A 3-MONTH regimen combining clofazimine and rifapentine for drug-susceptible pulmonary tuberculosis did not improve treatment outcomes and was associated with higher rates of severe adverse events, according to findings from the Phase 2c Clo-Fast trial.
Clo-Fast was an open-label, multicentre trial conducted at six sites across five countries, enrolling adults aged 18 years or older with sputum-positive, drug-susceptible tuberculosis, including those with HIV infection and CD4+ counts ≥100 cells/mm³. Participants were randomised to receive either a 13-week regimen of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine (group 1), a 6-month standard-of-care regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (group 2), or a pharmacokinetic sub-study without a clofazimine loading dose (group 3). The primary endpoint was time to sputum culture negativity by Week 12, with safety assessed by the occurrence of Grade 3 or higher adverse events over 65 weeks.
Among 104 participants, 55 in group 1 and 31 in group 2 were evaluable for efficacy. By Week 12, 89% of group 1 and 90% of group 2 had achieved culture conversion (adjusted hazard ratio: 1.21, 90% CI: 0.82–1.79; p=0.2089). However, Grade 3 or worse adverse events were significantly more frequent in the experimental arm (45% vs 16%; p=0.002). By Week 65, the cumulative probability of an unfavourable clinical or bacteriological outcome was 52% in group 1 compared with 27% in the control group (p=0.049). A 2-week loading dose of clofazimine tripled drug exposure and reached near steady state more rapidly without additional safety concerns. The trial was stopped early due to lack of clinical efficacy.
Although preclinical and early-phase studies suggested strong sterilising potential for clofazimine-containing regimens, Clo-Fast demonstrates that shortening treatment to 3 months using this combination is not viable for drug-susceptible tuberculosis. High rates of severe adverse events and unfavourable outcomes highlight the difficulty of translating murine and early human pharmacokinetic data into effective treatment-shortening strategies. Further research is needed to optimise treatment duration, regimen composition, and patient selection.
Reference
Metcalfe JZ et al; ACTG A5362 study team. A 3-month clofazimine-rifapentine-containing regimen for drug-susceptible tuberculosis versus standard of care (Clo-Fast): a randomised, open-label, phase 2c clinical trial. Lancet Infect Dis. 2025; DOI: 10.1016/S1473-3099(25)00436-0.
