ABSTRACT
BACKGROUND: COVID-19 vaccines have lessened the effects of the ongoing pandemic. Those vaccinated are less likely to be hospitalized than unvaccinated and, if hospitalized, have better outcomes. The literature is less developed on the effect of vaccination on disease burden and symptomatology in outpatient settings. We compared the symptom severity from SARS-CoV-2 infection among unvaccinated with those vaccinated within 6 months. We hypothesized that vaccinated individuals will have less symptom burden than unvaccinated. METHODS: We compared the proportion of COVID-19 symptoms at baseline from participants enrolled in the COVID-OUT trial, an outpatient treatment trial of SARS-CoV-2 infection. Adults aged 30-85 with a body mass index >= 25kg/m2 were eligible within 3 days of a positive COVID-19 test;symptoms not required but must be <7 days if present. 413 patients were enrolled through September 12, 2021. Of those, only 124 unvaccinated and 68 vaccinated within 6 months of enrollment provided baseline symptom data. We compared unvaccinated with those vaccinated using Fisher's Exact tests. We computed a total symptom score for each participant reflecting symptom severity and total number of symptoms, assigning numeric values to each grade of symptom severity (mild, moderate, severe), with more points given for higher severity. Treating the total symptom score as continuous, we fit a linear regression model to assess the association between total symptom score and vaccination status. RESULTS: A larger proportion of unvaccinated versus vaccinated reported chills/shivering (19% vs. 6%;p=0.01), diarrhea in the last 24 h (19% vs. 3%;p<0.01), feeling hot or feverish (30% vs. 6%;p<0.01), body aches (55% vs. 26%;p<0.01), and nausea (19% vs. 6%;p=0.02). A larger proportion of vaccinated versus unvaccinated had a stuffy/runny nose (56% vs. 35%;p<0.01). There was no significant difference in cough, headache, loss of smell or taste, fatigue, shortness of breath, difficulty breathing, sore throat, or vomiting between groups. The mean total symptom score for unvaccinated participants was 13.6 (95% CI: (12.4, 14.8)), significantly larger than the vaccinated average score of 11.2 (95% CI: (9.5, 12.8)) (p = 0.02). CONCLUSIONS: There appears to be an association between vaccination and symptom type and severity from COVID-19. Unvaccinated individuals reported more systemic symptoms (fever, chills, and diarrhea);Vaccinated reported more mucosal symptoms (runny nose). This difference could be due to differing IgG and IgA responses to vaccination and decline over time. Although vaccination was associated with a significantly lower total symptom score than those unvaccinated, the small difference may not track with functional outcomes such as return to work.
ABSTRACT
BACKGROUND: Traditionally, randomized clinical trials have relied on physical research centers to support subject recruitment and participation. The COVID-19 pandemic has highlighted the need to interact with subjects who are unable to physically visit research centers. By leveraging remote technology, such clinical trials may reach subjects in isolation and broaden geographical reach. We describe a fully remote, multisite randomized controlled clinical trial of outpatient COVID-19 treatments using a technologyenabled, decentralized approach. METHODS: We conducted a remote double-blind, randomized placebocontrolled trial (COVID-OUT). We identified subjects through medical records, patient advocacy groups, testing facilities, and multiformat advertising. They were recruited via brochure, electronic message, telephone outreach, and self-referral. Research staff across sites used the Research Electronic Data Capture (REDCap) system to manage local and central enrollment and were reallocated dynamically based on trial needs. Subjects were screened by phone, consented and randomized electronically and delivered study medication by courier or same-day mail. They were followed via their preferred communication method (phone, video, text, or email) to determine the study endpoints. RESULTS: 1195 non-hospitalized adults aged 30-85 years with laboratory confirmed infection with SARS-CoV-2 were enrolled into the COVID-OUT trial through January 6, 2022 over a span of 7 months. Initially starting as a 2- arm trial with 7 sites, the study expanded to a 6-arm trial with recruitment at 8 sites. To date, 9600 subjects have been screened with an enrollment rate of 12% from 822 zip codes. 25 research coordinators are involved across 8 sites, and the rate of study completion is 90%. CONCLUSIONS: Decentralized remote studies offer an efficient, low-touch way of performing research in the COVID-19 era. Our decentralized study design enables research with infectious, isolated subjects in widespread geographies, while maintaining safety of subjects, the research team, and public atlarge. Coordination across sites via RED Cap enabled programmatic efficiencies, including the ability to redistribute staffing support across enrollment sites for study drug distribution, follow-up calls, recruitment, and event reporting. We decreased overall costs by less need for physical research space. The decentralized infrastructure enabled nimble adaptations of the protocol, including increasing follow-up periods to assess long-COVID symptoms and adding study arms for additional outpatient treatments. Given the widespread availability of mobile phones and remote communication, decentralized trials show promise for improving reach and efficiency in both pandemic and nonpandemic times.
ABSTRACT
BACKGROUND: Breakthrough infection for COVID-19 post-vaccination are common. Data conflict on if vaccination decreases severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral load. We compared baseline symptoms and viral load between vaccinated and unvaccinated adults enrolled in a randomized trial of early outpatient COVID-19 treatment using generic medications. METHODS: The first 433 sequential participants enrolled in the COVIDOUT trial (prior to 9/12/21), a phase 3, double-blind, factorial design, place bocontrolled trial, were analyzed. Adults aged 30-85 with a body mass index (BMI) >= 25kg/m2 were eligible within 3 days of a positive COVID test and <7 days of symptoms. Log10 PCR viral loads were normalized to human RNase P by time from vaccination, vaccine status and symptoms. Participants were divided into viral load tertiles to analyze differences in proportion of participants reporting moderate or severe symptoms at baseline. RESULTS: Of 433 participants, 272 had known vaccine status and contributed optional nasal swabs for viral load measurement with a median age of 46 years and a median BMI of 31.2 kg/m 2 (IQR, 27.4, 36.4). Overall, 159 (58%) were women and 217 (80%) were white. The mean relative log10 viral load for those vaccinated <6 months from infection was 0.11 (95% CI, -0.48, 0.71), significantly lower than the unvaccinated (n=160, p=0.01). Those vaccinated >= 6months did not differ from the unvaccinated in viral load (mean 0.99, 95% CI, -0.41 to 2.40;p=0.85). The proportion of participants significantly varied by viral load tertiles for subjective fever, loss of smell, loss of taste, fatigue, myalgia, and stuffy/runny nose (all p<=0.02). The middle tertile contained the largest proportion of participants for each of these symptoms besides stuffy/ runny nose. There was no significant difference between viral load tertile groups at baseline for chills, cough, diarrhea, headache, nausea, dyspnea, sore throat, and vomiting (Figure 1). CONCLUSIONS: These data suggest vaccination within 6 months of infection is associated with a lower viral load, with viral loads returning to prevaccination levels after 6 months. Increased viral load was associated with worse fever, loss of smell/taste, fatigue, myalgia, and stuffy/runny nose.