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1.
JAMA Netw Open ; 5(4): e226920, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1782544

ABSTRACT

Importance: Monoclonal antibody (mAb) treatment decreases hospitalization and death in high-risk outpatients with mild to moderate COVID-19; however, only intravenous administration has been evaluated in randomized clinical trials of treatment. Subcutaneous administration may expand outpatient treatment capacity and qualified staff available to administer treatment, but the association with patient outcomes is understudied. Objectives: To evaluate whether subcutaneous casirivimab and imdevimab treatment is associated with reduced 28-day hospitalization and death compared with nontreatment among mAb-eligible patients and whether subcutaneous casirivimab and imdevimab treatment is clinically and statistically similar to intravenous casirivimab and imdevimab treatment. Design, Setting, and Participants: This prospective cohort study evaluated high-risk outpatients in a learning health system in the US with mild to moderate COVID-19 symptoms from July 14 to October 26, 2021, who were eligible for mAb treatment under emergency use authorization. A nontreated control group of eligible patients was also studied. Exposures: Subcutaneous injection or intravenous administration of the combined single dose of 600 mg of casirivimab and 600 mg of imdevimab. Main Outcomes and Measures: The primary outcome was the 28-day adjusted risk ratio or adjusted risk difference for hospitalization or death. Secondary outcomes included 28-day adjusted risk ratios and differences in hospitalization, death, a composite end point of emergency department admission and hospitalization, and rates of adverse events. Among 1959 matched adults with mild to moderate COVID-19, 969 patients (mean [SD] age, 53.8 [16.7] years; 547 women [56.4%]) who received casirivimab and imdevimab subcutaneously had a 28-day rate of hospitalization or death of 3.4% (22 of 653 patients) compared with 7.0% (92 of 1306 patients) in nontreated controls (risk ratio, 0.48; 95% CI, 0.30-0.80; P = .002). Among 2185 patients treated with subcutaneous (n = 969) or intravenous (n = 1216; mean [SD] age, 54.3 [16.6] years; 672 women [54.4%]) casirivimab and imdevimab, the 28-day rate of hospitalization or death was 2.8% vs 1.7%, which resulted in an adjusted risk difference of 1.5% (95% CI, -0.6% to 3.5%; P = .16). Among all infusion patients, there was no difference in intensive care unit admission (adjusted risk difference, 0.7%; 95% CI, -3.5% to 5.0%) or need for mechanical ventilation (adjusted risk difference, 0.2%; 95% CI, -5.8% to 5.5%). Conclusions and Relevance: In this cohort study of high-risk outpatients with mild to moderate COVID-19 symptoms, subcutaneously administered casirivimab and imdevimab was associated with reduced hospitalization and death when compared with no treatment. These results provide preliminary evidence of potential expanded use of subcutaneous mAb treatment, particularly in areas that are facing treatment capacity and/or staffing shortages.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Adult , Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Cohort Studies , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Prospective Studies , SARS-CoV-2
2.
NPJ Digit Med ; 5(1): 44, 2022 Apr 04.
Article in English | MEDLINE | ID: covidwho-1773999

ABSTRACT

The development of a shared data infrastructure across health systems could improve research, clinical care, and health policy across a spectrum of diseases, including sepsis. Awareness of the potential value of such infrastructure has been heightened by COVID-19, as the lack of a real-time, interoperable data network impaired disease identification, mitigation, and eradication. The Sepsis on FHIR collaboration establishes a dynamic, federated, and interoperable system of sepsis data from 55 hospitals using 2 distinct inpatient electronic health record systems. Here we report on phase 1, a systematic review to identify clinical variables required to define sepsis and its subtypes to produce a concept mapping of elements onto Fast Healthcare Interoperability Resources (FHIR). Relevant papers described consensus sepsis definitions, provided criteria for sepsis, severe sepsis, septic shock, or detailed sepsis subtypes. Studies not written in English, published prior to 1970, or "grey" literature were prospectively excluded. We analyzed 55 manuscripts yielding 151 unique clinical variables. We then mapped variables to their corresponding US Core FHIR resources and specific code values. This work establishes the framework to develop a flexible infrastructure for sharing sepsis data, highlighting how FHIR could enable the extension of this approach to other important conditions relevant to public health.

3.
Cancer J ; 28(2): 151-156, 2022.
Article in English | MEDLINE | ID: covidwho-1764719

ABSTRACT

ABSTRACT: Because of significant adaptations forced by the COVID-19 pandemic, resultant changes within health care delivery and clinical research introduced the potential for evaluation of novel evidence generation approaches in oncology. On July 26 and 27, 2021, the National Academies of Science, Engineering, and Medicine, National Cancer Policy Forum hosted a virtual workshop entitled "Cancer Care and Cancer Research in the Context of the COVID-19 Pandemic: A Workshop on Lessons Learned." This workshop examined changes in cancer care and cancer research that occurred in response to the COVID-19 pandemic and considered lessons learned from that experience. The goal was to identify what changes could improve the delivery of high-quality cancer care and the conduct of cancer clinical trials in the postpandemic era, with an emphasis on health equity. How can we sustain the valuable lessons learned that might accelerate progress and enhance clinical evidence generation for patients and clinicians? In this overview, we discuss ways in which the COVID-19 experience has catalyzed research efficiencies as well as fostered a broader array of trial design and research methods that may facilitate improved cancer drug development during the pandemic and beyond.


Subject(s)
COVID-19 , Neoplasms , COVID-19/epidemiology , Humans , Medical Oncology , Neoplasms/epidemiology , Neoplasms/therapy , Pandemics
4.
Am J Crit Care ; 31(2): 146-157, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1737135

ABSTRACT

BACKGROUND: Understanding COVID-19 epidemiology is crucial to clinical care and to clinical trial design and interpretation. OBJECTIVE: To describe characteristics, treatment, and outcomes among patients hospitalized with COVID-19 early in the pandemic. METHODS: A retrospective cohort study of consecutive adult patients with laboratory-confirmed, symptomatic SARS-CoV-2 infection admitted to 57 US hospitals from March 1 to April 1, 2020. RESULTS: Of 1480 inpatients with COVID-19, median (IQR) age was 62.0 (49.4-72.9) years, 649 (43.9%) were female, and 822 of 1338 (61.4%) were non-White or Hispanic/Latino. Intensive care unit admission occurred in 575 patients (38.9%), mostly within 4 days of hospital presentation. Respiratory failure affected 583 patients (39.4%), including 284 (19.2%) within 24 hours of hospital presentation and 413 (27.9%) who received invasive mechanical ventilation. Median (IQR) hospital stay was 8 (5-15) days overall and 15 (9-24) days among intensive care unit patients. Hospital mortality was 17.7% (n = 262). Risk factors for hospital death identified by penalized multivariable regression included older age; male sex; comorbidity burden; symptoms-to-admission interval; hypotension; hypoxemia; and higher white blood cell count, creatinine level, respiratory rate, and heart rate. Of 1218 survivors, 221 (18.1%) required new respiratory support at discharge and 259 of 1153 (22.5%) admitted from home required new health care services. CONCLUSIONS: In a geographically diverse early-pandemic COVID-19 cohort with complete hospital folllow-up, hospital mortality was associated with older age, comorbidity burden, and male sex. Intensive care unit admissions occurred early and were associated with protracted hospital stays. Survivors often required new health care services or respiratory support at discharge.


Subject(s)
COVID-19 , Aged , COVID-19/therapy , Female , Hospital Mortality , Hospitalization , Humans , Intensive Care Units , Male , Middle Aged , Pandemics , Respiration, Artificial , Retrospective Studies , SARS-CoV-2
5.
Clin Infect Dis ; 2022 Feb 18.
Article in English | MEDLINE | ID: covidwho-1706037

ABSTRACT

BACKGROUND: We studied humoral responses after COVID-19 vaccination across varying causes of immunodeficiency. METHODS: Prospective study of fully-vaccinated immunocompromised adults (solid organ transplant (SOT), hematologic malignancy, solid cancers, autoimmune conditions, HIV infection) versus non-immunocompromised healthcare-workers (HCW). The primary outcome was the proportion with a reactive test (seropositive) for IgG to SARS-CoV-2 receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. RESULTS: 1271 participants enrolled: 1,099 immunocompromised and 172 HCW. Compared to HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (p<0.01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus mRNA-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines, after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r=0.89, p<0.0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW. CONCLUSION: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCW. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.

6.
Learning Health Systems ; : 1, 2022.
Article in English | Academic Search Complete | ID: covidwho-1653311

ABSTRACT

Introduction Methods Results Conclusions Rapid, continuous implementation of credible scientific findings and regulatory approvals is often slow in large, diverse health systems. The coronavirus disease 2019 (COVID‐19) pandemic created a new threat to this common “slow to learn and adapt” model in healthcare. We describe how the University of Pittsburgh Medical Center (UPMC) committed to a rapid learning health system (LHS) model to respond to the COVID‐19 pandemic.A treatment cohort study was conducted among 11 429 hospitalized patients (pediatric/adult) from 22 hospitals (PA, NY) with a primary diagnosis of COVID‐19 infection (March 19, 2020 ‐ June 6, 2021). Sociodemographic and clinical data were captured from UPMC electronic medical record (EMR) systems. Patients were grouped into four time‐defined patient “waves” based on nadir of daily hospital admissions, with wave 3 (September 20, 2020 ‐ March 10, 2021) split at its zenith due to high volume with steep acceleration and deceleration. Outcomes included changes in clinical practice (eg, use of corticosteroids, antivirals, and other therapies) in relation to timing of internal system analyses, scientific publications, and regulatory approvals, along with 30‐day rate of mortality over time.The mean (SD) daily number of admissions across hospitals was 26 (29) with a maximum 7‐day moving average of 107 patients. System‐wide implementation of the use of dexamethasone, remdesivir, and tocilizumab occurred within days of release of corresponding seminal publications and regulatory actions. After adjustment for differences in patient clinical profiles over time, each month of hospital admission was associated with an estimated 5% lower odds of 30‐day mortality (adjusted odds ratio [OR] = 0.95, 95% confidence interval: 0.93‐0.97, P < .001).In our large LHS, near real‐time changes in clinical management of COVID‐19 patients happened promptly as scientific publications and regulatory approvals occurred throughout the pandemic. Alongside these changes, patients with COVID‐19 experienced lower adjusted 30‐day mortality following hospital admission over time. [ FROM AUTHOR] Copyright of Learning Health Systems is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

8.
Nat Med ; 28(1): 39-50, 2022 01.
Article in English | MEDLINE | ID: covidwho-1641982

ABSTRACT

Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/therapy , Complement Inactivating Agents/therapeutic use , Glucocorticoids/therapeutic use , Immunologic Factors/therapeutic use , Immunomodulation , Protein Kinase Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , Azetidines/therapeutic use , Bradykinin/analogs & derivatives , Bradykinin/therapeutic use , Bradykinin B2 Receptor Antagonists/therapeutic use , COVID-19/immunology , Dexamethasone/therapeutic use , Drug Combinations , Factor Xa Inhibitors/therapeutic use , Heparin/therapeutic use , Humans , Hydrocortisone/therapeutic use , Imatinib Mesylate/therapeutic use , Immunization, Passive , Interferon beta-1a/therapeutic use , Interferon beta-1b/therapeutic use , Interferon-gamma/therapeutic use , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Kallikrein-Kinin System , Piperidines/therapeutic use , Purines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2 , Sulfonamides/therapeutic use
9.
Contemp Clin Trials ; 113: 106652, 2022 02.
Article in English | MEDLINE | ID: covidwho-1560571

ABSTRACT

Outpatient treatments that limit progression to severe coronavirus disease 2019 (COVID-19) are of vital importance to optimise patient outcomes and public health. Monoclonal antibodies (mAb) demonstrated ability to decrease hospitalizations in randomized, clinical trials. However, there are many barriers to mAb treatment such as patient access and clinician education. There are no data comparing efficacy or safety of available mAbs. We sought to rapidly launch an adaptive platform trial with the goals of enhancing access to treatment, regardless of geography and socioeconomic status, and evaluating comparative efficacy and safety of available mAbs. Within 21 days from idea genesis, we allocated mAb treatment to all patients within the context of this clinical trial. Within 2 months, we closed the gap of the likelihood of receiving mAb, conditional on background positivity rate, between Black and White patients (Black patients 0.238; White patients 0.241). We describe trial infrastructure, lessons learned, and future directions for a culture of learning while doing.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Humans , SARS-CoV-2
10.
Am J Crit Care ; 31(2): 146-157, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1497459

ABSTRACT

BACKGROUND: Understanding COVID-19 epidemiology is crucial to clinical care and to clinical trial design and interpretation. OBJECTIVE: To describe characteristics, treatment, and outcomes among patients hospitalized with COVID-19 early in the pandemic. METHODS: A retrospective cohort study of consecutive adult patients with laboratory-confirmed, symptomatic SARS-CoV-2 infection admitted to 57 US hospitals from March 1 to April 1, 2020. RESULTS: Of 1480 inpatients with COVID-19, median (IQR) age was 62.0 (49.4-72.9) years, 649 (43.9%) were female, and 822 of 1338 (61.4%) were non-White or Hispanic/Latino. Intensive care unit admission occurred in 575 patients (38.9%), mostly within 4 days of hospital presentation. Respiratory failure affected 583 patients (39.4%), including 284 (19.2%) within 24 hours of hospital presentation and 413 (27.9%) who received invasive mechanical ventilation. Median (IQR) hospital stay was 8 (5-15) days overall and 15 (9-24) days among intensive care unit patients. Hospital mortality was 17.7% (n = 262). Risk factors for hospital death identified by penalized multivariable regression included older age; male sex; comorbidity burden; symptoms-to-admission interval; hypotension; hypoxemia; and higher white blood cell count, creatinine level, respiratory rate, and heart rate. Of 1218 survivors, 221 (18.1%) required new respiratory support at discharge and 259 of 1153 (22.5%) admitted from home required new health care services. CONCLUSIONS: In a geographically diverse early-pandemic COVID-19 cohort with complete hospital folllow-up, hospital mortality was associated with older age, comorbidity burden, and male sex. Intensive care unit admissions occurred early and were associated with protracted hospital stays. Survivors often required new health care services or respiratory support at discharge.


Subject(s)
COVID-19 , Aged , COVID-19/therapy , Female , Hospital Mortality , Hospitalization , Humans , Intensive Care Units , Male , Middle Aged , Pandemics , Respiration, Artificial , Retrospective Studies , SARS-CoV-2
11.
J Crit Care ; 64: 160-164, 2021 08.
Article in English | MEDLINE | ID: covidwho-1479628

ABSTRACT

PURPOSE: To measure the rate of recall of study participation and study attrition in survivors of acute respiratory distress syndrome(ARDS). MATERIALS/METHODS: In this ancillary study of the Re-evaluation of Systemic Early neuromuscular blockade(ROSE) trial, we measured the rate of study participation recall 3 months following discharge and subsequent study attrition at 6 months. We compared patient and hospital characteristics, and long-term outcomes by recall. As surrogate decision-makers provided initial consent, we measured the rate of patient reconsent and its association with study recall. RESULTS: Of 487 patients evaluated, recall status was determined in 386(82.7%). Among these, 287(74.4%) patients recalled participation in the ROSE trial, while 99(25.6%) did not. There was no significant difference in 6-month attrition among patients who recalled study participation (9.1%) and those who did not (12.1%) (p = 0.38). Patient characteristics were similar between groups, except SOFA scores, ventilator-free days, and length of stay. 330(68%) were reconsented. Compared to those not reconsented, significantly more patients who were reconsented recalled study participation(78% vs. 66%;p = 0.01). CONCLUSIONS: One in 4 ARDS survivors do not recall their participation in a clinical trial during hospitalization 3 months following hospital discharge, which did not influence 6-month attrition. However, more patients recall study participation if reconsent is obtained.


Subject(s)
Respiratory Distress Syndrome , Survivors , Clinical Trials as Topic , Humans , Mental Recall , Patient Discharge , Respiratory Distress Syndrome/therapy , Survivors/psychology
12.
Crit Care Med ; 49(11): 1974-1982, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1475880
13.
J Am Coll Emerg Physicians Open ; 2(5): e12550, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1427087

ABSTRACT

Monoclonal antibody (mAb) therapy can improve coronavirus disease 2019 outcomes when infused early in select patients. We sought to rapidly create and implement a program for emergency department (ED) mAb infusion to aid care. Using multiple strategies and actions-education, selection criteria, screening tools, rapid testing, compounding, and delivery-we infused 832 ED patients with a mAb. The screening tool identified 94.5% of these patients as potential candidates. Length of stay was nearly identical for patients who tested positive for coronavirus disease 2019 versus those requiring testing. Mild adverse reactions occurred in 2.3% of mAb infusions, and severe reactions occurred in 0.5% of infusions. We highlight a strategic approach for using the ED as a key coronavirus disease 2019 therapeutic site for this intervention and with high utility and low disruption.

14.
N Engl J Med ; 385(9): 777-789, 2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1343497

ABSTRACT

BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Heparin/administration & dosage , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , COVID-19/mortality , Critical Illness , Female , Hemorrhage/chemically induced , Heparin/adverse effects , Heparin/therapeutic use , Hospital Mortality , Humans , Logistic Models , Male , Middle Aged , Odds Ratio , Respiration, Artificial , Treatment Failure
15.
Open Forum Infect Dis ; 8(7): ofab254, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1305436

ABSTRACT

BACKGROUND: Monoclonal antibody treatment may prevent complications of coronavirus disease 2019 (COVID-19). We sought to quantify the impact of bamlanivimab monoclonal antibody monotherapy on hospitalization and mortality among outpatients at high risk of COVID-19 complications. METHODS: In this observational study we compared outpatients who received bamlanivimab monoclonal antibody from December 9, 2020 to March 3, 2021 to nontreated patients with a positive polymerase chain reaction or antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the same period who were eligible for monoclonal antibody treatment. The primary outcome was 28-day hospitalization or all-cause mortality, and the secondary outcome was hospitalization or emergency department visit without hospitalization. The risk-adjusted odds of study outcomes comparing bamlanivimab treated and untreated patients was determined using 1:5 propensity matching and multivariable logistic regression. RESULTS: Among 232 patients receiving bamlanivimab matched with 1160 comparator patients, the mean age was 67 years, 56% were female, and 196 (14%) of patients experienced hospitalization or mortality. After adjustment for propensity to receive treatment, bamlanivimab treatment was associated with a significantly reduced risk-adjusted odds of hospitalization or mortality within 28 days (odds ratio [OR], 0.40; 95% confidence interval [95% CI], 0.24-0.69; P < .001). Bamlanivimab treatment was also associated with a significantly lower risk adjusted odds of hospitalization or emergency department visit without hospitalization (OR, 0.54; 95% CI, 0.35-0.82; P = .004). The results were most strongly associated with patients age 65 years and older. CONCLUSIONS: Bamlanivimab monoclonal antibody monotherapy was associated with reduced hospitalizations and mortality within 28 days among outpatients with mild to moderate COVID-19.Use of bamlanivimab monotherapy for outpatients with mild to moderate COVID-19 infection was associated with reductions in hospitalizations and mortality within 28 days. Benefit was strongest in those age 65 years or older.

17.
Trials ; 22(1): 363, 2021 May 25.
Article in English | MEDLINE | ID: covidwho-1243818

ABSTRACT

OBJECTIVES: The primary objective is to evaluate the comparative effectiveness of COVID-19 specific monoclonal antibodies (mABs) with US Food and Drug Administration (FDA) Emergency Use Authorization (EUA), alongside UPMC Health System efforts to increase patient access to these mABs. TRIAL DESIGN: Open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization PARTICIPANTS: We will evaluate patients who meet the eligibility criteria stipulated by the COVID-19 mAB EUAs who receive mABs within the UPMC Health System, including infusion centers and emergency departments. EUA eligibility criteria include patients with mild to moderate COVID-19, <10 days of symptoms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization (elderly, obese, and/or with specific comorbidities). The EUA criteria exclude patients who require oxygen for the treatment of COVID-19 and patients already hospitalized for the treatment of COVID-19. We will use data collected for routine clinical care, including data entered into the electronic medical record and from follow-up calls. INTERVENTION AND COMPARATOR: The interventions are the COVID-19 specific mABs authorized by the EUAs. All aspects of mAB treatment, including eligibility criteria, dosing, and post-infusion monitoring, are as per the EUAs. As a comparative effectiveness trial, all patients receive mAB treatment, and the interventions are compared against each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mAB interventions will accordingly change. From November 2020 to February 2021, FDA issued EUAs for three mAB treatments (bamlanivimab; bamlanivimab and etesevimab; and casirivimab and imdevimab), and at trial launch on March 10, 2021 we evaluated all three. Due to a sustained increase in SARS-CoV-2 variants in the United States resistant to bamlanivimab administered alone, on March 24, 2021 the U.S. Government halted distribution of bamlanivimab alone, and UPMC accordingly halted bamlanivimab monotherapy on March 31, 2021. On April 16, 2021, FDA revoked the EUA for bamlanivimab monotherapy. At the time of manuscript submission, we are therefore evaluating the two mAB treatments authorized by EUAs (bamlanivimab and etesevimab; and casirivimab and imdevimab). MAIN OUTCOMES: The primary outcome is total hospital free days (HFD) at 28 days after mAB administration, calculated as 28 minus the number of days during the index stay (if applicable - e.g., for patients admitted to hospital after mAB administration in the emergency department) minus the number of days readmitted during the 28 days after treatment. This composite endpoint captures the number of days from the day of mAB administration to the 28 days thereafter, during which the patient is alive and free of hospitalization. Death within 28 days is recorded as -1 HFD, as the worst outcome. RANDOMISATION: We will start with equal allocation. Due to uncertainty in sample size, we will use a Bayesian adaptive design and response adaptive randomization to ensure ability to provide statistical inference despite variable sample size. When mABs are ordered by UPMC physicians as a generic referral order, the order is filled by UPMC pharmacy via therapeutic interchange. OPTIMISE-C19 provides the therapeutic interchange via random allocation. Infusion center operations teams and pharmacists use a mAB assignment application embedded in the electronic medical record to determine the random allocation. BLINDING (MASKING): This trial is open-label. However, outcome assessors conducting follow-up calls at day 28 are blinded to mAB assignment, and investigators are blinded to by-mAB aggregate outcome data until a statistical platform trial conclusion is reached. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Sample size will be determined by case volume throughout the course of the pandemic, supply of FDA authorized mABs, and by that needed to reach a platform trial conclusion of inferiority, superiority, or futility of a given mAB. The trial will continue as long as more than one mAB type is available under EUA, and their comparative effectiveness is uncertain. TRIAL STATUS: Protocol Version 1.0, February 24, 2021. Recruitment began March 10, 2021 and is ongoing at the time of manuscript submission. The estimated recruitment end date is February 22, 2022, though the final end date is dependent on how the pandemic evolves, mAB availability, and when final platform trial conclusions are reached. As noted above, due to U.S. Government decisions, UPMC Health System halted bamlanivimab monotherapy on March 31, 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04790786 . Registered March 10, 2021 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19 , Aged , Antibodies, Monoclonal/adverse effects , Bayes Theorem , Humans , Random Allocation , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
19.
Nat Commun ; 12(1): 2349, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1189222

ABSTRACT

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.


Subject(s)
COVID-19/drug therapy , COVID-19/mortality , Chloroquine/adverse effects , Hydroxychloroquine/adverse effects , Pregnancy Complications, Infectious/mortality , Adult , COVID-19/complications , COVID-19/virology , Child , Chloroquine/administration & dosage , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Comorbidity , Female , Humans , Hydroxychloroquine/administration & dosage , International Cooperation , Odds Ratio , Patient Participation/statistics & numerical data , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Infectious/virology , Randomized Controlled Trials as Topic/statistics & numerical data , SARS-CoV-2
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