe the frequency, magnitude, time course of and risk factors for QTc prolongation associated with the study regimen. 6. Demonstrate the feasibility and efficiency of implementing the new duration-randomized design in a multi-centre randomized trial of drug-resistant TB. 7. Determine if time to sputum culture conversion predicts optimal duration of treatment when stratified by extent of disease. 8. Describe the relationship between the duration of the experimental regimen and the proportion of participants with sustained cure at 104 weeks after randomization without treatment failure or relapse. 9. Assess vital status at 132 weeks post randomization.