An All-Oral 6-Month Regimen for Multidrug-Resistant TB (the NExT Study): A Multicenter, Randomized Controlled Trial

Rationale/objectives: Improving treatment outcomes, reducing drug toxicity, avoiding injectable agents, and shortening the treatment duration to 6-months (approximating that of rifampicin-susceptible tuberculosis) remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB).We conducted a multicentre randomised controlled trial in adults with MDR/RR-TB (i.e. without resistance to fluoroquinolones or aminoglycosides). Participants were randomly assigned (1:1 ratio) to a ~6-month all-oral regimen that included levofloxacin, bedaquiline and linezolid, or the standard-of-care ≥ 9-month WHO-approved injectable-based regimen. The primary endpoint was a favourable WHO-defined treatment outcome 24 months after treatment initiation.93 of 111 participants randomised were included in the modified intention-to-treat analysis; 51 (55%) were HIV co-infected (median CD4 count 158 cells/mL). Participants in the intervention arm were 2.2 times more likely to experience a favourable 24-month outcome than participants in the standard-of-care arm [RR 2.2 (1.2-4.1); p=0.006]. Toxicity-related drug substitution occurred more frequently in the standard-of-care arm [(65·9% (29/44) versus 36·7% (18/49), p= 0·001)]; 79.3% (23/29) due to kanamycin (mainly hearing loss; replaced by bedaquiline) in the standard-of-care arm, and 83·3% (15/18) due to linezolid (mainly anaemia) in the interventional arm. Culture conversion was significantly better in the intervention arm [HR 2.6 (1.4-4.9); p= 0.003] after censoring those with bedaquiline replacement in the standard-of-care arm.An all-oral 6-month levofloxacin, bedaquiline and linezolid-containing MDR/RR-TB regimen was associated with significantly improved 24-month treatment outcomes compared with traditional injectable-containing regimens. However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02454205.