An All-Oral 6-Month Regimen for Multi-Drug Resistant/Rifampicin-Resistant Tuberculosis: A Multi-Centre, Phase 3, Open Label, Randomised Controlled Trial (NeXT Study)

Background: Improving treatment outcomes, reducing drug toxicity, eliminating the need for injectable agents, and shortening the treatment duration to 6-months (the same as rifampicin-susceptible tuberculosis) remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Methods: 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. Findings: 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 ( 95% CI)  than participants in the standard-of-care arm [RR 2·2 (1·2–4·1); p=0·006]. They were also less likely, over a 24-month period, to experience an unfavourable outcome event than participants in the standard-of-care arm [HR 0·4, (0·2–0·6), p<0·001]. 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. Time to culture conversion was significantly better in the interventional arm [HR 2·6 (1·4–4·9); p= 0·003] after censoring those with bedaquiline replacement in the standard-of-care arm. Interpretation: 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. Trial Registration: The trial was registered on clinicaltrials.gov (NCT02454205). Funding: South African MRC, Pfizer, and the European and Developing Country Clinical Trial Partnership (EDCTP) Declaration of Interest: None to declare. Ethical Approval: An institutional review board or ethics committee at each participating trial site reviewed and approved the protocol and informed consent documents.