Reliability and Validity of an Instrument of COVID-19 Patient-Reported Symptoms in Outpatients.

Importance: Patient-reported outcome instruments are key in assessing COVID-19-related symptoms and associated burden. However, a valid and reliable instrument to assess symptom severity and progression among outpatients with COVID-19 is not yet available. Objectives: To assess the extent to which the Symptoms Evolution of COVID-19 (SE-C19) instrument is valid, reliable, and able to detect symptom changes in outpatients with COVID-19, as well as to establish a definition of symptom resolution. Design, Setting, and Participants: In this diagnostic/prognostic study, psychometric properties of SE-C19 were assessed in participants recruited into an ongoing, adaptive, phase 1/2/3, randomized, double-blind, placebo-controlled clinical trial, during 2020 to 2022. Adult outpatients with symptomatic COVID-19 were randomized 1:1:1 to receive 2.4 g or 8.0 g intravenous casirivimab and imdevimab or placebo, in outpatient centers at 114 sites, from 2 countries (US and Mexico). Main Outcomes and Measures: Reliability, validity, and sensitivity to change of the SE-C19 were assessed. SE-C19 and Patient Global Impression of Severity (PGIS) were administered daily from predose at day 1 to day 29. Results: Analysis was conducted on 657 adult outpatients (342 female patients [52.1%], 562 White patients [85.5%]), and 337 non-Hispanic patients [51.3%]. At baseline, patients reported a mean (SD) of 6.6 (3.9) symptoms (ie, rated as at least mild) with a mean (SD) of 3.8 (3.3) of these symptoms being rated as moderate or severe. Stable patients according to PGIS showed scores with intraclass correlation values indicating moderate-to-good test-retest reliability (ie, 0.50-0.90). At baseline, 20 item scores (87%) varied significantly across PGIS-defined groups, supporting the validity of the SE-C19. A symptom-resolution end point was defined after excluding the item sneezing due to its low ability to discriminate severity levels, and excluding confusion, rash, and vomiting, due to their low prevalence in this population. Symptom resolution required complete absence of all remaining items, except cough, fatigue, and headache, which could be mild or moderate in severity. A total of 19 of 23 items from the SE-C19 instrument were identified as valid and reliable to measure disease-related symptoms in outpatients with COVID-19. Conclusions and Relevance: This study identified 19 items that are valid and reliable to measure disease-related symptoms in outpatients with COVID-19, and proposed a definition of symptom resolution for potential use in future clinical trials.

Patient experience of symptoms and impacts of COVID-19: a qualitative investigation with symptomatic outpatients.

OBJECTIVES: There is little in-depth qualitative evidence of how symptoms manifest themselves in outpatients with COVID-19 and how these in turn impact outpatients' daily lives. The objective of the study was therefore to explore the experience of outpatients with COVID-19 qualitatively, concerning the symptomatic experience and its subsequent impact on daily life. SETTING: Qualitative research study comprising virtual in-depth, open-ended interviews with outpatients and clinicians. PARTICIPANTS: Thirty US adult patients with COVID-19 were interviewed within 21 days of diagnosis. Patients were 60% female and 87% white, who had to self-report one of the following: fever, cough, shortness of breath/difficulty breathing, change/loss of taste/smell, vomiting/diarrhoea or body/muscle aches. Five independent clinicians were also interviewed about their experience treating outpatients. PRIMARY AND SECONDARY OUTCOME MEASURES: Transcripts were analysed thematically to organise symptoms and impacts of daily life into higher-order overarching categories, and subsequently propose a conceptual model. The adequacy of the sample size was assessed by conceptual saturation analysis. RESULTS: Patient-reported concepts were organised into six symptom themes (upper respiratory, lower respiratory, systemic, gastrointestinal, smell and taste, and other) and seven impact themes (activities of daily living, broad daily activities, leisure/social activities, and physical, emotional, professional and quarantine-specific impacts). Symptom type, severity, duration and time of onset varied by patient. Clinicians endorsed all patient-reported symptoms. CONCLUSIONS: The manifestation of symptoms in outpatients is heterogeneous and affects all aspects of daily life. Outpatients offered new detailed insights into their symptomatic experiences, including heterogeneous experiences of smell and taste, and the impacts that symptoms had on their daily lives. Findings of this research may be used to supplement existing knowledge of the outpatient experience of mild-to-moderate COVID-19, to further inform treatment guidelines and to provide an evidence base for evaluating potential treatment benefits.

Development and content validation of the Symptoms Evolution of COVID-19: a patient-reported electronic daily diary in clinical and real-world studies.

BACKGROUND: At the onset of the COVID-19 pandemic, there was limited understanding of symptom experience and disease progression. We developed and validated a fit-for-purpose disease-specific instrument to assess symptoms in patients with COVID-19 to inform endpoints in an interventional trial for non-hospitalized patients. METHODS: The initial drafting of the 23-item Symptoms Evolution of COVID-19 (SE-C19) Instrument was developed based on the Centers for Disease Control and Prevention symptom list and available published literature specific to patients with COVID-19 as of Spring 2020. The measurement principles outlined in the Food and Drug Administration (FDA) Patient-Reported Outcomes (PRO) guidance and the FDA's series of four methodological Patient-Focused Drug Development guidance documents were also considered. Following initial development, semi-structured qualitative interviews were conducted with a purposive sample of 30 non-hospitalized COVID-19 patients. Interviews involved two stages: (1) concept elicitation, to obtain information about the symptoms experienced as a result of COVID-19 in the patients' own words, and (2) cognitive debriefing, for patients to describe their understanding of the SE-C19 instructions, specific symptoms, response options, and recall period to ensure the content of the SE-C19 is relevant and comprehensive. Five clinicians treating COVID-19 outpatients were also interviewed to obtain their insights on symptoms experienced by patients and provide input on the SE-C19. RESULTS: Patients reported no issues regarding the relevance or appropriateness of the SE-C19 instructions, including the 24-h recall period. The comprehensiveness of the SE-C19 was confirmed against the conceptualization of the patient experience of symptoms developed in the qualitative research. Minor conceptual gaps were revealed to capture nuances in the experience of nasal and gustatory symptoms and systemic manifestations of sickness. Almost all items were endorsed by patients as being appropriate, well understood, and easy to respond to. The clinicians largely approved all items, response options, and recall period. CONCLUSIONS: The qualitative research provided supportive evidence of the content validity of the SE-C19 to assess the symptoms of outpatients with COVID-19, and its use in clinical trials to evaluate the benefit of treatment. Minor changes may be considered to improve conceptual clarity and ease of responding.

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19.

BACKGROUND: In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. METHODS: In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated. RESULTS: Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log10 copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log10 copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups. CONCLUSIONS: REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.

BACKGROUND: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. METHODS: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients. RESULTS: Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group. CONCLUSIONS: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).