Treatment Effect Measures for Culture Conversion Endpoints in Phase IIb Tuberculosis Treatment Trials

Abstract

Phase IIb trials of tuberculosis therapy rely on early biomarkers of treatment effect. Despite limited predictive ability for clinical outcomes, culture conversion, the event in which an individual previously culture positive for Mycobacterium tuberculosis yields a negative culture after initiating treatment, is a commonly used endpoint. Lack of consensus on how to define the outcome and corresponding measure of treatment effect complicates interpretation and limits between-trial comparisons. We review common analytic approaches to measuring treatment effect and introduce difference in restricted mean survival times as an alternative to identify faster times to culture conversion and express magnitude of effect on the time scale. Findings from the PanACEA MAMS-TB trial are reanalyzed as an illustrative example. In a systematic review we demonstrate variability in analytic approaches, sampling strategies, and outcome definitions in phase IIb tuberculosis trials. Harmonization would allow for larger meta-analyses and may help expedite advancement of new tuberculosis therapeutics.

Keywords: clinical trials; phase II; randomized controlled trials; survival analysis; tuberculosis.

Figure 1.

Time to culture conversion: PanACEA MAMS TB trial. Time to stable culture conversion in liquid media, up to 12 weeks, in the mITT population based on reconstructed data. The cumulative probability of culture conversion by 12 weeks was .80 (95% CI, .66–.89) in the R35HZE arm and .70 (95% CI, .60–.77) in the control arm (Supplementary Text 2). The median time to culture conversion is 48 days in the R35HZE arm and 62 days in the control arm. The unadjusted hazard ratio is 1.50 (95% CI, 1.06–2.20), meaning that, on a given day, an individual still presenting as culture positive on the R35HZE regimen is 1.50 times as likely to experience culture conversion compared with an individual on the control regimen. The difference in RMSTs over 12 weeks of follow-up is 8 days (95% CI, 1–15 days), meaning that over 12 weeks of follow-up, those on the R35HZE regimen experienced culture conversion 8 days faster, on average, compared with those on the standard regimen. Dashed lines indicate the median culture conversion times in each arm and the time horizon for the difference in RMST (12 weeks). The shaded area between the Kaplan-Meier curves represents the estimated difference in RMSTs, 8 days. Abbreviations: CI, confidence interval; MAMS, Multi-Arm, Multi-Stage; mITT, modified intent-to-treat; RMST, restricted mean survival time; RMSTD, difference in restricted mean survival time; TB, tuberculosis.

Figure 2.

Trial selection flow. Abbreviations: EBA, early bactericidal activity; PK, pharmacokinetic; TB, tuberculosis.