ABSTRACT
Background: There is no valid and reliable patient self-reported measure assessing symptomology among outpatients with COVID-19. The Symptoms Evolution of COVID-19 (SE-C19) is a self-administered new instrument that includes 23 symptoms, each rated for severity at their worst moment within the last 24 hours. We studied the psychometric properties of SE-C19. Methods: Reliability, validity, and sensitivity to change of the SE-C19 were assessed in 657 outpatients with confirmed COVID-19 enrolled in NCT04425629. SE-C19 and Patient Global Impression of Severity (PGIS) were administered daily from baseline (predose at Day 1) to end of study (Day 29). Findings: Most patients (70.0%) were aged [≤]50 years and white (85.5%). At baseline, patients reported an average (SD) of 6.6 (3.9) symptoms (ie, rated as at least Mild) with 3.8 (3.3) of these symptoms being rated as Moderate or Severe. By Day 29, most symptoms had resolved; 74.4% of patients reported no symptoms and on average, only 0.6 (SD 1.5) were reported as at least Mild. Stable patients according to the 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 SE-C19. A symptom resolution endpoint was defined after excluding the item 'Sneezing', due to its low ability to discriminate severity levels, and 'Confusion', 'Rash', and 'Vomiting', due to their low prevalence in this population. Symptoms resolution required complete absence of all remaining items, except 'Cough', 'Fatigue', and 'Headache', which could be Mild or Moderate in severity. Interpretation: We identified 19 items that are valid and reliable to measure disease-related symptoms in COVID-19 outpatients and propose a definition of symptom resolution that could be used in future clinical trials and potentially, also in clinical practice.
Subject(s)
Exanthema , Headache , Vomiting , COVID-19 , ConfusionABSTRACT
Background: Hospitalized patients with Covid-19 experience high mortality rates, ranging from 10-30%. Casirivimab and imdevimab (REGEN-COV) is authorized in various jurisdictions for use in outpatients with Covid-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with REGEN-COV, but in most of the world, anti-spike monoclonal antibody therapy is currently not approved for use in hospitalized patients. Methods: In this phase 1/2/3 double-blind placebo-controlled trial, patients on low-flow or no supplemental oxygen hospitalized with Covid-19 were randomized (1:1:1) to 2.4 g or 8.0 g REGEN-COV or placebo and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response. Results: 1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the LS mean difference (REGEN-COV vs. placebo) for TWA change from baseline viral load was -0.28 log10 copies/mL (95% CI: -0.51, -0.05; P=0.0172). The primary clinical analysis of death or mechanical ventilation from day 6-29 in patients with high-viral load had a strong positive trend but did not reach significance. REGEN-COV reduced all-cause mortality in seronegative patients through day 29 (RRR, 55.6%; 95% CI: 24.2%, 74%). No safety concerns were noted overall nor in seropositive patients. Conclusions: In hospitalized patients with Covid-19 on low-flow or no oxygen, REGEN-COV treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients. (ClinicalTrials.gov number, NCT04426695.)
Subject(s)
COVID-19 , DeathABSTRACT
Importance: At the onset of the COVID-19 pandemic, there was limited understanding of symptom experience and disease progression. Objective: 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. Design: 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 in the Food and Drug Administration patient-reported outcomes guidance and the four methodological Patient-Focused Drug Development Guidances were also considered. Setting: Interviews were conducted virtually with patients recruited through a healthcare research firm. Participants: Semi-structured qualitative interviews were conducted with a purposive sample of 30 non-hospitalized patients with COVID-19 Intervention: Interviews involved two stages: (1) concept elicitation, to obtain information about the symptoms experienced as a result of COVID-19 in 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 interviewed to obtain their insights on symptoms experienced by patients and provide input on the SE-C19. Main Outcome and Measure: Patients reported no issues regarding the relevance or appropriateness of the SE-C19 instructions, including the recall period. The comprehensiveness of the SE-C19 was confirmed against the conceptual model 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 and well understood. The clinicians largely approved all items, response options, and recall period. Conclusions and Relevance: The qualitative research provided supportive evidence of the content validity of the SE-C19 instrument 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. Trial Registration: R10933-10987-COV-2067 (https://clinicaltrials.gov/ct2/show/NCT04425629)
Subject(s)
COVID-19ABSTRACT
Background: REGEN-COV (casirivimab and imdevimab) antibody cocktail reduced SARS-CoV-2 viral load in descriptive analyses of the first 275 Covid-19 outpatients in the phase 1/2 portion of an ongoing double-blind, seamless phase 1/2/3 trial. Methods: This final analysis of the phase 1/2 portion includes 799 patients: 275 (group-1) and 524 (group-2). Patients were randomized (1:1:1) to placebo, 2400mg REGEN-COV, or 8000mg REGEN-COV, and characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive/negative). Efficacy was assessed in patients with a positive baseline RT-qPCR result; safety was assessed in all treated patients. Prespecified hierarchical analyses of virologic endpoints in group-2 were performed to confirm previously reported descriptive analyses from group-1. The proportion of patients with [≥]1 Covid-19-related medically-attended visit (MAV) through day 29 was assessed in group-1+2. Results: Time-weighted average reduction in viral load (log10 copies/ml) through day 7 was significantly greater with REGEN-COV (combined 2400mg+8000mg dose groups) versus placebo in patients with baseline viral load >107 copies/ml (prespecified primary endpoint): -0.68 (95% CI, -0.94 to -0.41; P<0.0001). This reduction was -0.73 (P<0.0001) in serum antibody-negative patients and -0.36 (P=0.0003) in the overall population. Proportions of patients with [≥]1 Covid-19-related MAV were 2.8% (12/434) with REGEN-COV versus 6.5% (15/231) with placebo (P=0.024; relative risk reduction=57%), with greater relative risk reductions in MAVs in patients with [≥]1 risk factor for hospitalization (71%). Adverse events were similar across groups. Conclusions: REGEN-COV treatment of outpatients significantly reduced SARS-CoV-2 viral load and Covid-19-related medically-attended visits. (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.)
Subject(s)
COVID-19ABSTRACT
Background: Coronavirus disease 2019 (COVID-19) is an acute respiratory illness characterised by a range of symptoms. Severe cases of COVID-19 could lead to hospitalisation and intensive care unit admission. However, little is known about the symptomatic experience of outpatients with COVID-19, or its daily life impact; the objective of this qualitative research was to document this experience. Methods: Thirty US adult patients with COVID-19 were interviewed within 21 days of diagnosis. To be included, patients 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. Patients were asked open-ended questions to elicit their symptoms and the impacts COVID-19 had on their daily lives. Interviews were transcribed and inductively coded to perform thematic analysis and propose a conceptual model. The adequacy of the sample size was assessed by conceptual saturation analysis. Five independent clinicians were also interviewed about their experience treating outpatients with COVID-19. Findings: 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, physical impacts, emotional impacts, professional impacts and quarantine-specific impacts). Symptom type, severity, duration and time of onset varied greatly by patient. Clinicians endorsed all symptoms reported by patients. Interpretation: The manifestation of symptoms in outpatient COVID-19 is heterogeneous and affects all aspects of daily life. While reported symptoms were in line with previously published reports, patients offered new detailed insights into their symptomatic experiences and the impacts that symptoms had on their daily lives. Future studies should explore the symptoms and impacts of COVID-19 longitudinally, to better understand their early onset, their progression/resolution and the possible long-term implications of COVID-19. Funding: This research was sponsored and paid for by Regeneron Pharmaceuticals, Inc.
Subject(s)
Dyspnea , Fever , Cough , Vomiting , COVID-19 , Respiratory InsufficiencyABSTRACT
Background: REGEN-COV antibody cocktail (casirivimab with imdevimab) rapidly reduced viral load and decreased medically-attended visits in the phase 1/2 portion of this trial; REGEN-COV, retains activity in vitro against emerging SARS-CoV-2 variants of concern. Methods: The phase 3 portion of this adaptive, randomized, master protocol, included 4,057 Covid-19 outpatients with one or more risk factors for severe disease. Patients were randomized to a single treatment of intravenous placebo, or various doses of REGEN-COV, and followed for 28 days. The prespecified hierarchical analysis first compared REGEN-COV 2400mg dose vs concurrent placebo, then compared the 1200mg dose vs concurrent placebo, for endpoints assessing risk of hospitalization or death, and time to symptom resolution. Safety was evaluated in all treated patients. Results: Both REGEN-COV 2400mg and 1200mg significantly reduced Covid-19-related hospitalization or all-cause death compared to placebo (71.3% reduction [1.3% vs 4.6%; p<0.0001] and 70.4% reduction [1.0% vs 3.2%; p=0.0024], respectively). The median time to resolution of Covid-19 symptoms was 4 days shorter in both dose arms vs placebo (10 vs 14 days; p<0.0001). Efficacy of REGEN-COV was consistent across subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. REGEN-COV more rapidly reduced viral load than placebo. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200mg (1.1%) and 2400mg (1.3%) groups and grade [≥]2 infusion-related reactions were infrequent (<0.3% in all groups). Conclusions: Treatment with REGEN-COV was well-tolerated and significantly reduced Covid-19-related hospitalization or all-cause death, rapidly resolved symptoms, and reduced viral load. (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.)
Subject(s)
COVID-19 , DeathABSTRACT
BACKGROUNDSarilumab (anti-interleukin-6 receptor- monoclonal antibody) may attenuate the inflammatory response in Covid-19. METHODSWe performed an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial of intravenous sarilumab 200 mg or 400 mg in adults hospitalized with Covid-19. The phase 3 primary analysis population (cohort 1) was patients with critical Covid-19 receiving mechanical ventilation (MV) randomized to sarilumab 400 mg or placebo. The primary end point for phase 3 was the proportion of patients with [≥]1-point improvement in clinical status from baseline to day 22. RESULTSFour-hundred fifty-seven (457) and 1365 patients were randomized and treated in phases 2 and 3, respectively. Among phase 3 critical patients receiving MV (n=289; 34.3% on corticosteroids), the proportion with [≥]1-point improvement in clinical status (alive not receiving MV) at day 22 was 43.2% in sarilumab 400 mg and 35.5% in placebo (risk difference [RD] +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P=0.3261), representing a relative risk improvement of 21.7%. Day 29 all-cause mortality was 36.4% in sarilumab 400 mg versus 41.9% in placebo (RD -5.5%; 95% CI, -20.2 to 8.7; relative risk reduction 13.3%). In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio (HR) for death in sarilumab 400 mg compared with placebo was 0.76 (95% CI, 0.51 to 1.13) overall, improving to 0.49 (95% CI, 0.25 to 0.94) in patients receiving corticosteroids at baseline. CONCLUSIONIn hospitalized patients with Covid-19 receiving MV, numerical benefits with sarilumab did not achieve statistical significance, but benefit may be greater in patients receiving corticosteroids. A larger study is required to confirm this observed numerical benefit. (ClinicalTrials.gov number, NCT04315298)
Subject(s)
COVID-19ABSTRACT
Background: Elucidating the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and clinical outcomes is critical for understanding COVID-19.Methods: SARS-CoV-2 levels were analysed by quantitative real-time polymerase chain reaction (RT-qPCR) of naso- or oro-pharyngeal swab specimens collected at baseline and clinical outcomes were recorded over 60 days from 1362 COVID-19 hospitalised patients enrolled in a multi-center, randomized, placebo-controlled phase II/III trial of sarilumab for COVID-19 (NCT04315298).Findings: In post-hoc analyses, higher baseline viral load, measured by both RT-qPCR cycle threshold (Ct) and log10 copies/mL, was associated with greater supplemental oxygenation requirements and disease severity at study entry. Higher baseline viral load was associated with higher mortality, lower likelihood of improvement in clinical status and supplemental oxygenation requirements, and lower rates of hospital discharge. Viral load was not impacted by sarilumab treatment over time compared with placebo.Interpretation: These data support viral load as an important determinant of clinical outcomes in hospitalized patients with COVID-19 requiring supplemental oxygen or assisted ventilation.Trial Registration: NCT04315298Funding Statement: Supported by Regeneron Pharmaceuticals, Inc. and Sanofi. Certain aspects of this project have been funded in whole or in part with federal funds from the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number: HHSO100201700020C.Declaration of Interests: All authors are employees or employees and shareholders of Regeneron Pharmaceuticals, Inc.Ethics Approval Statement: The local institutional review board or ethics committee at each centre oversaw trial conduct and documentation. All patients provided written informed consent before participation. Ethics approval was obtained from the following ethics review boards: WCG IRB, Puyallup, WA (IRB00000533); Oregon Health & Science University, Portland, OR (MOD00027616); Institutional Review Board University of Florida, Gainesville, FL (IRB202000779); Columbia University, Human Research Protection Office and IRBs, New York, NY (IRB-AAAS9615); Johns Hopkins Medicine, Office of Human Subjects Research, IRB, Baltimore, MD (IRB00246576/CIR00058074); NYU School Of Medicine, New York, NY (I20-00351_MOD03); Northwestern University IRB, Chicago, IL (STU00212239-MOD0012); Westchester Medical Center, NY Medical College, Office of Research Administration, Valhalla, NY (IRBReg#00000428); Portland Health and Services IRB Providence – St. Johns, Portland, OR (MOD2020001024); Cornell Weill Medicine IRB, New York, NY (IRB00009419); Providence St. Joseph IRB, Renton, WA (MOD2020001029); Providence Health and Services IRB, Portland, OR (MOD2020000519); Ascension St. John Hospital, Tulsa, OK (IRB#00001980); Geisinger IRB, Danville, PA (IRB#0008345).
Subject(s)
COVID-19 , Coronavirus Infections , Severe Acute Respiratory Syndrome , Sleep Disorders, Circadian RhythmABSTRACT
Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in nature or identified from preclinical in vitro and in vivo studies and in the clinic. This study demonstrates that a combination of non-competing antibodies not only provides full coverage against currently circulating variants but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.