Fostamatinib for Hospitalized Adults With COVID-19 and Hypoxemia: A Randomized Clinical Trial.
| Title: | Fostamatinib for Hospitalized Adults With COVID-19 and Hypoxemia: A Randomized Clinical Trial. |
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| Authors: | Collins SP; Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Veterans Affairs Tennessee Valley Healthcare System, Geriatric Research, Education and Clinical Center, Nashville, Tennessee.; Shotwell MS; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.; Strich JR; Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland.; Gibbs KW; Department of Medicine, Wake Forest University, Winston-Salem, North Carolina.; de Wit M; Department of Medicine, Virginia Commonwealth University, Richmond.; Files DC; Department of Medicine, Wake Forest University, Winston-Salem, North Carolina.; Harkins M; Department of Internal Medicine, University of New Mexico, Albuquerque.; Hudock K; Department of Medicine, University of Cincinnati, Cincinnati, Ohio.; Merck LH; Department of Emergency Medicine, Virginia Commonwealth University Health System, Richmond.; Moskowitz A; Department of Medicine, Montefiore Medical Center, Bronx, New York.; Apodaca KD; Department of Internal Medicine, University of New Mexico, Albuquerque.; Barksdale A; Department of Medicine, University of Nebraska Medical Center, Omaha.; Safdar B; Department of Medicine, Yale University, New Haven, Connecticut.; Javaheri A; Department of Medicine, Washington University and John Cochran VA Medical Center, St Louis, Missouri.; Sturek JM; Department of Medicine, University of Virginia, Charlottesville.; Schrager H; Department of Medicine, Tufts School of Medicine, Newton-Wellesley Hospital, Newton, Massachusetts.; Iovine NM; Department of Medicine, University of Florida, Gainesville.; Tiffany B; Dignity Health, Phoenix, Arizona.; Douglas I; Department of Medicine, Denver Health Medical Center, Denver, Colorado.; Levitt J; Department of Medicine, Stanford University, Stanford, California.; Ginde AA; Department of Emergency Medicine, University of Colorado, Aurora.; Hager DN; Department of Medicine, Johns Hopkins University, Baltimore, Maryland.; Shapiro N; Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.; Duggal A; Department of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.; Khan A; Department of Medicine, Oregon Health and Science University, Portland.; Lanspa M; Department of Medicine, Intermountain Medical Center, Murray, Utah.; Chen P; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.; Gentile N; Department of Emergency Medicine, Temple University, Philadelphia, Pennsylvania.; Harris E; Department of Medicine, University of Utah Health Sciences, Salt Lake City.; Gong M; Department of Medicine, Jack D. Weiler Hospital, Albert Einstein College of Medicine, Bronx, New York.; Sellers S; Department of Medicine, University of North Carolina, Chapel Hill.; Goodwin AJ; Department of Medicine, Medical University of South Carolina, Charleston.; Tidswell MA; Department of Medicine, Baystate Health, Springfield, Massachusetts.; Filbin M; Department of Emergency Medicine, Massachusetts General Hospital, Boston.; Desai N; Department of Medicine, St Alexius Medical Center, Hoffman Estates, Illinois.; Gutiérrez F; Department of Medicine, Division of Infectious Diseases, Centro de Investigación Biomédica en Red (CIBERINFEC), Hospital General de Elche & Universidad Miguel Hernández, Alicante, Spain.; Estrada V; Hospital Clinico San Carlos, Ciber de Enfermedades Infecciosas, CIBERINFEC, Universidad Complutense de Madrid, Madrid, Spain.; Burgos J; Department of Infectious Diseases, Hospital Universitario Vall d'Hebron, Barcelona, Spain.; Boyles T; Clinical HIV Research Unit, Helen Joseph Hospital, Johannesburg, South Africa.; Paño-Pardo JR; Department of Infectious Diseases, Hospital Clinico Universitario Lozano Blesa, Jaragoza, Spain.; Hussen N; Department of Clinical Research, Worthwhile Clinical Trials (Lakeview Hospital), Benoni, South Africa.; Rosenberg Y; National Heart, Lung, and Blood Institute, Bethesda, Maryland.; Troendle J; National Heart, Lung, and Blood Institute, Bethesda, Maryland.; Bernard GR; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee.; Bistran-Hall AJ; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee.; Walsh K; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee.; Casey JD; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; DeClercq J; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.; Joly MM; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee.; Pulley J; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee.; Rice TW; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee.; Schildcrout JS; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.; Wang L; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.; Semler MW; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Self WH; Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee. |
| Corporate Authors: | ACTIV-4 Host Tissue Investigators |
| Source: | JAMA network open [JAMA Netw Open] 2024 Dec 02; Vol. 7 (12), pp. e2448215. Date of Electronic Publication: 2024 Dec 02. |
| Publication Type: | Journal Article; Randomized Controlled Trial; Multicenter Study; Clinical Trial, Phase III; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Medical Association Country of Publication: United States NLM ID: 101729235 Publication Model: Electronic Cited Medium: Internet ISSN: 2574-3805 (Electronic) Linking ISSN: 25743805 NLM ISO Abbreviation: JAMA Netw Open Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Chicago, IL : American Medical Association, [2018]- |
| MeSH Terms: | Hypoxia*/therapy ; Morpholines*/therapeutic use ; Oxazines*/therapeutic use ; Pyridines*/therapeutic use ; COVID-19 Drug Treatment*; COVID-19/mortality ; Hospitalization/statistics & numerical data ; Protein Kinase Inhibitors/therapeutic use ; Pyridazines/therapeutic use ; Pyrimidines/therapeutic use ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Double-Blind Method ; SARS-CoV-2 ; Treatment Outcome ; Aminopyridines |
| Abstract: | Importance: Fostamatinib, a spleen tyrosine kinase inhibitor, has been reported to improve outcomes of COVID-19.; Objective: To evaluate the efficacy and safety of fostamatinib in adults hospitalized with COVID-19 and hypoxemia.; Design, Setting, and Participants: This multicenter, phase 3, placebo-controlled, double-blinded randomized clinical trial was conducted at 41 US sites and 21 international sites between November 17, 2021, and September 27, 2023; the last follow-up visit was December 31, 2023. Participants were adults aged 18 years or older hospitalized with acute SARS-CoV-2 infection and hypoxemia. Data were analyzed between January 10 and March 8, 2024.; Interventions: Fostamatinib, 150 mg orally twice daily for 14 days, or placebo.; Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome classifying a participant's status at day 28 based on mortality and duration of supplemental oxygen use. An adjusted odds ratio (AOR) greater than 1.0 was considered to indicate superiority of fostamatinib over placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included elevated transaminase values, neutropenia, and hypertension.; Results: Of the 400 participants randomized (median age, 67 years [IQR, 58-76 years]; 210 [52.5%] men), 199 received fostamatinib and 201 received placebo. The mean (SD) number of oxygen-free days was 13.4 (12.4) in the fostamatinib group and 14.2 (12.1) in the placebo group (unadjusted mean difference, -1.26 days [95% CI, -3.52 to 1.00 days]; AOR, 0.82 [95% credible interval (CrI), 0.58-1.17]). Mortality at 28 days occurred in 22 of 195 patients (11.3%) in the fostamatinib group and 16 of 197 (8.1%) in the placebo group (AOR, 1.44; 95% CrI, 0.72-2.90). Aspartate aminotransferase elevation occurred more commonly in the fostamatinib group (23 [11.6%]) than in the placebo group (11 [5.5%]; AOR, 2.28; 95% CrI, 1.07-4.84). Other safety outcomes were similar between groups.; Conclusions and Relevance: In this randomized clinical trial of adults hospitalized with COVID-19 and hypoxemia, fostamatinib did not increase the number of oxygen-free days compared with placebo. These results do not support the hypothesis that fostamatinib improves outcomes among adults hospitalized with hypoxemia during the Omicron era.; Trial Registration: ClinicalTrials.gov Identifier: NCT04924660. |
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| Grant Information: | OT2 HL156812 United States HL NHLBI NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS; UM1 TR004409 United States TR NCATS NIH HHS; R01 NS113393 United States NS NINDS NIH HHS; UL1 TR002243 United States TR NCATS NIH HHS |
| Contributed Indexing: | Investigator: RC Becker; G Del Zoppo; P Henke; R Holubkov; M Johnson; K Kerr; HI Lipman; F Lurie; B Pitt; SK Vesely; JL Fleg; D Aamodt; D Clark; JB Collins; S Dixon; M Cook; C Gatewood; J Graves; D Hunter; C Jordan; S Ko; UB Lekqauwa; I Lopez; D McKeel; D Orozco; N Prato; A Qi; K Stagner; K Vermillion; S Winchell; T Young; E Masuda; A Siddiqui; C Brooks; C Fletcher; A Duffy; P Walsh; J Moody; T Sobande; A Ali; Y Henry; F Ogueri; A Sierto; M Sanchez Grande; C Spinello; O Anthony; M Sieracki; M Tomlin; A Pozniak; T Leaver; P Parks; J Johnson; R Walsh; B Bales; K Miller; D Torr; C Files; K Gibbs; D Ward; L Landreth; L Parks; L Flores; JP Teixeira; S Cardenas; JA Ceniceros; AG Cunningham; S Kunkel; DM Lovato; B Zimmerman; T Nguyen; W Zeger; N Wiedel; S Stilinovic; C Foster; J Flannigan; C Brokowski; J Lu; M Solberg; D Lee; B Tiffany; C Tanner; A Taylor; J Zumbahl; A Syed; J Mason; PEH Jackson; RW Coleman; HM Haughey; K Cherabuddi; R Wakeman; K Fairbank-Haynes; AJ Rogers; JG Wilson; R Vojnik; C Perez; D Wyles; TD Hiller; JL Oakes; AZ Garcia; F Martinez; J Fickes-Siler; DJ Douin; A Baduashvili; H Kramer; L Chauhan; A Martinez; J Peers; K Schauer; L Finck; J Bastman; A Licursi; S Hayes; N Kurtzman; E Rosseto; D Scaffidi; N Shapiro; J Pak; G Allada; G Briceno; J Peña; M Oh; M Gong; A Mohamed; L Andrea; R Nair; W Nkemdirim; S Boujid; M Torres; O Garcia; H Ali; S Beselman; Y Eby; V Klimov; RD Hite; H Tanzeem; C Droege; J Winter; S Mucha; N Thiruchelvam; M Siuba; O Mehkri; S Jackman; A Caudill; E Bayoumi; E Pascual; PE Chen; SS Torbati; T Parimon; B Rosen; Y Matusov; MJ Lanspa; ID Peltan; SM Brown; JR Carr; DB Knox; LM Leither; B Lopez; B Galen; N Gentile; D Isenberg; H Reimer; P Cincola; ES Harris; SJ Callahan; MB Yamane; MA Barrios; N Desai; A Bharara; M Keller; P Majumder; C Dohe; K Hibbert; J Margolin; B Parry; MA Tidswell; JS Steingrub; L De Souza; C Kardos; D Gallant; RL DeFoe; S Romain; S Ouellette; S Estrada; R Kindle; B Tiru; H Smithline; C Garcia; C Terry; M Blender; A Grady; A Powell; PC Hou; MA Hasdianda; SE Miyawaki; M Umale; VD Cantos; CF Kelley; PA Rebolledo; S Kandiah; R Cook; B Hall; C Root; J Brown; C Foster; P Powers; P Lankford-Turner; B Patel; R Abrencillo; R Anguillon-Prada; R Huebinger; G Patarroyo Aponte; S Ghazi Rizvi; E Vidales; I Udoh-Bradford; M Masiá; S Padilla; G Telenti; P Mascarell; J García-Abellán; Á Botella; C Robledano; V Estrada; R Homen; J Rodriguez-Añover; J Burgos; T Boyles; Z Mkhabela; G Pellejero; E Morte-Romea; S Letona-Carbajo; M José Esquillor; C Toyas; S Loscos; N Hussen; C Guijarro; M Velasco-Arribas; E Custódio João Filho; EC de Oliveira Souza; C Boesecke; J Rockstroh; M Ripa; S Nozza |
| Molecular Sequence: | ClinicalTrials.gov NCT04924660 |
| Substance Nomenclature: | 0 (Morpholines); 0 (Oxazines); 0 (Protein Kinase Inhibitors); 0 (Pyridazines); 0 (Pyridines); 0 (Pyrimidines); SQ8A3S5101 (fostamatinib); 0 (Aminopyridines) |
| Entry Date(s): | Date Created: 20241203 Date Completed: 20241203 Latest Revision: 20260306 |
| Update Code: | 20260306 |
| PubMed Central ID: | PMC11615712 |
| DOI: | 10.1001/jamanetworkopen.2024.48215 |
| PMID: | 39625722 |
| Database: | MEDLINE |
Journal Article; Randomized Controlled Trial; Multicenter Study; Clinical Trial, Phase III; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't