Validity and Characterization of Time to Symptom Resolution Outcome Measures in the ACTIV-2/A5401 Outpatient COVID-19 Treatment Trial

Abstract

Background: Time to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation.

Methods: ACTIV-2/A5401 trial participants completed a COVID-19 diary assessing 13 targeted symptoms and global experience (overall COVID-19 symptoms, return to pre-COVID-19 health) daily for 29 days. We evaluated concordance of time to sustained (2 days) resolution of all targeted symptoms (TSR) with resolution of overall symptoms and return to health in participants receiving placebo.

Results: The analysis included 77 high-risk and 81 standard-risk participants with overall median 6 days of symptoms at entry and median age 47 years, 50% female, 82% white, and 31% Hispanic/Latino. Correlation between TSR and resolution of overall symptoms was 0.80 and 0.68, and TSR and return to health, 0.66 and 0.57 for high- and standard-risk groups, respectively. Of the high- and standard-risk participants, 61% and 79%, respectively, achieved targeted symptom resolution, of which 47% and 43%, respectively, reported symptom recurrence. Requiring >2 days to define sustained resolution reduced the frequency of recurrences.

Conclusions: There was good internal consistency between TSR and COVID-19-specific global outcomes, supporting TSR as a trial end point. Requiring >2 days of symptom resolution better addresses natural symptom fluctuations but must be balanced against the potential influence of non-COVID-19 symptoms.

Clinical trials registration: NCT04518410.

Keywords: ACTIV-2; COVID-19; internal validity; patient-reported outcomes; symptom diary; symptom outcomes; symptom rebound; symptom recurrence; time to symptom resolution.