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Clinical Trial
. 2024 Dec 2;7(12):e2448215.
doi: 10.1001/jamanetworkopen.2024.48215.

Fostamatinib for Hospitalized Adults With COVID-19 and Hypoxemia: A Randomized Clinical Trial

Sean P Collins  1   2 , Matthew S Shotwell  3 , Jeffrey R Strich  4 , Kevin W Gibbs  5 , Marjolein de Wit  6 , D Clark Files  5 , Michelle Harkins  7 , Kris Hudock  8 , Lisa H Merck  9 , Ari Moskowitz  10 , Krystle D Apodaca  7 , Aaron Barksdale  11 , Basmah Safdar  12 , Ali Javaheri  13 , Jeffrey M Sturek  14 , Harry Schrager  15 , Nicole M Iovine  16 , Brian Tiffany  17 , Ivor Douglas  18 , Joseph Levitt  19 , Adit A Ginde  20 , David N Hager  21 , Nathan Shapiro  22 , Abhijit Duggal  23 , Akram Khan  24 , Michael Lanspa  25 , Peter Chen  26 , Nina Gentile  27 , Estelle Harris  28 , Michelle Gong  29 , Subhashini Sellers  30 , Andrew J Goodwin  31 , Mark A Tidswell  32 , Michael Filbin  33 , Neeraj Desai  34 , Felix Gutiérrez  35 , Vicente Estrada  36 , Joaquin Burgos  37 , Tom Boyles  38 , Jose R Paño-Pardo  39 , Nazreen Hussen  40 , Yves Rosenberg  41 , James Troendle  41 , Gordon R Bernard  42   43 , Amanda J Bistran-Hall  43 , Kelly Walsh  43 , Jonathan D Casey  42 , Josh DeClercq  3 , Meghan Morrison Joly  43 , Jill Pulley  43 , Todd W Rice  42   43 , Jonathan S Schildcrout  3 , Li Wang  3 , Matthew W Semler  42 , Wesley H Self  1   43 ; ACTIV-4 Host Tissue Investigators
Collaborators, Affiliations
Clinical Trial

Fostamatinib for Hospitalized Adults With COVID-19 and Hypoxemia: A Randomized Clinical Trial

Sean P Collins et al. JAMA Netw Open. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Collins reported receiving personal fees from Enanta Pharmaceuticals outside the submitted work. Dr Shotwell reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Gibbs reported receiving grants from the NIH for the ACTIV-4 Host Tissue platform during the conduct of the study and from the US Department of Defense outside the submitted work. Dr de Wit reported receiving grants from the NIH during the conduct of the study. Dr Files reported receiving grants from the NIH during the conduct of the study and personal fees from Novartis for serving on the advisory board outside the submitted work. Dr Harkins reported receiving grants from the University of New Mexico during the conduct of the study. Dr Merck reported receiving grants from the NIH, the National Center for Advancing Translational Sciences, the Bill and Melinda Gates Foundation, the Patient-Centered Outcomes Research Institute, Regeneron, Merck, CTSI, and Incyte during the conduct of the study. Dr Safdar reported receiving grants from the Centers for Disease Control and Prevention (CDC) during the conduct of the study. Dr Javaheri reported receiving grants from the NIH during the conduct of the study. Dr Sturek reported receiving grants from the NIH during the conduct of the study. Dr Schrager reported receiving funds from Vanderbilt University to conduct the clinical trial of fostamatinib during the conduct of the study. Dr Douglas reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI), NIH to Denver Health Medical Center during the conduct of the study. Dr Ginde reported receiving grants from the NIH during the conduct of the study. Dr Hager reported receiving grants from the NIH via Vanderbilt University Medical Center in the form of per capita payment for enrolled participants in the ACTIV-4 Host Tissue Platform during the conduct of the study. Dr Khan reported receiving research funding grants from 4DMedical, Direct Biologics, Eli Lilly, United Therapeutics, and Dompé Pharmaceuticals outside the submitted work and having patent PCT/IB2024/050399 pending, affiliated with Oregon Health and Science University. Dr Chen reported receiving personal fees from Rigel Pharmaceuticals outside the submitted work. Dr Gong reported receiving grants from the NIH to conduct the study during the conduct of the study; receiving grants from the NIH and CDC for other trials outside the submitted work and serving as a scientific advisor for Novartis and Regeneron for sepsis trials unrelated to this manuscript; and serving on the data safety and monitoring board for other intensive care unit trials: REPLENISH, BEST ICU, and PALM. Dr Sellers reported receiving grants from the NHLBI, NIH during the conduct of the study and grants from the NHLBI, NIH and personal fees from Sanofi outside the submitted work. Dr Filbin reported receiving grants from the NIH during the conduct of the study. Dr Estrada reported receiving nonfinancial support from Gilead and Janssen and grants from ViiV Healthcare outside the submitted work. Dr Bernard reported receiving grants from the NIH during the conduct of the study. Dr Casey reported receiving a travel grant from Fisher & Paykel to speak at a conference outside the submitted work. Dr Rice reported receiving grants from the NIH paid to the institution during the conduct of the study and receiving personal fees from Cumberland Pharmaceuticals, Inc, for serving as senior director of medical affairs and from Cytovale, Inc, for consulting outside the submitted work. Dr Schildcrout reported receiving grants from the NHLBI during the conduct of the study. Dr Semler reported receiving grants from the NHLBI during the conduct of the study and personal fees from Baxter Healthcare Inc for serving on a medical advisory board outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Screening, Randomization, and Participation in the Fostamatinib Trial
LV indicates left ventricular; mITT, modified intention-to-treat; RAAS, renin angiotensin aldosterone system. aThe criteria were not mutually exclusive; some potential participants met multiple criteria for ineligibility. bThe patient, clinical team, or both was not pursuing full medical management (eg, a do-not-intubate order). cThe patient was to be discharged from the hospital before the study procedures could be initiated, the patient was enrolled in another trial, or the patient’s situation presented logistical challenges for trial enrollment. dPatients eligible for more than 1 trial were randomized with equal probability to a specific trial. The Randomization subsection of the Methods section gives more details on randomization.
Figure 2.
Figure 2.. Primary Outcome of Oxygen-Free Days Between Randomization and Day 28
The day of randomization was study day 0. The total sample size was 400 participants in the fostamatinib trial. Participants were followed up until the earlier of death or day 28. A, The proportion of participants who were deceased or liberated from supplemental oxygen was calculated using the number of patients for whom information was available for that day. Incomplete follow-up, especially pertaining to oxygenation status, meant that some participants were not included in the calculation for that day, which along with allowing for patients to resume supplemental oxygen after a period of liberation, led to nonmonotonicity in the figure. B, The oxygen-free days outcome demonstrated null results for fostamatinib vs placebo, with point estimates in the direction of inferiority (adjusted odds ratio [AOR], 0.82; 95% credible interval, 0.58-1.17).
Figure 3.
Figure 3.. Differential Treatment Effect
Odds ratios were adjusted for sex, age group, and baseline World Health Organization (WHO) ordinal scale level. No formal test of heterogeneity of treatment effect was implemented. An oxygen-free day was calculated as 28 minus the number of days between randomization (day 0) and liberation from new supplemental oxygen use during the 28 days. Participants who died before day 28 were coded as having −1 oxygen-free days (worst possible outcome). The subgroup analyses of oxygen-free days included participants with partially observed data (only known to be within a certain range). Additional information appears in eFigure 3 in Supplement 2, including the number of participants with partially observed oxygen-free days. ACE indicates angiotensin-converting enzyme; AOR, adjusted odds ratio; ARB, angiotensin receptor blocker; HFNC, high-flow nasal cannula; NIV, noninvasive. aNot prespecified as a subgrouping variable; thus, differential treatment effect by sex was a post hoc analysis. bThe WHO COVID-19 clinical progression scale is described in the Outcomes subsection of the Methods section. There were 2 participants (1 in the placebo arm, 1 in the fostamatinib arm) with baseline WHO level of 3 who were hypoxemic and thus qualified for the trial and none with a WHO level of 7 at baseline. cParticipants with unknown vaccination status were excluded (23 receiving placebo and 21 receiving fostamatinib).
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