A Standardized Approach for Collection of Objective Data to Support Outcome Determination for Late-Phase Tuberculosis Clinical Trials

Ekaterina V. Kurbatova, Patrick P.J. Phillips, Susan E. Dorman, Erin E. Sizemore, Kia E. Bryant, Anne E. Purfield, Jessica Ricaldi, Nicole E. Brown, John L. Johnson, Carole L. Wallis, Joseph P. Akol, Oksana Ocheretina, Nguyen Van Hung, Harriet Mayanja-Kizza, Madeleine Lourens, Rodney Dawson, Nguyen Viet Nhung, Samuel Pierre, Yeukai Musodza, Justin ShenjeSharlaa Badal-Faesen, Stalz Charles Vilbrun, Ziyaad Waja, Lakshmi Peddareddy, Nigel A. Scott, Yan Yuan, Stefan V. Goldberg, Susan Swindells, Richard E. Chaisson, Payam Nahid

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Rationale: We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary tuberculosis (TB). Objectives: We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcomes for all participants were achieved. Methods: A PPTR event was defined as the occurrence of one or more prespecified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology. Measurements and Main Results: Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 wk). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome and between 13.8% and 14.7% of participants with favorable and not-assessable outcomes. A total of 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve a disease-free cure. Conclusions: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials.

Original languageEnglish (US)
Pages (from-to)1376-1382
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume207
Issue number10
DOIs
StatePublished - May 15 2023

Keywords

  • TB
  • endpoints ascertainment bias
  • multicenter randomized trial
  • noninferiority
  • outcomes

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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