Background:
Clo-Fast (ACTG A5362; NCT04311502) is a randomized, controlled, open-label phase IIc clinical trial evaluating the safety and efficacy of a 3-month rifapentine (P1200mg)/clofazimine (CFZ)-containing regimen versus 6-month standard of care (SOC) for drug-susceptible (DS) TB that stopped enrollment early due to lack of clinical efficacy. We present results from data through Sept 25, 2023, when the last participant completed study treatment.
Methods:
Adults enrolled at six sites in Malawi, Zimbabwe, South Africa, India, and Haiti. Randomization, stratified on HIV status and advanced disease on chest X-ray, was to: Arm 1 (13-week experimental regimen): 3PHZEC; Arm 2 (26-week SOC): 2RHZE/4RH; or Arm C (PK subgroup without CFZ load, then SOC): 1PHZEC/1RHZE/4RH. The primary outcomes were (efficacy) time to stable liquid culture conversion through week 12 and (safety) proportion experiencing an AE ≥ grade 3 through week 65 in Arms 1 and 2. The proportion with an unfavorable clinical/bacteriologic outcome in Arms 1 and 2 by week 65 was a key secondary outcome.
Results:
Between June 2021 and April 2023, when the trial was stopped for inefficacy per DSMB recommendation, we enrolled 58 of 110 planned participants to Arm 1, 31 of 55 planned participants to Arm 2, and 15 of 20 planned participants to Arm C. Most participants were male (79%), 29% were living with HIV (median baseline CD4+ 265 cell/mm3, IQR 185-379 cell/mm3), 71% had radiographically advanced TB disease, and 25% were 3+ smear-positive at entry. Median (IQR) follow-up on study was was 50.2 weeks (39.7, 57.6 weeks). By week 12, 89% (n=48) in Arm 1 and 90% (n=28) of participants in Arm 2 achieved stable culture conversion (adjusted HR 1.17, 90% CI, 0.79 to 1.73, adjusted for baseline HIV status and presence of advanced disease). The cumulative proportion of participants experiencing an AE ≥ grade 3 was higher in Arm 1 (46%) than Arm 2 (16%; difference 30%, 90% CI 14-45%), driven by change in creatinine clearance in Arm 1. The cumulative probability of an unfavorable outcome in Arm 1 was 49% (95% CI 34-67%) versus 34% (95% CI 19-58%) among Arm 2 participants (difference -15%; 95% CI -41% to 11%). The table describes the clinical/bacteriologic unfavorable outcome events.
Conclusions:
A 13-week regimen containing CFZ and rifapentine was not efficacious for treatment of DS-TB. The SOC arm also had a high rate of unfavorable events, despite high week 12 culture conversion.
