BACKGROUND:Electronic medical record database studies suggest that underlying allergic diathesis is a risk factor for COVID-19 but may attenuate outcomes. OBJECTIVE:To evaluate the effect of background atopic conditions on outcomes across clinical trials in patients with and without COVID-19 treated with casirivimab plus imdevimab (CAS + IMD). METHODS:This analysis included 4057 outpatients with acute COVID-19. Supplementary analyses involved 2652 patients without COVID-19, investigating prevention in the home or community settings. Participants were randomized to CAS + IMD or placebo. Participants with atopic conditions were identified by medical history and categorized as follows: (1) any atopic condition; (2) atopic conditions excluding asthma; (3) asthma excluding other atopic conditions; and (4) no atopic conditions. Assessments included time to hospitalization/death and change in viral load from baseline to day 7 analyzed using adjusted regression methodologies. RESULTS:Among placebo subjects, the adjusted risk of hospitalization/death was 52% lower in those with an atopic background without asthma vs those without atopy (hazard ratio [HR]: 0.48; 95% CI, 0.31-0.74; P < .001). The adjusted risk of hospitalization/death in patients receiving placebo was 2.90 times higher for those with asthma only vs those without atopic conditions (HR, 2.90; CI, 1.55-5.48; P < .001). The HR for hospitalization/death for CAS + IMD vs placebo was 0.26 for patients without atopy (CI, 0.12-0.58; P < .001), 0.17 (CI, 0.06-0.49; P < .001) for patients with atopic conditions excluding asthma, and 0.32 (CI, 0.16-0.63; P < .001) for those with asthma only. In the prevention studies, unvaccinated subjects with atopic conditions excluding asthma exhibited more than 2-fold increase in the rate of contracting COVID-19 vs those without atopy (HR, 2.10; CI, 1.05-4.21; P = .037). Adjustment for imbalance in antihistamine use had little effect on estimates. CONCLUSION:In COVID-19 prevention and treatment, atopic disease was associated with heightened susceptibility to infection but better clinical outcomes. CAS + IMD improved clinical outcomes in both cases.

BACKGROUND:Chronic pain due to osteoarthritis (OA) causes considerable burden, and current treatment options are limited. This phase III study aimed to compare the efficacy and safety of fasinumab, an investigational, anti-nerve growth factor monoclonal antibody, with placebo and naproxen in patients with moderate-to-severe pain due to OA of the knee or hip. METHODS:Patients with difficult-to-treat OA were randomised 3:3:3:1 to fasinumab 1 mg subcutaneous (SC) every 4 weeks (Q4W), fasinumab 1 mg SC every 8 weeks (Q8W), naproxen 500 mg orally two times a day or placebo. The co-primary endpoints were changes in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain and physical function subscale scores (0-10) from baseline to week 16 for fasinumab versus placebo; comparison with naproxen was a secondary endpoint. Safety was also assessed. RESULTS:Of 3307 patients randomised, 1801 were included in the analysis for efficacy, and 3014 were included in the safety analysis. Statistically significantly greater reductions in the WOMAC pain and physical function scores, respectively, at week 16 were seen for fasinumab 1 mg Q4W (-2.90 and -2.78) compared with placebo (-2.32 and -2.10) and naproxen (-2.61 and -2.41); all p<0.005. Adjudicated arthropathies (AAs) and joint replacements occurred in all treatment groups, but were higher in the fasinumab 1 mg Q8W and 1 mg Q4W groups than in the placebo and naproxen groups. Patients with AAs: 7.2%, 9.7%, 1.1% and 2.6%, respectively; patients with joint replacements: 5.6%, 6.4%, 3.4% and 3.1%, respectively. Of the AAs in the fasinumab arms, 95.0% and 75.5% were rapid-progressive OA type 1 in the 1 mg Q8W and 1 mg Q4W arms, respectively. No new safety concerns were identified. CONCLUSION:In a difficult-to-treat population with OA, fasinumab 1 mg Q4W achieved clinically meaningful improvements by week 16 versus placebo and naproxen. The safety profile was similar to that previously observed for fasinumab. TRIAL REGISTRATION NUMBER:NCT03161093.

Purpose:Casirivimab and imdevimab (CAS+IMD) has been shown to improve clinical outcomes (death/mechanical ventilation) in seronegative hospitalized patients with COVID-19. The objective of the current analysis was to assess whether time to administration of CAS+IMD, from the start of COVID-19 symptoms, influenced these outcomes. Patients and Methods:This was a post hoc analysis of Study 2066 (conducted between 10 June 2020 and 9 April 2021), a Phase I/II/III trial investigating the safety and efficacy of CAS+IMD (single intravenous dose) vs placebo in hospitalized adult patients with COVID-19. The primary outcome in this analysis was death or mechanical ventilation. Two populations of patients were assessed: efficacy (n = 738) and exploratory (full analysis set-exploratory data analysis [FAS-EDA]; n = 1115). Time to administration was defined as the number of days of COVID-19 prior to treatment, 4 days being the first quartile, which was considered early treatment administration of CAS+IMD. Results:Odds of death or mechanical ventilation were higher in those aged 50-70 years (odds ratio [OR]: 2.98; 95% confidence interval [CI], 1.62-5.91; P = 0.0008) and >70 years (OR: 4.50; 95% CI, 2.45-8.96; P = 0.001) than those aged <50 years. Overall, patients who received CAS+IMD <4 days after first COVID-19 symptoms had better outcomes than patients receiving CAS+IMD ≥4 days, on adjusted analyses (efficacy OR: 0.42; 95% CI, 0.20-0.80; P = 0.0122; FAS-EDA OR: 0.63; 95% CI, 0.38-1.01; P = 0.0664). These differences were most notable in those aged 50-70 years (OR: 0.24; 95% CI, 0.05-0.70; P = 0.0219). Conclusion:Early monoclonal antibody treatment is associated with better outcomes in hospitalized patients with severe COVID-19.

OBJECTIVE:Fasinumab is an investigational, fully-human, monoclonal antibody against nerve growth factor. Studies have shown that patients treated with fasinumab have statistically and clinically significant improvements in pain and physical function, but more frequently experience joint‑related adverse events compared with placebo-treated patients. This post hoc analysis explored biological changes associated with fasinumab therapy. DESIGN:Changes in bone and mineralization markers (total alkaline phosphatase, bone-specific alkaline phosphatase [BSAP], procollagen type 1 N-terminal propeptide [P1NP], osteocalcin, and type I collagen cross-linked C-telopeptide) and inflammation (C-reactive protein [CRP]) were analyzed alongside magnetic resonance imaging in patients from Phase 2 and 3 clinical studies evaluating fasinumab in patients with osteoarthritis of the knee or hip. RESULTS:In total, 5772 patients were included in this analysis. Dose-related increases in markers of bone formation/mineralization (alkaline phosphatase, BSAP, osteocalcin, and P1NP) were observed following treatment with fasinumab. Patients with arthropathies showed larger increases in alkaline phosphatase when compared with patients without (6 mg Q8W difference 10.36 U/L, 95% CI: 0.06-20.66 U/L at Week 16). Increases in CRP were also noted following fasinumab treatment, and again, larger increases were seen in patients with arthropathies versus those without (6 mg Q8W difference 3.09 mg/L, 95% CI: 0.07-6.12 mg/L at Week 16). Increases in CRP returned to near baseline levels following the last fasinumab treatment. CONCLUSIONS:In this post hoc analysis, signals for bone turnover/mineralization, and inflammation increased following treatment with fasinumab. Increases were generally dose-dependent, reversible, and more pronounced in patients with arthropathy than those without.

Background Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes. Methods This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA. Participants were randomly assigned (per prespecified randomisation ratios within enrolment waves) according to a computer-generated randomisation scheme, stratified by age (<65 years and >= 65 years), to various intravenous or subcutaneous doses of casirivimab and imdevimab before, after, or at the same time as mRNA-1273 or to mRNA-1273 only. The doses of casirivimab and imdevimab were chosen to mimic various time intervals between receipt of 1200 mg of the mAb and the first dose of a primary series with mRNA-1273. The primary endpoint was vaccine-induced 50% inhibitory dilution neutralising antibody titres to SARS-CoV-2 spike protein, 56 days after the first vaccination. Secondary endpoints included vaccine-induced total antibodies to SARS-CoV-2 antigens and incidence of treatment-emergent adverse events. Exploratory endpoints included blood-derived T-cell and B-cell responses. The per-protocol set was used for the analysis of the primary endpoint and included all randomly assigned participants who received both doses ofthe vaccine and completed the injection or infusion of casirivimab and imdevimab per protocol, had no evidence of SARS-CoV-2 infection in the past or in the 56 days after the first dose of vaccine, and did not receive any intervention outside of the study that could alter the immune response. Safety was assessed in the safety analysis set, which included all randomly assigned participants who had received one or more doses of mRNA-1273 or any study drug, and analysed based on treatment received. The study is registered with ClinicalTrials.gov, NCT04852978, and is complete. Findings Between April 29, 2021, and Nov 21, 2022, 807 participants were assessed for eligibility and 295 were randomly assigned. 293 participants were included in the safety analysis set and 260 were included in the per-protocol set. All vaccinated participants developed neutralising antibodies to SARS-CoV-2, with median titres above the published protective threshold (100 IU/mL) against the SARS-CoV-2 D614G variant (considered a reference strain at the time the initial COVID-19 vaccines were developed). Titres were decreased up to 4-fold (median titres 280-450 IU/mL for casirivimab and imdevimab vs 1160 IU/mL for vaccine only on day 56) when casirivimab and imdevimab was given 85 days or less before vaccination (150-1200 mg intravenously) or co-administered subcutaneously (600 mg or 1200 mg) with vaccination. Minimal reduction in neutralisation titres was observed in the 48 mg and 12 mg intravenous groups, corresponding to receipt of casirivimab and imdevimab 113 days and 169 days, respectively, before vaccination, and when administering the vaccine 6 days before the mAb. Across all groups, mAbs had a minimal effect on vaccine- induced total antibodies and T-cell responses to the spike protein. Casirivimab and imdevimab plus mRNA-1273 was generally well tolerated; a slight increase in treatment-emergent adverse events was observed in the casirivimab and imdevimab plus vaccine groups versus the vaccine-only group. Interpretation Casirivimab and imdevimab administration before or at the time of COVID-19 vaccination reduced the elicitation of SARS-CoV-2 neutralising antibodies, but minimal effect was observed when vaccination occurred before mAb administration. Although the clinical significance of this decrease in neutralisation is unclear, this evidence suggests that further investigation of potential interactions could be warranted before concurrent clinical use of mAbs and vaccines targeting the same viral proteins as their main modes of action for the prevention or treatment of infectious diseases. Funding Regeneron Pharmaceuticals and F Hoffmann-La Roche. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Osteoarthritis (OA) causes significant musculoskeletal pain. This study assessed the efficacy and safety of fasinumab, an investigational nerve growth factor inhibitor, in patients with moderate-to-severe OA pain of the knee/hip. In this Phase 3, randomized, double-blind, placebo- and non-steroidal anti-inflammatory drug (NSAID)-controlled study, patients with OA (Kellgren-Lawrence grade ≥ 2; Western Ontario and McMaster Universities Arthritis Index [WOMAC] pain score ≥ 4) received (2:1:1:1) fasinumab 1 mg every 4 weeks, diclofenac 75 mg twice daily, celecoxib 200 mg daily, or placebo for 24 weeks. Co‑primary endpoints were change in WOMAC pain and physical function scores to Week 24 versus placebo. For safety, joints were imaged in all patients at pre‑specified times, regardless of symptoms. Of 4531 patients screened, 1650 were randomized. At Week 24, greater improvements were observed for fasinumab versus placebo; least-squares mean difference: –0.63 (p = 0.0003) for WOMAC pain and –0.64 (p = 0.0003) for physical function. Improvements were numerically greater for fasinumab versus NSAIDs for physical function (–0.64 versus –0.31; nominal p < 0.05) and pain (–0.63 versus − 0.39; p = NS). Adjudicated arthropathies occurred in 1.6

BACKGROUND:In this post hoc analysis of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, we evaluated the efficacy of alirocumab in patients with probable heterozygous familial hypercholesterolemia (HeFH) or type III hyperlipoproteinemia (T3HLP). METHODS:Patients had clinical HeFH if baseline low-density lipoprotein cholesterol was ≥250 mg/dL and the qualifying acute coronary syndrome event occurred before age 55 (men) or 60 years (women), or if baseline low-density lipoprotein cholesterol was ≥330 mg/dL. Patients had T3HLP if the ratio, validated using the UK Biobank database, of non-high-density lipoprotein cholesterol/apolipoprotein B was >2.6. Genetic variation affecting low-density lipoprotein cholesterol levels (HeFH) and APOE genotypes (T3HLP) was assessed in a pharmacogenomics subgroup. RESULTS:In total, 5.8% of patients from ODYSSEY OUTCOMES and 5.9% from the pharmacogenomics subgroup qualified as having clinical HeFH. In the pharmacogenomics subgroup, 295 patients (2.5%) had genetically confirmed HeFH; 45.8% also qualified as having clinical HeFH. Lipid responses and clinical benefits of alirocumab were similar in all patients with or without HeFH. In the ODYSSEY OUTCOMES cohort, 30 of 18 924 patients (0.16%) were identified as having T3HLP. The pharmacogenomics subgroup included 13 of these 30 patients, of whom 7 (53.8%) were APOE2/2 homozygotes. Lipid responses to alirocumab in patients with T3HLP were comparable with those in the general population. In those with genetic dyslipidemia, adverse event incidence was similar to the overall group. CONCLUSIONS:In ODYSSEY OUTCOMES, individuals with HeFH were common while those with T3HLP were rare. In their lipid responses, carriers of both conditions benefited from alirocumab. REGISTRATION:URL: https://clinicaltrials.gov; Unique identifier: NCT01663402.

Purpose: Osteoarthritis (OA) is a chronic disease where breakdown and loss of cartilage leads to pain, primarily in the joints. Nerve growth factor inhibitors (eg, fasinumab) can reduce pain, but have been associated with nervous system adverse events (AEs). Here we describe the results of a Phase 2, randomized, double-blind, placebo-controlled study and a series of nonclinical analyses investigating the effects of fasinumab on peripheral nerve function and ganglion anatomy. Methods: In the Phase 2 study, 180 adults with knee or hip OA and moderate-to-severe pain inadequately controlled with analgesics, who could not tolerate/were unwilling to take opioids, received subcutaneous fasinumab 1 mg every 4 weeks or placebo for 12 weeks. The primary endpoint was change from baseline to Week 16 in conduction velocity and amplitude for the peroneal, sural, and ulnar nerves. Secondary endpoints included peripheral sensory events. The nonclinical analyses involved adult and developing Sprague-Dawley rats and developing cynomolgus monkeys; endpoints included baseline and isoproterenol‑induced hemodynamic parameters, dorsal root ganglia (DRG) and superior cervical ganglia (SCG) volumes, neuron volumes and counts, and volumes and counts of specific neural subsets. Findings: In the Phase 2 study, nerve conduction velocities and action potential amplitudes between baseline and Week 16 were generally within normal ranges. There were no compelling differences in nerve conduction tests between fasinumab- and placebo-treated patients. Incidences of AEs, including peripheral sensory AEs, were similar between fasinumab and placebo. In the nonclinical analyses, neither hemodynamic parameters nor DRG and SCG stereological parameters were statistically significantly different between fasinumab-treated and isotype control antibody–treated rats. Implications: No clinically meaningful differences were observed between fasinumab- and placebo-treated patients for nerve conduction velocities and action potential amplitudes. In the nonclinical studies, no significant changes could be detected in adult rat ganglion anatomical parameters or hemodynamic parameters at a variety of fasinumab doses. Results from these studies demonstrated that fasinumab did not affect the tested nervous system parameters in adult humans or rats.Trial registration number: NCT02447276; https://clinicaltrials.gov/study/NCT02447276.

Objective:Nerve growth factor (NGF) inhibitors have been shown to provide pain relief in patients with osteoarthritis but are associated with adjudicated arthropathies (AAs). Exploratory analyses were performed to identify whether peripheral biomarkers routinely collected in trials can predict AAs, independent of known clinical covariates. Methods:Clinical and biomarker data from seven phase 2/3 fasinumab trials were pooled, and 33 laboratory baseline and week 16 change variables were assessed. Individuals with AA were identified and propensity score matched 1:1 to non-AA controls, creating four unique sets of non-AA individuals. Random forest machine learning models were used. Variables with >30 % missing data were excluded. The training/validation set included 75 % of the available dataset; 10 % formed the working validation test set, and 15 % a held-back test set. Area under the curve of the receiving operating characteristic (AUROC) and ranked feature importance were assessed across models using peripheral biomarkers to predict AA vs non-AA individuals. Results:Of the final dataset (n = 11,490), 911 AA individuals were compared with four unique sets of non-AA individuals (n = 878-908). The AUROC was 0.51-0.57 for biomarkers at baseline and 0.54-0.62 for biomarker changes at week 16. Change in alkaline phosphatase (ALP) from baseline to week 16 was the only important variable identified consistently across models. ALP was also elevated by several points on average in individuals receiving fasinumab. Conclusion:Change in ALP (baseline to week 16) was associated with AA events after treatment with fasinumab. Other measured peripheral biomarkers were not linked with AA events.

Plasma lipid levels are modulated by systemic infection and inflammation; it is unknown whether these changes reflect inflammatory responses or caused directly by pathogen presence. We explored the hypothesis that anti-inflammatory intervention via interleukin 6 receptor (IL-6R) blockade would influence plasma lipid levels during severe infection and evaluated the association of plasma lipid changes with clinical outcomes. Sarilumab (monoclonal antibody blocking IL-6R) efficacy was previously assessed in patients with coronavirus disease 2019 (COVID-19) (NCT04315298). This analysis determined whether strong inflammatory reduction by sarilumab in patients with COVID-19 pneumonia of increasing severity (severe, critical, multisystem organ dysfunction) affected plasma lipid changes between day 1 and day 7 of study therapy. Baseline lipid levels reflected the presence of acute systemic infection, characterized by very low HDL-C, low LDL-C, and moderately elevated triglycerides (TGs). Disease severity was associated with progressively more abnormal lipid levels. At day 7, median lipid levels increased more in the sarilumab versus placebo group (HDL-C +10.3%, LDL-C +54.7%, TG +32% vs. HDL-C +1.7%, LDL-C +15.4%, TG +8.8%, respectively). No significant association between lipid changes and clinical outcomes was observed. In conclusion, severe-to-critical COVID-19 pneumonia causes profound HDL-C depression that is only modestly responsive to strong anti-IL-6R inflammatory intervention. Conversely, LDL-C depression is strongly responsive to IL-6R blockade, with LDL-C levels likely returning to the predisease set point. These results advance our understanding of the complex relationship between serum lipids and infection/inflammation and suggest that HDL-C depression during acute contagious disease is driven by infection and not IL-6-mediated inflammation.

Objective:Apolipoprotein B (ApoB) and lipoprotein (a) (Lp[a]) are predictors of cardiovascular disease (CVD) risk; therefore, current recommendations for CVD risk assessment and management advocate that patients receive testing for ApoB and Lp(a) in addition to the standard lipid panel. However, US guidelines around ApoB and Lp(a) testing have evolved over time and vary slightly by expert committee. The objective of this analysis was to estimate the number of insured individuals in the USA who received any component of a lipid test, or ApoB and/or Lp(a) testing, during 2019. Methods:We conducted a cross-sectional analysis to estimate the prevalence of any component of a lipid test, ApoB, and/or Lp(a) in the USA using four different claim data sources (including Medicaid, Medicare, and commercially insured enrollees). Prevalence estimates were age-, sex-, payor-, and region-standardized to the 2019 US Annual Social and Economic Supplement of the Current Population Survey. We also described the clinical profile of patients who received lipid testing between 2019 and 2021 (cohort analysis) in Optum claims database. Enrollees were grouped into four non-mutually exclusive cohorts based on their completion of any component of the lipid panel, ApoB, Lp(a), or ApoB and Lp(a). Results:In the prevalence cohort, over a third (38 %) of insured adults in the USA underwent testing for any component of a lipid panel in 2019. This proportion was higher for individuals aged ≥65 years compared to younger adults (62% vs 31 %). The proportion of ApoB and Lp(a) testing represented only <1 % of testing for any component of a lipid panel. In the cohort analysis, we found that lipid testing increased with age and comorbidities. Conclusion:These data should be considered by guideline-issuing agencies and organizations to develop education campaigns encouraging more frequent use of tests beyond the standard lipid panel.

Background Patients with recent acute coronary syndrome (ACS) commonly experience chest pain, which affects quality of life even when not due to recurrence of ACS. This post hoc analysis of ODYSSEY OUTCOMES assessed the effect of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, on the incidence of chest pain not due to recurrent ACS. Methods Patients with recent ACS (n=18,894) and elevated atherogenic lipoprotein levels despite optimized statin therapy were randomized to subcutaneous alirocumab or matching placebo every 2 weeks. Alirocumab dose was adjusted to target low-density lipoprotein cholesterol (LDL-C) 25–50 mg/dL (0.6–1.3 mmol/L) and to avoid consecutive LDL-C <15 mg/dL (0.39 mmol/L). Non-hospitalized chest pain adverse events and chest pain events requiring hospitalization but negatively adjudicated for recurrent ACS were assessed. Results Chest pain not requiring hospitalization was reported as an adverse event in 1490 patients, including 7.5% and 8.3% of alirocumab and placebo groups, respectively. Hospitalization for chest pain negatively adjudicated for recurrent ACS occurred in 952 patients, including 4.8% and 5.3% of alirocumab and placebo groups, respectively. Adjusting for baseline covariates, alirocumab use was associated with 8.1% lower risk of chest pain (either non-hospitalized or hospitalized events) versus placebo (HR: 0.919; 95% CI: 0.845–0.998; P=0.046); a landmark analysis at 7 months showed a larger, 11.7% risk reduction (HR: 0.883; 95% CI: 0.793–0.984; P=0.024). Conclusions Alirocumab use is associated with reduced incidence of chest pain events after ACS, including those not requiring hospitalization and those requiring hospitalization but not adjudicated as recurrent ACS. Trial registration NCT01663402

Background: Pain associated with osteoarthritis (OA) is frequently disabling; treatments are often ineffective or intolerable. Fasinumab selectively inhibits nerve-growth factor and has shown efficacy for the management of OA pain. Methods: In this randomized, double-blind, phase III safety study, patients with moderate-to-severe OA pain and history of inadequate pain relief received placebo or fasinumab (at 1, 3, 6, and 9 mg every 4 weeks [Q4W] and 1 and 6 mg every 8 weeks [Q8W] for 52 weeks). Primary safety endpoints included adverse events, adjudicated arthropathies (AAs), and joint replacements (JRs). Co-primary endpoints of an efficacy sub-study were change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores. During the study, higher fasinumab doses were discontinued for safety; 1 mg doses continued. Results: Of 13,945 patients screened, 5331 were randomized; 1074 were included in the efficacy sub-study. AAs and JRs occurred in all groups. Increased severity of disease at baseline was associated with higher rates of AAs and JRs. A dose-dependent risk of AA or JR was observed for fasinumab; in the 1 mg groups, only a small percentage of patients with JR had prior AA. Fasinumab significantly improved WOMAC pain and physical function scores compared with placebo; least squares mean differences versus placebo were-1.22 and-1.20 for 1 mg Q4W and-0.73 and-0.74 for 1 mg Q8W, respectively (P<0.001). Conclusion: AAs and JRs showed a dose relationship to fasinumab and were associated with baseline OA status. Fasinumab achieved statistically significant improvements in WOMAC pain and physical function scores compared with placebo.

Objectives There is limited qualitative research on patients’ experiences with long COVID-19, and how specific symptoms impact their daily lives. The study aimed to understand patients’ lived experiences of long COVID-19 and to develop a conceptual model representing the symptoms and their impact on overall quality of life.Setting Qualitative study consisting of a comprehensive literature review, and in-depth clinician and patient semistructured interviews.Participants Forty-one adult patients with long COVID-19, of whom 18 (44%) were recruited through Regeneron Pharmaceuticals’s clinical trials and 23 (56%) through recruitment agencies; 85.4% were female and 73.2% were White. Five independent clinicians treating patients with long COVID-19 were interviewed. Concept saturation was also assessed.Primary and secondary outcomes Interview transcripts were analysed thematically to identify concepts of interest spontaneously mentioned by patients, including symptoms and their impacts on daily life, to guide the development of the conceptual model.Results Findings from the literature review and clinician and patient interviews resulted in the development of a conceptual model comprising two overarching domains: symptoms (upper respiratory tract, lower respiratory tract, smell and taste, systemic, gastrointestinal, neurocognitive and other) and impacts (activities of daily living, instrumental activities of daily living, physical impacts, emotional, social/leisure activities and professional impacts). Saturation was achieved for the reported impacts. The symptoms reported were heterogenic; neurocognitive symptoms, such as numbness, ringing in ears, haziness, confusion, forgetfulness/memory problems, brain fog, concentration, difficulties finding the right word and challenges with fine motor skills, were particularly pertinent for several months.Conclusion The conceptual model, developed based on patient experience data of long COVID-19, highlighted numerous symptoms that impact patients’ physical and mental well-being, and suggests humanistic unmet needs. Prospective real-world studies are warranted to understand the pattern of long COVID-19 experienced in larger samples over longer periods of time.

This study aimed to assess the effects of a monoclonal antibody (mAb) combination on symptoms, daily function, and overall health-related quality of life. We analyzed patient-reported outcomes data from symptomatic outpatients in a phase 1/2/3 trial. Patients with confirmed SARS-CoV-2 infection and ≥ 1 risk factor for severe COVID-19 received mAb treatment (casirivimab plus imdevimab 1200 mg) or placebo. Prespecified exploratory assessments included time to sustained symptoms resolution, usual health, and return to usual activities (assessed daily for 29 days). The trial was conducted from September 2020 to February 2021, prior to widespread COVID-19 vaccination programs and Omicron-lineage variants against which casirivimab + imdevimab is not active. In this analysis 736 outpatients received mAb and 1341 received placebo. Median time to sustained symptoms resolution was consistently shorter with mAb versus placebo (≥ 2 consecutive days: 14 vs 17 days, [nominal p = 0.0017]; ≥ 3 consecutive days: 17 vs 21 days, [nominal p = 0.0046]). Median time to sustained return to usual health and usual activities were both consistently shorter with mAb versus placebo (≥ 2 consecutive days: 12 vs 15 days [nominal p = 0.0001] and 9 vs 11 days [nominal p = 0.0001], respectively; ≥ 3 consecutive days: 14 vs 18 days [nominal p = 0.0003] and 10 vs 13 days [nominal p = 0.0041], respectively). mAb treatment against susceptible SARS-CoV-2 strains improved how patients feel and function, as evidenced by shortened time to sustained symptoms resolution and return to usual health and activities. Future studies are warranted to assess the patient experience with next generation mAbs. Registration number, NCT04425629; Submission date June 11, 2020.

OBJECTIVE:To examine the prevalence of preexisting articular bone pathology in patients with hip or knee pain due to osteoarthritis (OA) screened for fasinumab clinical trials. METHOD:This post-hoc analysis included patients with OA screened for three phase 3 fasinumab studies (NCT02683239, NCT03161093, NCT03304379). During screening, participants who met other clinical inclusion/exclusion criteria underwent radiography of knees, hips, and shoulders. Those with Kellgren-Lawrence grade (KLG) ≥ 2 for index joint and without an exclusionary finding proceeded to magnetic resonance imaging (MRI) of index, contralateral, and KLG ≥ 3 joints. Exclusionary findings included bone fragmentation/collapse, bone loss/resorption, osteonecrosis, and fracture, by either X-ray or MRI. Participants with extensive subchondral cysts were also excluded. Prevalence of abnormalities on radiographs and MRIs are reported. RESULTS:Of 27,633 participants screened, 21,997 proceeded to imaging. Of these, 1203 (5.5%) were excluded due to the presence of ≥ 1 joint with severe articular bone pathology (X-ray or MRI): bone fragmentation/collapse (2.60%), subchondral insufficiency fracture (SIF; 1.67%), osteonecrosis (1.11%), and significant bone loss (0.32%). Additionally, 3.13% screen-failed due to extensive subchondral cysts. More than half of the exclusions due to bone fragmentation/collapse (386/572), osteonecrosis (141/245) and significant bone loss (59/71), and approximately one third of SIF (133/367) and extensive subchondral cysts (229/689) were evident on X-rays. CONCLUSIONS:Approximately one in 20 participants with OA who met the clinical screening criteria for fasinumab phase 3 trials were later excluded due to preexisting severe articular bone pathology findings by X-ray or MRI.

The safety of casirivimab + imdevimab (CAS + IMD) (anti-severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] monoclonal antibodies [mAbs]) in pediatric outpatients with coronavirus disease 2019 (COVID-19) was evaluated in a randomized phase 1/2/3 trial. Consistent with adults, CAS + IMD was generally well tolerated with low drug-induced immunogenicity rates. The findings support the development of next-generation anti-SARS-CoV-2 mAbs for at-risk pediatric patients. Casirivimab and imdevimab (CAS + IMD) treatment was well-tolerated in pediatric outpatients with >= 1 risk factor for severe coronavirus disease 2019 (COVID-19), with similar safety and pharmacokinetic profiles as observed in adults. CAS + IMD was associated with low rates of COVID-19-related medically attended visits.