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Clinical Trial
. 2023 Aug 31;228(Suppl 2):S83-S91.
doi: 10.1093/infdis/jiad300.

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

Kara W Chew  1 , Carlee Moser  2 , Eunice Yeh  2 , David A Wohl  3 , Eric S Daar  4 , Justin Ritz  2 , Arzhang Cyrus Javan  5 , Joseph J Eron  3 , Judith S Currier  1 , Davey M Smith  6 , Michael D Hughes  2 ; ACTIV-2/A5401 Study Team
Affiliations
Clinical Trial

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

Kara W Chew et al. J Infect Dis. .

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.

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Conflict of interest statement

Potential conflicts of interest . K. W. C. reports research funding to the institution from Merck Sharp & Dohme; and is a consultant for Pardes Biosciences. D. A. W. has received funding to the institution to support research; and honoraria for advisory boards and consulting from Gilead Sciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; and research support through the institution from Gilead Sciences and GSK/ViiV. J. J. E. is an ad hoc consultant to GSK/VIR; and data monitoring committee chair for Adagio phase 3 studies. J. S. C. has consulted for Merck and Company. D. M. S. has consulted for Evidera, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Reported symptom severity on each study day: (A) worst symptom severity recorded across all 13 targeted symptoms among high-risk participants; (B) worst symptom severity recorded across all 13 targeted symptoms among standard-risk participants; (C) symptom severity by overall COVID-19 symptoms assessment among high-risk participants; and (D) symptom severity by overall COVID-19 symptoms assessment among standard-risk participants. C and D, Response options were “no symptoms,” “mild,” “moderate,” “severe,” and “very severe.” No participants recorded “very severe” symptoms.
Figure 2.
Figure 2.
Reported return to health status on each study day among (A) high-risk and (B) standard-risk participants, and percentage of participants reporting presence of each of the 13 targeted symptoms among (C) high-risk and (D) standard-risk participants. C and D, Symptoms are ordered by ascending prevalence at day 0. Abbreviations: SOB, shortness of breath; diff, difficulty; obst/cong, obstruction/congestion.
Figure 3.
Figure 3.
Internal validity of time to sustained resolution of all targeted symptoms (for 2 days) measure for high- and standard-risk participants. Presented are scatterplots of time to sustained resolution of all targeted symptoms for 2 days (primary outcome measure) against time to sustained resolution of overall COVID-19 symptoms (for 2 days) and time to sustained return to health (for 2 days) for high-risk participants (A and B) and standard-risk participants (C and D). Spearman rank correlations assessed the association between the measures. Circles indicate times that were observed for both outcomes; crosses indicate times that were censored because of end of diary follow-up (values of 27 for 1 or both outcomes) or premature discontinuation of diary completion (values less than 27 for 1 or both outcomes).
Figure 4.
Figure 4.
Pattern of daily diary entries for the outcome of time to sustained (2 days) targeted symptom resolution for (A) high-risk and (B) standard-risk groups. Each row represents a participant. Meeting the outcome of all targeted symptoms resolved is given by a black dot. Green, orange, and purple boxes indicate days on which participants recorded at least 1 of 13 targeted symptoms being present (self-reported severity of mild, moderate, or severe) in their symptom diary. The color of the box reflects the worst symptom severity reported of all symptoms recorded as being present (green box if the worst severity reported was mild, orange box if the worst severity was moderate, and purple box if the worst severity was severe). An x indicates days when no data were recorded. Participants are grouped by outcome, from the top of the figure down: participants who never met the outcome, participants who met the outcome and did not report recurrent symptoms (ie, stayed resolved), and participants who met the outcome but subsequently reported recurrence of at least 1 targeted symptom.
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