Tuberculosis · Drug ResistanceNine-Month All-Oral Regimens for Rifampin-Resistant Tuberculosis: Results of the endTB Trial

Rifampin-resistant tuberculosis (RR-TB) accounts for roughly 410,000 new cases each year, yet the World Health Organization estimates that only 40% are diagnosed and treated, and that treatment succeeds in 65% of those who are.² Historically this has meant 18 to 24 months of therapy, frequently including injectable aminoglycosides or polypeptides, with regimens built largely on expert opinion and pooled observational data rather than randomised evidence.¹

Three trials launched between 2016 and 2017 set out to change that. STREAM stage 2 tested a nine-month, seven-drug regimen containing bedaquiline,³ and TB-PRACTECAL examined three six-month regimens built around bedaquiline, linezolid and pretomanid, alone or with moxifloxacin or clofazimine.⁴ The third, endTB, evaluated five nine-month regimens combining the newer agents bedaquiline and delamanid with the repurposed drugs clofazimine and linezolid. It is that trial which is summarised here.¹

Participants aged 15 years and older with fluoroquinolone-susceptible pulmonary RR-TB, confirmed by WHO-endorsed rapid tests, were enrolled at 12 sites in Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru and South Africa between February 2017 and October 2021. HIV status and CD4 count were not exclusion criteria. Pregnancy, elevated liver enzymes, uncorrectable electrolyte disorders, a QTcF interval of 450 msec or more, resistance or prior exposure of 30 days or more to bedaquiline, delamanid, clofazimine or linezolid, and 15 days or more of any second-line antituberculosis drug during the current episode all excluded participation.¹

Of 754 participants randomised, 699 entered the modified intention-to-treat analysis and 562 the per-protocol analysis. Assignment used Bayesian response-adaptive randomisation, with the probability of allocation to each group updated monthly from interim analyses of treatment response at weeks 8 and 39. Each experimental regimen ran for 39 weeks.¹

The primary endpoint was a favourable outcome at week 73, defined as the absence of any unfavourable outcome together with either two consecutive negative cultures, one of them between weeks 65 and 73, or favourable bacteriological, radiological and clinical evolution. Unfavourable outcomes were death from any cause, modification of the regimen, or the start of new RR-TB treatment. Secondary endpoints assessed favourable outcomes at weeks 39 and 104. Safety endpoints covered grade 3 or higher adverse events, serious adverse events, death, discontinuation of a trial drug for an adverse event, and events of special interest including hepatotoxicity, haematologic toxicity, optic neuritis, peripheral neuropathy and QTcF prolongation by week 73.¹

Among the 699 participants in the modified intention-to-treat population, 264 (37.8%) were women and the median age was 32 years (IQR 23–44), with 25 (3.6%) under 18. Ninety-eight (14.0%) were living with HIV, 568 (81.3%) had a sputum smear graded 1+ or higher, and 399 (57.1%) had cavitation on chest radiography.¹

In the modified intention-to-treat population, 80.7% of participants on standard therapy had a favourable outcome at week 73 (95% CI 72.4–87.3). Four experimental regimens met the noninferiority margin of −12 percentage points in this analysis: BCLLfxZ, BLMZ, BDLLfxZ and DCMZ. Results in the per-protocol population supported these findings except for DCMZ, which was not noninferior there. DCLLfxZ did not meet the margin.¹

Outcomes were consistent across the secondary endpoints at weeks 39 and 104 and in adjusted and sensitivity analyses. No significant treatment differences emerged across subgroups by week 73, although the authors note that geographic region, prior exposure to second-line agents, cavitary disease, HIV status and low body-mass index may all influence response. BCLLfxZ showed a longer time to an unfavourable outcome than standard therapy (hazard ratio 0.48, 95% CI 0.23–0.98).¹

Grade 3 or higher adverse events were frequent in every group, and least frequent in two of the experimental groups rather than in standard therapy: they affected 54.8% of the BLMZ group and 55.7% of the BCLLfxZ group, rising to 61.4% with BDLLfxZ, against 62.7% on standard therapy. Serious adverse events were similar throughout, from 13.1% with BCLLfxZ to 16.7% with DCMZ and with standard therapy. Fifteen participants (2.0%) had died by week 73 and 18 (2.4%) by week 104. No death was attributed to a trial drug.¹

Among events of special interest, hepatotoxicity was most frequent with BLMZ (18.3%) and least frequent with BDLLfxZ (6.3%), against 7.1% on standard therapy. Haematologic toxicity ran from 7.4% with BCLLfxZ to 10.5% with DCLLfxZ, compared with 10.3% on standard therapy. Peripheral neuropathy ranged from 2.4% with DCLLfxZ to 7.1% with BDLLfxZ, against 4.8% on standard therapy. QTcF prolongation was confined to the two regimens containing clofazimine with moxifloxacin or bedaquiline: 4.2% with DCMZ and 3.3% with BCLLfxZ.¹

Three regimens — BLMZ, BCLLfxZ and BDLLfxZ — were noninferior to standard therapy across every analysis, achieving favourable outcomes in more than 85% of participants and exceeding reported global averages. Deaths were rare even among participants with coexisting conditions and cavitary disease, and grade 3 or higher adverse events, while common, were generally unrelated to the trial drugs.¹

Linezolid-related toxicity was lower in the experimental groups than might have been expected, which the authors suggest may reflect dose reduction after 16 weeks. QTcF prolongation beyond 500 msec was infrequent and occurred mainly in participants taking clofazimine, bedaquiline or moxifloxacin, consistent with the established safety profile of those drugs.¹

The authors set out two main limitations. Because the regimens differed in duration, neither trial staff nor participants were blinded to group assignment. WHO guidance was also revised twice during the trial, although the effect on the comparator was limited: 81.5% of standard-therapy regimens already matched the updated recommendations.¹

1. Guglielmetti, L., Khan, U., Velásquez, G. E., Gouillou, M., Abubakirov, A., Baudin, E., Berikova, E., Berry, C., Bonnet, M., Cellamare, M., Chavan, V., Cox, V., Dakenova, Z., de Jong, B. C., Ferlazzo, G., Karabayev, A., Kirakosyan, O., Kiria, N., Kunda, M., Lachenal, N., … endTB Clinical Trial Team. (2025). Oral regimens for rifampin-resistant, fluoroquinolone-susceptible tuberculosis. The New England Journal of Medicine, 392(5), 468–482. https://doi.org/10.1056/NEJMoa2400327
2. World Health Organization. (2023). Global tuberculosis report 2023. World Health Organization. https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023
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5. Morgan, H., Ndjeka, N., Hasan, T., Gegia, M., Mirzayev, F., Nguyen, L. N., Schumacher, S., Schlub, T. E., Naidoo, K., & Fox, G. J. (2024). Treatment of multidrug-resistant or rifampicin-resistant tuberculosis with an all-oral 9-month regimen containing linezolid or ethionamide in South Africa: A retrospective cohort study. Clinical Infectious Diseases, 78(6), 1698–1706. https://doi.org/10.1093/cid/ciae145
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