endTB (Expand New Drugs for TB): treatment of multidrug-resistant tuberculosis using regimens based on bedaquiline or delamanid
Design
Phase 3, multinational, open-label, randomized
Context
endTB aims to find shorter, less toxic and more effective treatments for 'multidrug-resistant TB' (MDR-TB). In this randomized, controlled, open-label, multi-country Phase III trial, 5 experimental regimens containing 1 or 2 new drugs in patients with fluoroquinolone-susceptible MDR-TB are trailed. The objective is to assess whether the efficacy of experimental regimens at Week 73 is non-inferior to that of the control.
Our Role
Statistics & Data Management
Partners
- Médecins Sans Frontières
- Partners In Health
- IRD
- Unitaid
- Ministries of Health of the countries involved in the study
Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis.
METHODS
Phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points.
RESULTS
Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy.
CONCLUSIONS
Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis.
Read the publications
Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis.
Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.
Estimating the effect of hepatitis C infection on multidrug-resistant tuberculosis treatment outcomes under hypothetical interventions on regimen composition and adherence.
Characterizing treatment adherence trajectories in the endTB multisite cohort of drug-resistant tuberculosis patients: an application of group-based trajectory modelling.
Sputum culture reversion in longer treatments with bedaquiline, delamanid, and repurposed drugs for drug-resistant tuberculosis.
Results in key subgroups of patients with drug-resistant tuberculosis
Methods
For each subgroup, proportion of favourable outcome at Week 73 was calculated in each arm. Risk differences and 95% confidence intervals were estimated in the modified intention-to-treat population (mITT), which included all randomized participants who took at least one dose of study treatment and had a positive prerandomization tuberculosis culture. Results in each arm were plotted on forest plots.
Results
In HIV-infected patients, efficacy results are consistent with the overall results in endTB1 and endTB2 while in endTB3 the effect of trt favours the control arm. No differences from the overall population were observed in any of the 3 arms in patients with a more severe disease, while treatment effect in patients with low BMI, favours the control arm in all 3 arms. Treatment effect in patients with diabetes, favours the experimental arm in all 3 arms.
Conclusion
All 3 arms could reasonably be used in patients with severe disease or diabetes. endTB1 and endTB2 appeared to be particularly efficacious in HIV positive patients. Longer or regimens with more drugs may achieve better results in patients with low BMI. Additional research is needed to confirm these findings.
Treatment of children and adolescents with MDR/RR-TB regimens containing bédaquiline and delamanid
Methods
The endTB observational study is a prospective, multi-site study. Children and adolescents aged 19 years and below are included in this analysis. We report the frequency and outcomes of clinically relevant adverse events of special interest (AESI) and end of treatment outcomes.
Results
A total of 190 children and adolescents from 14 countries were included (< 5 years: 4, 5-14 years: 20, 15- 19 years: 166), 47% had BMI < 18.5 Kg/m2, 6% were HIV positive, 68% previously treated with second-line drugs, 52% had fluoroquinolone resistance, 71% cavity or bilateral disease on chest Xray. Initial treatment contained bedaquiline only (51%), delamanid only (39%) or both (10%) as part of a multidrug regimen. Other frequently used drugs were linezolid (82%), cycloserine (71%), clofazimine (70%) and fluoroquinolones (69%). End of treatment outcomes were 85% success, 5% death, 4% failure, 4% lost to follow and 2% not evaluated. Most common clinically relevant AEIs were peripheral neuropathy, electrolyte depletion and hearing loss with 26 (16%), 24 (15%) and 11 (7%) patients experiencing at least one event respectively. Two patients (1%) experienced clinically relevant QT interval prolongation which resolved without sequelae. Among patients experiencing hearing loss 4 (36%) resolved, 4 (36%) resolved with sequelae, 1 (9%) did not resolve, and 2 (18%) had unknown outcomes. Among patients experiencing peripheral neuropathy, 14 (54%) resolved, 9 (35%) resolved with sequelae, 3 (11%) did not resolve.
Conclusion
Treatment of MDR/RR-TB with bedaquiline and delamanid is effective and well tolerated amongst children and adolescents. All oral regimens should be scaled up as recommended by WHO for these age groups.
