Time until Relapse in Tuberculosis Treatment Trials: Implication for Phase 3 Trial Design

Abstract

To the Editor: The number of new drugs and combinations for tuberculosis treatment that require testing has increased during the past 5 years; however, the number of trial sites in high-burden countries capable of conducting registration-quality trials is limited. The primary endpoint for response to treatment in most earlier phase 3 trials was relapse at least 24 months after completion of therapy. Coupled with the large number of patients required and the challenge of following up patients in resource-constrained settings, the long length of follow-up has meant that such trials require upwards of 5 years to enroll and complete. If the length of follow-up could be shortened without missing a substantial number of relapses, the time and resources necessary to complete such trials could be reduced. Investigators have reexamined the timing of relapse in earlier studies to inform regulatory authorities and guide the design of future trials. In a reanalysis of trials conducted from 1970 to 1983 by the British Medical Research Council, 78% of relapses occurred within 6 months of stopping treatment and 91% occurred within 12 months (1). To add to this information, we examined data from a recent phase 3 randomized trial of shortening treatment from 6 to 4 months in adults with drug-susceptible tuberculosis (TB) done in Brazil, Uganda, and the Philippines (2). Subjects were followed with sputum cultures monthly during treatment and every 3 months thereafter for a total of 30 months after beginning treatment. Eighteen of 370 patients developed recurrent TB. Two recurrences due to exogenous reinfection were excluded. The mean time after treatment until relapse was 7 ± 4.4 months. Of the 16 relapses, 11 (69%) occurred within the first 6 months after stopping treatment, 13 (81%) occurred within 12 months, and 15 (94%) occurred within 18 months. The timing of relapse did not differ between sites. Our results support reconsideration of the follow-up time required after treatment in phase 3 registration trials of new TB drugs and regimens for drug-susceptible TB.