Comments
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.
*These authors contributed equally to this work.
‡Retired.
Supported by U.S. Centers for Disease Control and Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Division of Tuberculosis Elimination contracts 200-2009-32582, 200-2009-32593, 200-2009-32594, 200-2009-32589, 200-2009-32597, 200-2009-32598, 75D30119C06702, 75D30119C06701, 75D30119C06703, 75D30119C06222, 75D30119C06225, and 75D30119C06010; and by the National Institute of Allergy and Infectious Diseases of the NIH under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC, the National Institute of Allergy and Infectious Diseases, or the U.S. Department of Health and Human Services.
Author Contributions: Study conception and design: E.V.K., P.P.J.P., S.E.D., E.E.S., S.V.G., S.S., R.E.C., and P.N. Data collection: E.V.K., E.E.S., K.E.B., A.E.P., J.R., N.E.B., J.L.J., C.L.W., J.P.A., O.O., N.V.H., H.M.-K., M.L., R.D., N.V.N., S.P., Y.M., J.S., S.B.-F., S.C.V., Z.W., L.P., N.A.S., Y.Y., S.V.G., and P.N. Data analysis: P.P.J.P. and K.E.B. Data interpretation: E.V.K., P.P.J.P., S.E.D., S.S., R.E.C., and P.N. Drafting of the initial manuscript: E.V.K., P.P.J.P., S.E.D., and P.N. Critical review of the final draft of the manuscript: E.V.K., P.P.J.P., S.E.D., E.E.S., K.E.B., A.E.P., J.R., N.E.B., J.L.J., C.L.W., J.P.A., O.O., N.V.H., H.M.-K., M.L., R.D., N.V.N., S.P., Y.M., J.S., S.B.-F., S.C.V., Z.W., L.P., N.A.S., Y.Y., S.V.G., S.S., R.E.C., and P.N. Access and verification of underlying data: P.P.J.P., N.A.S., and K.E.B.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.202206-1118OC on February 15, 2023
Author disclosures are available with the text of this article at www.atsjournals.org.
