A MAJOR international trial has found that a shorter, all-oral regimen for pre-extensively drug-resistant tuberculosis (pre-XDR) did not meet non-inferiority criteria compared to the longer standard of care, raising important considerations for future treatment strategies.
Pre-XDR tuberculosis, defined as multidrug- or rifampicin-resistant TB with additional resistance to fluoroquinolones, presents significant therapeutic challenges. The phase 3 endTB-Q trial aimed to evaluate the efficacy and safety of a 6–9 month regimen comprising bedaquiline, delamanid, linezolid, and clofazimine (BDLC) compared with the WHO-recommended longer, individualised standard of care. Conducted across ten hospitals in six countries (India, Kazakhstan, Lesotho, Pakistan, Peru, and Vietnam), the open-label, stratified, randomised controlled trial enrolled patients aged ≥15 with confirmed pulmonary pre-XDR TB. Participants were randomly assigned 2:1 to the BDLC or control group, with treatment duration tailored according to disease extent and microbiological response. Investigators and laboratory staff were masked to treatment allocation, while site staff and participants were not.
Of 1,030 individuals screened, 324 were enrolled (219 in the BDLC group and 105 in the control group). Most (64%) had extensive disease, and 71% of those in the BDLC group were assigned to the 9-month regimen. At Week 73, favourable outcomes were reported in 87% of the BDLC group and 89% of the control group in the modified intention-to-treat population (adjusted risk difference 0.2%, 95% CI: -9.1 to 9.5), and in 88% versus 93% in the per-protocol population (-3.5%, -12.8 to 5.9). Although clinical outcomes were broadly similar, the study failed to meet the non-inferiority margin of -12%. Grade 3 or higher adverse events occurred in 68% of the BDLC group and 73% of controls. Eight deaths occurred in the BDLC group and two in the control group by Week 73.
While BDLC showed promise for patients with limited disease, outcomes in those with extensive disease were less favourable, suggesting the need for longer or reinforced regimens. These findings provide critical evidence to inform the development of stratified treatment strategies for this complex and growing patient population.
Reference
Guglielmetti L et al; endTB-Q Clinical Trial Team. Bedaquiline, delamanid, linezolid, and clofazimine for rifampicin-resistant and fluoroquinolone-resistant tuberculosis (endTB-Q): an open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial. Lancet Respir Med.2025; DOI: 10.1016/S2213-2600(25)00194-8.
