A randomized trial of icosapent ethyl in ambulatory patients with COVID-19

Andrew Kosmopoulos, Deepak L Bhatt, Gus Meglis, Raj Verma, Yi Pan, Adrian Quan, Hwee Teoh, Maya Verma, Lixia Jiao, Robert Wang, Rebecca A Juliano, Mahesh Kajil, Mikhail N Kosiborod, Basel Bari, Abdullahi A Berih, Mallory Aguilar, Antonnette Escano, Andrew Leung, Idelta Coelho, Makoto Hibino, Rafael Díaz, R Preston Mason, Ph Gabriel Steg, Tabassome Simon, Alan S Go, Andrew P Ambrosy, Richard Choi, Arthur M Kushner, Lawrence A Leiter, Mohammed Al-Omran, Subodh Verma, C David Mazer, Andrew Kosmopoulos, Deepak L Bhatt, Gus Meglis, Raj Verma, Yi Pan, Adrian Quan, Hwee Teoh, Maya Verma, Lixia Jiao, Robert Wang, Rebecca A Juliano, Mahesh Kajil, Mikhail N Kosiborod, Basel Bari, Abdullahi A Berih, Mallory Aguilar, Antonnette Escano, Andrew Leung, Idelta Coelho, Makoto Hibino, Rafael Díaz, R Preston Mason, Ph Gabriel Steg, Tabassome Simon, Alan S Go, Andrew P Ambrosy, Richard Choi, Arthur M Kushner, Lawrence A Leiter, Mohammed Al-Omran, Subodh Verma, C David Mazer

Abstract

The coronavirus disease 2019 (COVID-19) pandemic remains a source of considerable morbidity and mortality throughout the world. Therapeutic options to reduce symptoms, inflammatory response, or disease progression are limited. This randomized open-label trial enrolled 100 ambulatory patients with symptomatic COVID-19 in Toronto, Canada. Results indicate that icosapent ethyl (8 g daily for 3 days followed by 4 g daily for 11 days) significantly reduced high-sensitivity C-reactive protein (hs-CRP) and improved symptomatology compared with patients assigned to usual care. Specifically, the primary biomarker endpoint, change in hs-CRP, was significantly reduced by 25% among treated patients (-0.5 mg/L, interquartile range [IQR] [-6.9,0.4], within-group p = 0.011). Conversely, a non-significant 5.6% reduction was observed among usual care patients (-0.1 mg/L, IQR [-3.2,1.7], within-group p = 0.51). An unadjusted between-group primary biomarker analysis was non-significant (p = 0.082). Overall, this report provides evidence of an early anti-inflammatory effect of icosapent ethyl in a modest sample, including an initial well-tolerated loading dose, in symptomatic outpatients with COVID-19. ClinicalTrials.gov Identifier: NCT04412018.

Keywords: Health sciences; Medicine.

Conflict of interest statement

A.K., G.M., R.V., Y.P., A.Q., M.V., M.K., B.B., A.A.B., M.A., A.E., A.L., I.C., M.H., and M.A. declare no competing interests. D.L.B. reports receiving advisory board fees from Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, and Regado Biosciences; reports serving on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; reports serving as a chair member for the American Heart Association Quality Oversight Committee; reports serving on data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by 10.13039/100006279St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by 10.13039/100006520Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by 10.13039/501100002973Daiichi Sankyo), and Population Health Research Institute; reports receiving honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by 10.13039/100001003Boehringer Ingelheim; AEGIS-II executive committee funded by 10.13039/100008322CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by 10.13039/501100003122Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), the Journal of the American College of Cardiology (guest editor; associate editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by 10.13039/100004326Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); reports receiving other fees from Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); reports receiving research funding from 10.13039/100000046Abbott, Afimmune, Amarin, 10.13039/100000042Amgen, 10.13039/100004325AstraZeneca, 10.13039/100004326Bayer, 10.13039/100001003Boehringer Ingelheim, 10.13039/100002491Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, 10.13039/100008322CSL Behring, 10.13039/501100003769Eisai, 10.13039/100009933Ethicon, 10.13039/501100004914Ferring Pharmaceuticals, 10.13039/100005632Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, 10.13039/100010721Ironwood, Ischemix, 10.13039/100005205Janssen, Lexicon, 10.13039/100004312Lilly, 10.13039/100004374Medtronic, MyoKardia, 10.13039/100004336Novartis, 10.13039/501100009708Novo Nordisk, Owkin, 10.13039/100004319Pfizer, PhaseBio, PLx Pharma, 10.13039/100009857Regeneron, 10.13039/100004337Roche, 10.13039/100004339Sanofi, Synaptic, 10.13039/100015237The Medicines Company, and 89Bio; reports receiving royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); reports serving as a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; reports serving as a trustee for American College of Cardiology; and reports carrying out unfunded research for FlowCo, Merck, and Takeda. H.T. reports receiving personal fees from HLS Therapeutics for work conducted outside of the scope of the submitted work. L.J., R.W., and R.A.J. are employees and stockholders of Amarin Pharma, Inc. M.N.K. reports receiving research grant from Astra Zeneca and 10.13039/100001003Boehringer Ingelheim; served on the consultant/advisory board of Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck (Diabetes), Novo Nordisk, Sanofi, and Vifor Pharma; other research support from Astra Zeneca; and honorarium fees from Astra Zeneca, Boehringer Ingelheim, and Novo Nordisk. R.D. has received a research grant from AMARIN for the PREPARE-IT trial. R.P.M. reports receiving grants and consulting fees from Amgen, Amarin, Cleveland Clinic, and Pfizer. P.G.S. reports receiving research grants from Bayer, Merck, Sanofi, and Servier; served on the steering committee, DMC, or CEC of Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, BristolMyersSquibb, Idorsia, Myokardia, Novartis, Pfizer, Regeneron, Sanofi, and Servier; and served as a speaker or consultant for Amgen, Mylan, and Novo Nordisk. T.S. reports receiving grant support, lecture fees, and board membership from 10.13039/100004325AstraZeneca, fees for board membership from Bristol-Myers Squibb, fees for board membership from Bristol-Myers Squibb, consulting fees and fees for board membership from Sanofi, consulting fees and lecture fees from Novartis, and grant support from 10.13039/501100002336Daiichi Sankyo, 10.13039/100004312Eli Lilly, 10.13039/100004330GlaxoSmithKline, Merck Sharpe & Dohme, 10.13039/100004336Novartis, and 10.13039/100004339Sanofi. A.S.G. has received research grant funding through his institution from 10.13039/100014389Amarin Pharma, Inc. A.P.A. was supported by a Mentored Patient-Oriented Research Career Development Award (K23HL150159) through the National Heart, Lung, and Blood Institute, received relevant research support through grants to his institution from 10.13039/100014389Amarin Pharma, Inc., 10.13039/100001316Abbott, and 10.13039/100004336Novartis, and received modest reimbursement for travel from Novartis. R.C. reports receiving honoraria from (advisory board, speakers' bureaus, conference sponsorship) AstraZeneca, Bayer, Boehringer Ingelheim/Lilly, BMS/Pfizer, HLS Therapeutics, Novartis, Sanofi, and Servier; receiving research funding (as site investigator) from 10.13039/100004325AstraZeneca and 10.13039/100004326Bayer; serving as an equity holder for HLS Therapeutics. A.M.K. discloses the following relationships - DFCM, University of Toronto - Pri-Med Planning Committee Member & Moderator; College of Family Physicians of Canada - Member, SP Upskilling Committee; Ontario College of Family Physicians - Chair, OCFP Awards Committee; Humber River Hospital - Chief, Department of Family & Community Medicine, Program Director, Pri-Med Canada Conference; Canadian Journal of Urology - Chair, CJU Scientific Planning Committee; Canadian Urological Association - Member, Planning Committee & Moderator; Canadian Medical and Surgical Knowledge Translation Research Group - Steering Committee Member; Amgen, AstraZeneca, Alliance, Bausch Health, BMS, GSK, ICEBM, Janssen, Lilly, Merck, NovoNordisk, Pediapharm, Pfizer, Sanofi, Spectrum Therapeutics, HLS Therapeutics - Moderator. L.A.L. reports receiving personal fees from Abbott, Esperion, Janssen, Lexicon, Novo Nordisk, Pfizer, Sanofi, Merck, and Boehringer Ingelheim and grants and personal fees from Astra Zeneca, 10.13039/100004326Bayer, 10.13039/100004312Eli Lilly, Kowa, 10.13039/100004336Novartis, and 10.13039/100015237The Medicines Company, outside the submitted work. S.V. reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, 10.13039/100004334Merck, 10.13039/100004336Novartis, 10.13039/501100009708Novo Nordisk, 10.13039/100004319Pfizer, PhaseBio, 10.13039/100004339Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. C.D.M. has received advisory board honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, and Octapharma.

© 2021 The Author(s).

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Study CONSORT diagram A schematic outlining the number of individuals who were assessed for eligibility, randomized, and included in the analyses. Thirteen people declined to participate. Approximately, 79% of individuals assessed for eligibility consented to participate and were subsequently randomized. Of the 50 individuals randomized to each group, data from 12% (n = 6) of the IPE group and 6% (n = 3) of the usual care group were not analyzed for the primary biomarker endpoint based on the lack of paired biomarker data.
Figure 2
Figure 2
Baseline symptoms COVID-19 symptoms within 72 hr preceding the baseline visit. Although the IPE group was slightly more symptomatic, the entire study population presented with a large number of baseline symptoms. Almost all patients (98% and 94% in the IPE group and usual care group, respectively) had myalgia. Over half of individuals in both groups had the presence of a cough. Within the IPE arm, 50 ± 2% of patients experienced loss of taste, loss of smell, or a fever. These symptoms were present in approximately one-third of the usual care arm. The remaining categories (sore throat and shortness of breath) displayed not more than a 40% prevalence in either group. All between-group comparisons were non-significant. Data shown are for the intention-to-treat population.
Figure 3
Figure 3
Change in total and individual domain FLU-PRO symptom prevalence and scores (A) FLU-PRO and COVID-19-specific symptom prevalence. The prevalence of FLU-PRO and COVID-19-specific (loss of taste, loss of smell) symptoms at baseline and follow-up distributed by total and individual domains. A significant reduction in the total (p = 0.005) and body/systemic (p = 0.006) domains occurred between groups. A numerically larger reduction in chest/respiratory symptoms occurred in the IPE (69%) compared with the usual care cohort (53%), although not a significant difference. The remaining domains had similar reductions in prevalence between groups. Values shown are based on the number of patients with complete paired data and non-zero treatment compliance. All domains within the IPE and usual care cohorts had significant within-group differences, comparing the number of symptomatic patients at baseline versus follow-up, via Chi-square analyses: IPE (p 

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