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

Publication date: Aug 31, 2023

Time to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation. 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. 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. 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. NCT04518410.

Concepts Keywords
Coronavirus ACTIV-2
Daily Ambulatory Care
Hispanic COVID-19
Nct04518410 COVID-19
Outpatient COVID-19 Drug Treatment
internal validity
Middle Aged
patient-reported outcomes
symptom diary
symptom outcomes
symptom rebound
symptom recurrence


Type Source Name
disease VO time
disease IDO symptom
disease MESH COVID-19
disease VO frequency
drug DRUGBANK Tropicamide

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