Research: A standardized approach for collection of objective data to support outcome determination for late-phase Tuberculosis clinical trials

15 May 2023
TB; endpoints ascertainment bias; multicenter randomized trial; noninferiority; outcomes.
15 May 2023

Dr Justin Shenje has co-authored: "A standardized approach for collection of objective data to support outcome determination for late-phase TB clinical trials" appearing in American Journal of Respiratory and Critical care Medicine. 

Factors associated with prevalent Mycobacterium tuberculosis infection and disease among adolescents and adults exposed to rifampin-resistant tuberculosis in the household

 

Rationale: We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT 02410772), 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.

Keywords: multicenter randomized trial; noninferiority; outcomes; TB; endpoints ascertainment bias

 

Citation: Kurbatova EV, Phillips PPJ, Dorman SE, Sizemore EE, Bryant KE, Purfield AE, Ricaldi J, Brown NE, Johnson JL, Wallis CL, Akol JP, Ocheretina O, Van Hung N, Mayanja-Kizza H, Lourens M, Dawson R, Nhung NV, Pierre S, Musodza Y, Shenje J, Badal-Faesen S, Vilbrun SC, Waja Z, Peddareddy L, Scott NA, Yuan Y, Goldberg SV, Swindells S, Chaisson RE, Nahid P. A Standardized Approach for Collection of Objective Data to Support Outcome Determination for Late-Phase Tuberculosis Clinical Trials.American Journal of Respiratory and Critical care Medicine., 207(10):1376-1382. Read publication.