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Randomized Controlled Trial
. 2023 Aug;148(5):381-390.
doi: 10.1161/CIRCULATIONAHA.123.065190. Epub 2023 Jun 25.

Effect of the P-Selectin Inhibitor Crizanlizumab on Survival Free of Organ Support in Patients Hospitalized for COVID-19: A Randomized Controlled Trial

Scott D Solomon  1 , Charles J Lowenstein  2 , Ankeet S Bhatt  1   3 , Alexander Peikert  1 , Orly Vardeny  4 , Mikhail N Kosiborod  5 , Jeffrey S Berger  6 , Harmony R Reynolds  6 , Stephanie Mavromichalis  6 , Anya Barytol  1 , Andrew D Althouse  7 , James F Luther  7 , Eric S Leifer  8 , Andrei L Kindzelski  8 , Mary Cushman  9 , Michelle N Gong  10 , Lucy Z Kornblith  11 , Pooja Khatri  12 , Keri S Kim  13 , Lisa Baumann Kreuziger  14 , Lana Wahid  15 , Bridget-Anne Kirwan  16 , Mark W Geraci  7 , Matthew D Neal  7 , Judith S Hochman  6 ; ACTIV4a Investigators
Affiliations
Randomized Controlled Trial

Effect of the P-Selectin Inhibitor Crizanlizumab on Survival Free of Organ Support in Patients Hospitalized for COVID-19: A Randomized Controlled Trial

Scott D Solomon et al. Circulation. 2023 Aug.

Abstract

Background: COVID-19 has been associated with endothelial injury, resultant microvascular inflammation and thrombosis. Activated endothelial cells release and express P-selectin and von Willebrand factor, both of which are elevated in severe COVID-19 and may be implicated in the disease pathophysiology. We hypothesized that crizanlizumab, a humanized monoclonal antibody to P-selectin, would reduce morbidity and death in patients hospitalized for COVID-19.

Methods: An international, adaptive, randomized controlled platform trial, funded by the National Heart, Lung, and Blood Institute, randomly assigned 422 patients hospitalized with COVID-19 with moderate or severe illness to receive either a single infusion of the P-selectin inhibitor crizanlizumab (at a dose of 5 mg/kg) plus standard of care or standard of care alone in an open-label 1:1 ratio. The primary outcome was organ support-free days, evaluated on an ordinal scale consisting of the number of days alive free of organ support through the first 21 days after trial entry.

Results: The study was stopped for futility by the data safety monitoring committee. Among 421 randomized patients with known 21-day outcomes, 163 patients (77%) randomized to the crizanlizumab plus standard-of-care arm did not require any respiratory or cardiovascular organ support compared with 169 (80%) in the standard-of-care-alone arm. The adjusted odds ratio for the effect of crizanlizumab on organ support-free days was 0.70 (95% CI, 0.43-1.16), where an odds ratio >1 indicates treatment benefit, yielding a posterior probability of futility (odds ratio <1.2) of 98% and a posterior probability of inferiority (odds ratio <1.0) of 91%. Overall, there were 37 deaths (17.5%) in the crizanlizumab arm and 27 deaths (12.8%) in the standard-of-care arm (hazard ratio, 1.33 [95% CrI, 0.85-2.21]; [probability of hazard ratio>1] = 0.879).

Conclusions: Crizanlizumab, a P-selectin inhibitor, did not result in improvement in organ support-free days in patients hospitalized with COVID-19.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT04505774.

Keywords: COVID-19; P-selectin; crizanlizumab.

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Conflict of interest statement

Disclosures Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI. Dr Solomon has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros. Dr Lowenstein has received research grants from Novartis and NIH/National Heart, Lung, and Blood Institute (R01 HL134894, R33 HL14179, 1OT2HL156812, and R01 HL139553). Dr Peikert reports a research grant from the German Research Foundation. Dr Vardeny has received institutional research support from AstraZeneca, Bayer, and Cardurion and has served as a consultant or advisory board member for AstraZeneca, Cardior, Cytokinetics, and Sanofi-Pasteur. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. He holds stock options from Artera Health and Saghmos Therapeutics. Dr Berger reports research grants from NIH and American Heart Association and has consulted for Janssen, Amgen, and Amarin. Dr Reynolds reports receiving grants from the National Heart, Lung and Blood Institute during the conduct of the study, as well as nonfinancial support from Abbott Vascular, Siemens, and Royal Phillips outside the submitted work. Dr Althouse is an employee of Medtronic. Dr Gong reports receiving grants from NIH, Agency for Healthcare Research and Quality, and the US Centers for Disease Control and Prevention and receiving personal fees from Regeneron for serving on the data safety monitoring board for monoclonal antibody trials in COVID-19. Dr Kornblith reports receiving personal fees from Cerus Corp, University of Maryland, Coagulant Therapeutics, and Gamma Diagnostics. Dr Khatri receives grant funding as a principal investigator from NIH and Cerenovus; consulting fees as a scientific advisor to Basking Biosciences, Bayer, Diamedica, Lumosa, and Shionogi; and royalties for online publication from UpToDate. Dr Kim reports grants from NIH during the conduct of the study, funding from Eisai outside the submitted work, and personal fees from NIH for committee service indirectly related to the research. Dr Baumann Kreuziger reports that her institution received funding from NIH to perform the study. Dr Kirwan (through SOCAR Research) received grants from NIH. Dr Neal serves as chief medical officer for Haima Therapeutics and has received grants from the National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences , Department of Defense, Haemonetics, and Instrumentation Laboratories. He has received personal fees from Haemonetics, Takeda, CSL Behring, and Janssen Pharmaceuticals. Dr Hochman reports receiving research support for the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) from Merck Sharp & Dohme, Omron Healthcare Inc, Amgen, Espero BioPharma, Sunovion Pharmaceuticals, AstraZeneca Pharmaceuticals, LP, Arbor Pharmaceuticals, NIH, Medtronic, Royal Philips NV (formerly Volcano Corp), and Abbott Vascular Inc (formerly St. Jude Medical Inc) and receiving financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals, LP. She is study chair for ACTIV-4a under a National Heart, Lung, and Blood Institute–University of Pittsburgh grant subaward. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.
Eligibility and randomization in the ACTIV-4a trial of crizanlizumab in patients hospitalized for COVID-19. a Randomization stratified by site and by illness severity. bA total of 187 participants were included in the organ support–free days [OSFD]) end-point assessment. cA total of 186 participants were included in the OSFD end point assessment. dTwenty-three participants were included in the OSFD end-point assessment. eTwenty-five participants were included in the OSFD end-point assessment. ACTIV-4a indicates Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE.
Figure 2.
Figure 2.
Effect of randomization to crizanlizumab plus standard of care vs standard of care alone on the number of days not requiring respiratory or cardiovascular organ support. Criza indicates crizanlizumab.
Figure 3.
Figure 3.
Effect of randomization to crizanlizumab plus standard of care vs standard of care alone on time to death in patients hospitalized for COVID-19. Criza indicates crizanlizumab.
See this image and copyright information in PMC

Comment in

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