Psychometric evaluation of the Symptoms of Infection with Coronavirus-19 (SIC): results from a cross-sectional study and a phase 3 clinical trial.

BACKGROUND: The Symptoms of Infection with Coronavirus-19 (SIC) is a 30-item patient-reported outcome (PRO) measure scored by body system composites to assess signs/symptoms of coronavirus disease 2019 (COVID-19). In addition to cross-sectional and longitudinal psychometric evaluations, qualitative exit interviews were conducted to support the content validity of the SIC. METHODS: In a cross-sectional study, adults diagnosed with COVID-19 in the United States completed the web-based SIC and additional PRO measures. A subset was invited to participate in phone-based exit interviews. Longitudinal psychometric properties were assessed in ENSEMBLE2, a multinational, randomized, double-blind, placebo-controlled, phase 3 trial of the Ad26.COV2.S COVID-19 vaccine. Psychometric properties evaluated included structure, scoring, reliability, construct validity, discriminating ability, responsiveness, and meaningful change thresholds of SIC items and composite scores. RESULTS: In the cross-sectional study, 152 participants completed the SIC (mean age, 51.0 ± 18.6 years) and 20 completed follow-up interviews. Fatigue (77.6%), feeling unwell (65.8%), and cough (60.5%) were symptoms most frequently reported. SIC inter-item correlations were all positive and mostly moderate (r ≥ 0.3) and statistically significant. SIC items and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) scores correlated as hypothesized (all r ≥ 0.32). Internal consistency reliabilities of all SIC composite scores were satisfactory (Cronbach's alpha, 0.69-0.91). SIC composite scores correlated moderately (r = 0.30-0.49) to strongly (r ≥ 0.50) with PROMIS-29 scores and Patient Global Impression of Severity (PGIS) ratings (all P < 0.01). A variety of signs/symptoms were cited in exit interviews, and participants considered the SIC straightforward, comprehensive, and easy to use. From ENSEMBLE2, 183 participants with laboratory-confirmed moderate to severe/critical COVID-19 were included (51.5 ± 14.8 years). Strong test-retest reliabilities were observed for most SIC composite scores (intraclass correlations ≥ 0.60). Statistically significant differences across PGIS severity levels were found for all but 1 composite score, supporting known-groups validity. All SIC composite scores demonstrated responsiveness based on changes in PGIS. CONCLUSIONS: The psychometric evaluations provided strong evidence for the reliability and validity of the SIC for measuring COVID-19 symptoms, supporting its use in vaccine and treatment trials. In exit interviews, participants described a broad range of signs/symptoms consistent with previous research, further supporting the content validity and format of the SIC.

Coronavirus disease 2019 (COVID-19) is a serious disease that continues to evolve globally. Researchers developed the Symptoms of Infection with Coronavirus-19 (SIC), a 30-item questionnaire designed for patients to report signs and symptoms of COVID-19. In this study, the researchers formally analyzed how well the SIC measures the patient experience with COVID-19, using survey and clinical trial data as well as telephone interviews. Adults with COVID-19 and at least 2 bothersome symptoms completed the web-based survey, and some of these individuals also participated in in-depth interviews. Participants in a clinical trial for a COVID-19 vaccine also completed the SIC measure. The SIC was compared with other commonly used questionnaires that evaluate patient experience. The most commonly reported symptoms of COVID-19 were fatigue, feeling unwell, cough, weakness, and headache. The items for individual symptoms (e.g., "cough") and combined scores for body systems (e.g., "respiratory system") performed well in statistical analyses. Participants found the SIC to be straightforward, comprehensive, and easy to use. The SIC may prove useful in the future for vaccine and treatment trials for COVID-19.

Efficacy and Safety of an Ad26.RSV.preF-RSV preF Protein Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) can cause serious lower respiratory tract disease in older adults, but no licensed RSV vaccine currently exists. An adenovirus serotype 26 RSV vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) in combination with RSV preF protein was previously shown to elicit humoral and cellular immunogenicity. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b, proof-of-concept trial to evaluate the efficacy, immunogenicity, and safety of an Ad26.RSV.preF-RSV preF protein vaccine. Adults who were 65 years of age or older were randomly assigned in a 1:1 ratio to receive vaccine or placebo. The primary end point was the first occurrence of RSV-mediated lower respiratory tract disease that met one of three case definitions: three or more symptoms of lower respiratory tract infection (definition 1), two or more symptoms of lower respiratory tract infection (definition 2), and either two or more symptoms of lower respiratory tract infection or one or more symptoms of lower respiratory tract infection plus at least one systemic symptom (definition 3). RESULTS: Overall, 5782 participants were enrolled and received an injection. RSV-mediated lower respiratory tract disease meeting case definitions 1, 2, and 3 occurred in 6, 10, and 13 vaccine recipients and in 30, 40, and 43 placebo recipients, respectively. Vaccine efficacy was 80.0% (94.2% confidence interval [CI], 52.2 to 92.9), 75.0% (94.2% CI, 50.1 to 88.5), and 69.8% (94.2% CI, 43.7 to 84.7) for case definitions 1, 2, and 3, respectively. After vaccination, RSV A2 neutralizing antibody titers increased by a factor of 12.1 from baseline to day 15, a finding consistent with other immunogenicity measures. Percentages of participants with solicited local and systemic adverse events were higher in the vaccine group than in the placebo group (local, 37.9% vs. 8.4%; systemic, 41.4% vs. 16.4%); most adverse events were mild to moderate in severity. The frequency of serious adverse events was similar in the vaccine group and the placebo group (4.6% and 4.7%, respectively). CONCLUSIONS: In adults 65 years of age or older, Ad26.RSV.preF-RSV preF protein vaccine was immunogenic and prevented RSV-mediated lower respiratory tract disease. (Funded by Janssen Vaccines and Prevention; CYPRESS ClinicalTrials.gov number, NCT03982199.).

Development of patient- and observer-reported outcome measures to assess COVID-19 signs and symptoms in children and adolescents.

BACKGROUND: The Symptoms of Infection with Coronavirus-19 (SIC) is a 30-item patient-reported outcome measure to evaluate the presence and severity of COVID-19 signs/symptoms in adults. This study expanded the context of use of the adult SIC among adolescents aged 12-17 years and supported a pediatric adaptation (the Pediatric SIC [PedSIC]) for caregiver assessment of signs/symptoms in children aged < 12 years. METHODS: Draft versions of the PedSIC and reference materials containing sign/symptom definitions for adolescents, based on an assessment of the reading level of SIC items by a professional linguist, were developed to facilitate accurate completion of the SIC by adolescents and observer-report (PedSIC) by caregivers. For adolescents, reference materials were intended to provide definitions for selected signs/symptoms identified to have a higher reading level. Iterative rounds of cognitive debriefing interviews were conducted from November 2020 to January 2021 to evaluate adolescent understanding of the SIC reference materials and inform refinement of the PedSIC for caregivers of children too young to reliably self-report. Participants were identified via databases of individuals who previously expressed interest in participating in qualitative research and were then screened for eligibility. Recruitment quotas were established to improve sample diversity. Thematic analysis and descriptive statistics were used to assess qualitative and demographic data, respectively. RESULTS: Nine healthy adolescents (mean [SD, range] age, 14 [1.76, 12-17] years, 56% female, 22% non-White; round 1, n = 6; round 2, n = 3) and 17 caregivers (mean [SD, range] age, 34 [6.28, 26-41] years, 59% female, 35% non-White; round 1, n = 9; round 2, n = 8) were interviewed. Adolescents understood the majority of signs/symptoms (22 of the 30 SIC items) without assistance or use of the reference materials during the cognitive debriefing interview. Definitions were added to the reference materials for 5 additional items, and clarifications provided to existing definitions for 3 items. Seven observer-report (PedSIC) items were modified following feedback from caregivers of healthy young children. Reference materials (similar to those for adolescent use) were developed to support caregiver understanding of the intent of the PedSIC items collecting input from children ages ≥ 5- < 12 years. CONCLUSIONS: Results support using the SIC, PedSIC, and their associated reference materials to evaluate the presence and severity of COVID-19 signs/symptoms in adolescents and children aged < 12 years via caregiver-supported report, respectively.

Development of a novel patient-reported outcome measure to assess signs and symptoms of COVID-19.

BACKGROUND: Given the urgent need for vaccines and treatments for coronavirus disease 2019 (COVID-19), the Symptoms of Infection with Coronavirus-19 (SIC), a comprehensive, patient-reported outcome (PRO) measure of signs and symptoms associated with COVID-19, was developed in full alignment with current US regulatory guidance to support evaluations of vaccines and treatments in development. METHODS: An initial version of the SIC was developed to address concepts identified through a targeted literature review and consultation with experts in infectious diseases and clinicians routinely managing COVID-19 in a hospital setting. A qualitative study was conducted in sites in the United States among 31 participants aged ≥ 18 years who were English-speaking and willing and able to provide informed consent and a self-reported history by telephone or online method. The measure was refined based on additional feedback from the clinicians and three iterative rounds of combined concept elicitation and cognitive debriefing interviews conducted with patients, caregivers, and healthy volunteers. RESULTS: Among 39 scientific articles identified in the literature review, 35 COVID-19 signs and symptoms were reported and confirmed during interviews with clinicians, patients, and caregivers. Patients and healthy participants suggested changes for refining the draft SIC to ensure consistent interpretation and endorsed both the 24-h recall period and use of an 11-point numeric rating scale (NRS) for capturing change in symptom severity. The final version of the SIC captures the daily presence or absence of 30 symptoms and a rating of severity for 25 of the 30 symptoms using an NRS for those symptoms reported as present. CONCLUSIONS: The SIC comprehensively addresses observations described in the literature, by clinicians, and by patients, and captures patients' experiences with COVID-19 in a manner that minimizes complexity and facilitates completion for both patients and healthy volunteers. This measure is thus appropriate for use in clinical trials of both therapeutics and vaccines for COVID-19.