Haley Morin

All Publications

• The impact of California's staffing mandate and the economic recession on registered nurse staffing levels: A longitudinal analysis. Nursing outlook Dierkes, A., Do, D., Morin, H., Rochman, M., Sloane, D., McHugh, M. 1800

  Abstract

  BACKGROUND: Despite the importance of adequate hospital nurse staffing, California is the only state with minimum nurse-to-patient ratio mandates. The health care workforce is historically "countercyclical"-exhibiting growth during economic recessions when employment in other sectors is shrinking.PURPOSE: This study was to examine how staffing mandates impact hospital nurse staffing during economic recessions.METHOD: We compared hospital nurse staffing in California and in other states over 20 years to examine differences before and after the California mandate and, within the postmandate period, before, during, and after the Great Recession of 2008.FINDINGS: Staffing differences increased during the postmandate period due to faster growth in California staffing compared to other states, except during the Great Recession, when staffing remained stable in California but declined in other states.DISCUSSION: State legislators deliberating staffing mandates should consider the protective factor such policies provide during economic recessions and the implications for the quality and safety of care.

  View details for DOI 10.1016/j.outlook.2021.09.007

  View details for PubMedID 34920888

• Depression and Anxiety Symptoms During and After Pediatric Asthma Hospitalization. Hospital pediatrics Morin, H., Worsley, D., Zhang, X., Faerber, J., Pettit, A. R., Kenyon, C. C., Doupnik, S. K. 2021; 11 (11): 1272-1280

  Abstract

  OBJECTIVES: Depression and anxiety are common in children with asthma, and asthma hospitalization is an underused opportunity to identify mental health concerns. We assessed depression and anxiety symptoms during asthma hospitalization and 1 to 2 months post discharge.METHODS: This prospective cohort study included children aged 7 to 17 years who were hospitalized for asthma exacerbation. Participants completed the self-report PROMIS (Patient-Reported Outcomes Measurement Information System) depression and anxiety symptom scales (T score mean = 50, SD = 10) during hospitalization and 1 to 2 months after discharge. Higher scores indicate more symptoms and/or greater severity. We compared patients' scores during hospitalization and at follow-up using paired t tests and examined individual patients' depression and anxiety symptom trajectories using a Sankey diagram.RESULTS: Among 96 participants who completed the study, 53% had elevated symptoms of depression, anxiety, or both either during hospitalization or after discharge. During hospitalization, 38% had elevated depression symptoms and 45% had elevated anxiety symptoms. At postdischarge follow-up, 18% had elevated depression symptoms and 20% had elevated anxiety symptoms. We observed all possible symptom trajectories: symptoms during hospitalization that persisted (especially if both depression and anxiety symptoms were present), symptoms that resolved, and symptoms that were present at follow-up only.CONCLUSIONS: Just more than half of youth hospitalized for asthma exacerbation experienced depression and/or anxiety symptoms during hospitalization or at follow-up. Patients who had both depression and anxiety symptoms during hospitalization were the most likely to have persistent symptoms at follow-up. Screening at both time points may be useful to identify mental health symptoms.

  View details for DOI 10.1542/hpeds.2020-000950

  View details for PubMedID 34670757

• Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Aggarwal, N. R., Nordwall, J., Braun, D. L., Chung, L., Coslet, J., Der, T., Eriobu, N., Ginde, A. A., Hayanga, A. J., Highbarger, H., Holodniy, M., Horcajada, J. P., Jain, M. K., Kim, K., Laverdure, S., Lundgren, J., Natarajan, V., Nguyen, H. H., Pett, S. L., Phillips, A., Poulakou, G., Price, D. A., Robinson, P., Rogers, A. J., Sandkovsky, U., Shaw-Saliba, K., Sturek, J. M., Trautner, B. W., Waters, M., Reilly, C. 2024

  Abstract

  Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials.A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models.Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time.Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

  View details for DOI 10.1093/cid/ciad780

  View details for PubMedID 38376212

• Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19. The Journal of infectious diseases Jensen, T. O., Grandits, G. A., Jain, M. K., Murray, T. A., Grund, B., Shaw-Saliba, K., Matthay, M. A., Abassi, M., Ardelt, M., Baker, J. V., Chen, P., Dewar, R. L., Goodman, A. L., Hatlen, T. J., Highbarger, H. C., Holodniy, M., Lallemand, P., Laverdure, S., Leshnower, B. G., Looney, D., Moschopoulos, C. D., Mugerwa, H., Murray, D. D., Mylonakis, E., Nagy-Agren, S., Rehman, M. T., Rupert, A., Stevens, R. A., Turville, S., Weintrob, A., Wick, K., Lundgren, J., Ko, E. R. 2023

  Abstract

  Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood.Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and d-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models.Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale.Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed.NCT04501978.

  View details for DOI 10.1093/infdis/jiad446

  View details for PubMedID 37948759

• Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial. The Lancet. Respiratory medicine Brown, S. M., Barkauskas, C. E., Grund, B., Sharma, S., Phillips, A. N., Leither, L., Peltan, I. D., Lanspa, M., Gilstrap, D. L., Mourad, A., Lane, K., Beitler, J. R., Serra, A. L., Garcia, I., Almasri, E., Fayed, M., Hubel, K., Harris, E. S., Middleton, E. A., Barrios, M. A., Mathews, K. S., Goel, N. N., Acquah, S., Mosier, J., Hypes, C., Salvagio Campbell, E., Khan, A., Hough, C. L., Wilson, J. G., Levitt, J. E., Duggal, A., Dugar, S., Goodwin, A. J., Terry, C., Chen, P., Torbati, S., Iyer, N., Sandkovsky, U. S., Johnson, N. J., Robinson, B. R., Matthay, M. A., Aggarwal, N. R., Douglas, I. S., Casey, J. D., Hache-Marliere, M., Georges Youssef, J., Nkemdirim, W., Leshnower, B., Awan, O., Pannu, S., O'Mahony, D. S., Manian, P., Awori Hayanga, J. W., Wortmann, G. W., Tomazini, B. M., Miller, R. F., Jensen, J. U., Murray, D. D., Bickell, N. A., Zatakia, J., Burris, S., Higgs, E. S., Natarajan, V., Dewar, R. L., Schechner, A., Kang, N., Arenas-Pinto, A., Hudson, F., Ginde, A. A., Self, W. H., Rogers, A. J., Oldmixon, C. F., Morin, H., Sanchez, A., Weintrob, A. C., Cavalcanti, A. B., Davis-Karim, A., Engen, N., Denning, E., Taylor Thompson, B., Gelijns, A. C., Kan, V., Davey, V. J., Lundgren, J. D., Babiker, A. G., Neaton, J. D., Lane, H. C. 2023

  Abstract

  There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure.TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761.Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10).Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy.National Institutes of Health.

  View details for DOI 10.1016/S2213-2600(23)00147-9

  View details for PubMedID 37348524

• Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial. JAMA network open Berger, J. S., Neal, M. D., Kornblith, L. Z., Gong, M. N., Reynolds, H. R., Cushman, M., Althouse, A. D., Lawler, P. R., McVerry, B. J., Kim, K. S., Baumann Kreuziger, L., Solomon, S. D., Kosiborod, M. N., Berry, S. M., Bochicchio, G. V., Contoli, M., Farkouh, M. E., Froess, J. D., Gandotra, S., Greenstein, Y., Hade, E. M., Hanna, N., Hudock, K., Hyzy, R. C., Ibáñez Estéllez, F., Iovine, N., Khanna, A. K., Khatri, P., Kirwan, B. A., Kutcher, M. E., Leifer, E., Lim, G., Lopes, R. D., Lopez-Sendon, J. L., Luther, J. F., Nigro Maia, L., Quigley, J. G., Wahid, L., Wilson, J. G., Zarychanski, R., Kindzelski, A., Geraci, M. W., Hochman, J. S. 2023; 6 (5): e2314428

  Abstract

  Platelet activation is a potential therapeutic target in patients with COVID-19.To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19.This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients.Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor.The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis.At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77).In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19.ClinicalTrials.gov Identifier: NCT04505774.

  View details for DOI 10.1001/jamanetworkopen.2023.14428

  View details for PubMedID 37227729

• The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19. Annals of internal medicine 2022

  Abstract

  Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge.114 centers in 10 countries.Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms.Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively.Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity.Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available.Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

  View details for DOI 10.7326/M22-0924

  View details for PubMedID 36037469

  View details for PubMedCentralID PMC9447373

• Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial LANCET INFECTIOUS DISEASES Self, W. H., Sandkovsky, U., Reilly, C. S., Vock, D. M., Gottlieb, R. L., Mack, M., Golden, K., Dishner, E., Vekstein, A., Ko, E. R., Der, T., Franzone, J., Almasri, E., Fayed, M., Filbin, M. R., Hibbert, K. A., Rice, T. W., Casey, J. D., Hayanga, J., Badhwar, V., Leshnower, B. G., Sharifpour, M., Knowlton, K. U., Peltan, I. D., Bakowska, E., Kowalska, J., Bowdish, M. E., Sturek, J. M., Rogers, A. J., Files, D., Mosier, J. M., Gong, M. N., Douin, D. J., Hite, R., Trautner, B. W., Jain, M. K., Gardner, E. M., Khan, A., Jensen, J., Matthay, M. A., Ginde, A. A., Brown, S. M., Higgs, E. S., Pett, S., Weintrob, A. C., Chang, C. C., Murrary, D. D., Gunthard, H. F., Moquete, E., Grandits, G., Engen, N., Grund, B., Sharma, S., Cao, H., Gupta, R., Osei, S., Margolis, D., Zhu, Q., Polizzotto, M. N., Babiker, A. G., Davey, V. J., Kan, V., Thompson, B., Gelijns, A. C., Neaton, J. D., Lane, H., Lundgren, J. D., ACTIV-3 Theropeutics Inpatients CO 2022; 22 (5): 622-635

  Abstract

  We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.US National Institutes of Health and Operation Warp Speed.

  View details for DOI 10.1016/S1473-3099(21)00751-9

  View details for Web of Science ID 000821471300027

  View details for PubMedID 34953520

  View details for PubMedCentralID PMC8700279

• Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA Berger, J. S., Kornblith, L. Z., Gong, M. N., Reynolds, H. R., Cushman, M., Cheng, Y., McVerry, B. J., Kim, K. S., Lopes, R. D., Atassi, B., Berry, S., Bochicchio, G., de Oliveira Antunes, M., Farkouh, M. E., Greenstein, Y., Hade, E. M., Hudock, K., Hyzy, R., Khatri, P., Kindzelski, A., Kirwan, B., Baumann Kreuziger, L., Lawler, P. R., Leifer, E., Lopez-Sendon Moreno, J., Lopez-Sendon, J., Luther, J. F., Nigro Maia, L., Quigley, J., Sherwin, R., Wahid, L., Wilson, J., Hochman, J. S., Neal, M. D., ACTIV-4a Investigators, Newman, J., Geraci, M., Maggioni, A., Kamel, H., Goligher, E. C., Zarychanski, R., Everett, B. M., van Diepen, S., Le Gal, G., Siegal, D. M., Galanaud, J., Hegde, S., Kim, Y., Rost, N. S., Singhal, A. B., Contreras, A., Mavromichalis, S., Iturrate, E., Gilsenan, M., Naumova, A., Roberts, A., Levine, J., Leeper, C. M., Angus, D. C., Martinez, M., Schreiber, J., Froess, J., Stehle, C. E., Vadlamudi, A. S., Sciurba, F., Morris, A., Music, E., de Brouwer, S., Perrin, E., Gombault, C., Bula, S., Nelson, M., Daelemans, C., Paraz, L., Detry, M. A., McGlothlin, A., Quintana, M., Crawford, A., Sin, D., Diene, E., Gwiszcz, E., Hogan, I., Holden, A., Ringwood, N., Fitzgerald, L., Morin, H., Nunez-Garcia, B., Kornblith, A. E., Hendrickson, C. M., Lee, D., Nguyen, V., Shelley, I., Broaddrick, S., Atal, N., Huang, D. T., Wunderly, R., Buxton, M., Roberts, T., Linstrum, K., McNamara, A., Weissman, A., Barbee, D., Berryman, E., Frasure, J., Sulken, A., Ianof, J. N., Mazza, L., Morata, J., Cafarella, C. M., Suiama, M. A., de Lima Franco, D., Escobedo, J., Martinez, A., Ohara, P., Assis, D., Manzalini, C., Corsi, S., Campo, G., Prieto, P., Prieto, R., Garg, S., Fonseco, R., Reese, S., Mohammed, O., Dolor, R., Ortel, T. L., Wolfe, C., Plump, M., Nair, R., Nkemdirim, W., Chen, J., Galen, B., Moskowitz, A., Keller, N., Yuriditsky, E., Horowitz, J., Hindenburg, A., Chkhikvadze, T., Bassoli, L., Costa, T., Lopez-Sendon Moreno, J. L., Rodriguez Jorge, F., Garcia Madrona, S., Morillo Guerrero, R., Alpanes Buesa, M., Nieto Royo, R., Besse Diaz, R., Diz Farina, S., Gonzalez Garcia, A., da Silva Junior, O., Pradela, C., Jorge, C., Buka, M., Costa, O., Frassatto, D., Vieira, J., Dutra, P., Moreira, L., da Silva, N., Prado, N., Martins, A., Centurione, A., de Matos Soeiro, A., Avancini Caramori, P. R., Coppola, N., Contoli, M., Lopez-de-Sa, E., Worner, F., Lopez-Bernus, A., Gonzalez Juanatey, J. R., Peteiro, J., Gandotra, S., Krishnan, V., Widmer, R., Satterwhite, L., Macchiavelli, A., Hanna, N., Patel, H., Lyubarova, R., Gashi, E., Alvaro, A., Pan, S., Vallurupalli, S., Iovine, N., Nair, R., Jathavedam, A., Shah, A., Duggal, A., Khan, A., Matthay, M. A., Prekker, M. E., Lim, G., Moore, S., Costantini, T. W., Kutcher, M. E., Joseph, B., Bromberg, M., Effron, M. B., Pishko, A., Sheehan, J. P., Gaddh, M., Rezai, K., Latorre, J. G., Liang, C., Ajani, Z., Guo, S., Whitson, M. 1800; 327 (3): 227-236

  Abstract

  Importance: Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19.Objective: To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19.Design, Setting, and Participants: An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021.Interventions: Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n=293) or a therapeutic dose of heparin only (usual care) (n=269) in a 1:1 ratio for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor.Main Outcomes and Measures: The composite primary outcome was organ support-free days evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, -1 to 21 days; higher scores indicate less organ support and better outcomes). The primary safety outcome was major bleeding by 28 days as defined by the International Society on Thrombosis and Hemostasis.Results: Enrollment of non-critically ill patients was discontinued when the prespecified criterion for futility was met. All 562 patients who were randomized (mean age, 52.7 [SD, 13.5] years; 41.5% women) completed the trial and 87% received a therapeutic dose of heparin by the end of study day 1. In the P2Y12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37%. The median number of organ support-free days was 21 days (IQR, 20-21 days) among patients in the P2Y12 inhibitor group and was 21 days (IQR, 21-21 days) in the usual care group (adjusted odds ratio, 0.83 [95% credible interval, 0.55-1.25]; posterior probability of futility [defined as an odds ratio <1.2], 96%). Major bleeding occurred in 6 patients (2.0%) in the P2Y12 inhibitor group and in 2 patients (0.7%) in the usual care group (adjusted odds ratio, 3.31 [95% CI, 0.64-17.2]; P=.15).Conclusions and Relevance: Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y12 inhibitor in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in an increased odds of improvement in organ support-free days within 21 days during hospitalization.Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

  View details for DOI 10.1001/jama.2021.23605

  View details for PubMedID 35040887