Estetrol Is Safe and Well Tolerated during Treatment of Hospitalized Men and Women with Moderate COVID-19 in a Randomized, Double-Blind Study

DOI record: { "DOI": "10.3390/jcm12123928", "ISSN": [ "2077-0383" ], "URL": "http://dx.doi.org/10.3390/jcm12123928", "abstract": "<jats:p>Epidemiological data suggest that the severe acute respiratory syndrome coronavirus 2 infection rate is higher in women than in men, but the death rate is lower, while women (&gt;50 years) on menopausal hormone therapy (MHT) have a higher survival rate than those not on MHT. Classical oral estrogen enhances the synthesis of coagulation markers and may increase the risk of thromboembolic events that are common in coronavirus disease 2019 (COVID-19). The favorable hemostatic profile of estetrol (E4) might be suitable for use in women who are receiving estrogen treatment and contract COVID-19. A multicenter, randomized, double-blind, placebo-controlled, phase 2 study (NCT04801836) investigated the efficacy, safety, and tolerability of E4 versus placebo in hospitalized patients with moderate COVID-19. Eligible postmenopausal women and men (aged ≥ 18 years old) were randomized to E4 15 mg or placebo, once daily for 21 days, in addition to the standard of care (SoC). The primary efficacy endpoint of improvement in COVID-19 (percentage of patients recovered at day 28) between the placebo and E4 arms was not met. E4 was well tolerated, with no safety signals or thromboembolic events, suggesting that postmenopausal women can safely continue E4-based therapy in cases of moderate COVID-19 managed with SoC.</jats:p>", "alternative-id": [ "jcm12123928" ], "author": [ { "ORCID": "https://orcid.org/0000-0001-8285-3573", "affiliation": [ { "name": "Mithra Pharmaceuticals, 4000 Liège, Belgium" }, { "name": "Department of Obstetrics and Gynecology, University of Liège, 4000 Liège, Belgium" } ], "authenticated-orcid": false, "family": "Foidart", "given": "Jean Michel", "sequence": "first" }, { "affiliation": [ { "name": "Department of Infectious Diseases and Hepatology, Wrocław Medical University, 51149 Wrocław, Poland" } ], "family": "Simon", "given": "Krzysztof", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Reproductive Biology, Case Western Reserve Medical School, Cleveland, OH 44106, USA" } ], "family": "Utian", "given": "Wulf H.", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Endocrinology and Metabolism, Tulane University School of Medicine, New Orleans, LA 70112, USA" } ], "family": "Mauvais-Jarvis", "given": "Franck", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-7644-5298", "affiliation": [ { "name": "Department of Pharmacy, Namur Thrombosis and Hemostasis Center, Faculty of Medicine, University of Namur, 5000 Namur, Belgium" }, { "name": "QUALIblood s.a., 5000 Namur, Belgium" } ], "authenticated-orcid": false, "family": "Douxfils", "given": "Jonathan", "sequence": "additional" }, { "affiliation": [ { "name": "Mithra Pharmaceuticals, 4000 Liège, Belgium" } ], "family": "Dixon", "given": "Graham", "sequence": "additional" }, { "affiliation": [ { "name": "tranScrip Ltd., Wokingham RG41 5TP, Berkshire, UK" } ], "family": "Barrington", "given": "Philip", "sequence": "additional" } ], "container-title": "Journal of Clinical Medicine", "container-title-short": "JCM", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2023, 6, 9 ] ], "date-time": "2023-06-09T06:03:18Z", "timestamp": 1686290598000 }, "deposited": { "date-parts": [ [ 2025, 1, 6 ] ], "date-time": "2025-01-06T09:19:02Z", "timestamp": 1736155142000 }, "funder": [ { "DOI": "10.13039/100031579", "doi-asserted-by": "crossref", "id": [ { "asserted-by": "crossref", "id": "10.13039/100031579", "id-type": "DOI" } ], "name": "Mithra Pharmaceuticals" } ], "indexed": { "date-parts": [ [ 2025, 2, 21 ] ], "date-time": "2025-02-21T19:30:55Z", "timestamp": 1740166255621, "version": "3.37.3" }, "is-referenced-by-count": 2, "issue": "12", "issued": { "date-parts": [ [ 2023, 6, 8 ] ] }, "journal-issue": { "issue": "12", "published-online": { "date-parts": [ [ 2023, 6 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 6, 8 ] ], "date-time": "2023-06-08T00:00:00Z", "timestamp": 1686182400000 } } ], "link": [ { "URL": "https://www.mdpi.com/2077-0383/12/12/3928/pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1968", "original-title": [], "page": "3928", "prefix": "10.3390", "published": { "date-parts": [ [ 2023, 6, 8 ] ] }, "published-online": { "date-parts": [ [ 2023, 6, 8 ] ] }, "publisher": "MDPI AG", "reference": [ { "DOI": "10.4103/bbrj.bbrj_109_20", "article-title": "Is ivermectin–Azithromycin combination the next step for COVID-19?", "author": "Hussien", "doi-asserted-by": "crossref", "first-page": "101", "journal-title": "Biomed. Biotechnol. Res. J.", "key": "ref_1", "volume": "4", "year": "2020" }, { "DOI": "10.1055/s-0040-1718735", "article-title": "Immunoinflammatory, Thrombohaemostatic, and Cardiovascular Mechanisms in COVID-19", "author": "Gencer", "doi-asserted-by": "crossref", "first-page": "1629", "journal-title": "Thromb. Haemost.", "key": "ref_2", "volume": "120", "year": "2020" }, { "DOI": "10.1038/s41569-020-0360-5", "article-title": "COVID-19 and the cardiovascular system", "author": "Zheng", "doi-asserted-by": "crossref", "first-page": "259", "journal-title": "Nat. Rev. Cardiol.", "key": "ref_3", "volume": "17", "year": "2020" }, { "DOI": "10.3389/fimmu.2015.00635", "article-title": "The Immune System Is a Natural Target for Estrogen Action: Opposing Effects of Estrogen in Two Prototypical Autoimmune Diseases", "author": "Khan", "doi-asserted-by": "crossref", "first-page": "635", "journal-title": "Front. Immunol.", "key": "ref_4", "volume": "6", "year": "2016" }, { "DOI": "10.1016/0002-9378(95)90433-6", "article-title": "Hormone replacement therapy reduces the reactivity of monocytes and platelets in whole blood—A beneficial effect on atherogenesis and thrombus formation?", "author": "Aune", "doi-asserted-by": "crossref", "first-page": "1816", "journal-title": "Am. J. Obstet. Gynecol.", "key": "ref_5", "volume": "173", "year": "1995" }, { "DOI": "10.1080/13697137.2022.2139599", "article-title": "Impact of estetrol (E4) on hemostasis, metabolism and bone turnover in postmenopausal women", "author": "Douxfils", "doi-asserted-by": "crossref", "first-page": "55", "journal-title": "Climacteric", "key": "ref_6", "volume": "26", "year": "2023" }, { "DOI": "10.1016/j.contraception.2020.08.015", "article-title": "Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters", "author": "Douxfils", "doi-asserted-by": "crossref", "first-page": "396", "journal-title": "Contraception", "key": "ref_7", "volume": "102", "year": "2020" }, { "DOI": "10.1080/17512433.2022.2054413", "article-title": "Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause", "author": "Arnal", "doi-asserted-by": "crossref", "first-page": "121", "journal-title": "Expert Rev. Clin. Pharmacol.", "key": "ref_8", "volume": "15", "year": "2022" }, { "DOI": "10.1210/clinem/dgac511", "article-title": "Low Thrombin Generation in Users of a Contraceptive Containing Estetrol and Drospirenone", "author": "Morimont", "doi-asserted-by": "crossref", "first-page": "135", "journal-title": "J. Clin. Endocrinol. Metab.", "key": "ref_9", "volume": "108", "year": "2022" }, { "DOI": "10.1016/j.mce.2018.06.010", "article-title": "Effect of estetrol, a selective nuclear estrogen receptor modulator, in mouse models of arterial and venous thrombosis", "author": "Valera", "doi-asserted-by": "crossref", "first-page": "132", "journal-title": "Mol. Cell. Endocrinol.", "key": "ref_10", "volume": "477", "year": "2018" }, { "DOI": "10.1186/s12916-020-01851-z", "doi-asserted-by": "crossref", "key": "ref_11", "unstructured": "Seeland, U., Coluzzi, F., Simmaco, M., Mura, C., Bourne, P.E., Heiland, M., Preissner, R., and Preissner, S. (2020). Evidence for treatment with estradiol for women with SARS-CoV-2 infection. BMC Med., 18." }, { "DOI": "10.1371/journal.pone.0257051", "doi-asserted-by": "crossref", "key": "ref_12", "unstructured": "Costeira, R., Lee, K.A., Murray, B., Christiansen, C., Castillo-Fernandez, J., Ni Lochlainn, M., Capdevila Pujol, J., Macfarlane, H., Kenny, L.C., and Buchan, I. (2021). Estrogen and COVID-19 symptoms: Associations in women from the COVID Symptom Study. PLoS ONE, 16." }, { "DOI": "10.1016/S1473-3099(20)30637-X", "doi-asserted-by": "crossref", "key": "ref_13", "unstructured": "WHO Working Group on the Clinical Characterisation and Management of Covid Infection (2020). A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect. Dis., 20, e192–e197. Correction in Lancet Infect. Dis. 2020, 20, e250." }, { "DOI": "10.1056/NEJMoa2007764", "article-title": "Remdesivir for the treatment of COVID-19—Final report", "author": "Beigel", "doi-asserted-by": "crossref", "first-page": "1813", "journal-title": "N. Engl. J. Med.", "key": "ref_14", "volume": "383", "year": "2020" }, { "DOI": "10.1101/2021.02.11.21249258", "doi-asserted-by": "crossref", "key": "ref_15", "unstructured": "The RECOVERY Collaborative Group (2021). Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet, 397, 1637–1645." }, { "DOI": "10.1056/NEJMoa2028700", "article-title": "Tocilizumab in Hospitalized Patients with Severe COVID-19 Pneumonia", "author": "Rosas", "doi-asserted-by": "crossref", "first-page": "1503", "journal-title": "N. Engl. J. Med.", "key": "ref_16", "volume": "384", "year": "2021" }, { "DOI": "10.1186/s12879-022-07068-0", "doi-asserted-by": "crossref", "key": "ref_17", "unstructured": "Vegivinti, C.T.R., Evanson, K.W., Lyons, H., Akosman, I., Barrett, A., Hardy, N., Kane, B., Keesari, P.R., Pulakurthi, Y.S., and Sheffels, E. (2022). Efficacy of antiviral therapies for COVID-19: A systematic review of randomized controlled trials. BMC Infect. Dis., 22." }, { "DOI": "10.1101/2021.02.16.21251853", "doi-asserted-by": "crossref", "key": "ref_18", "unstructured": "Dambha-Miller, H., Hinton, W., Joy, M., Feher, M., and Lusignan, S.d. (2021). Mortality in COVID-19 amongst women on Hormone Replacement Therapy or Combined Oral Contraception: A cohort study. medRxiv." }, { "DOI": "10.1016/j.maturitas.2022.10.005", "article-title": "Effect of menopausal hormone therapy on COVID-19 severe outcomes in women—A population-based study of the US National COVID Cohort Collaborative (N3C) data", "author": "Yoshida", "doi-asserted-by": "crossref", "first-page": "39", "journal-title": "Maturitas", "key": "ref_19", "volume": "170", "year": "2023" }, { "DOI": "10.1503/cmaj.211698", "article-title": "Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: A randomized controlled trial", "author": "Ali", "doi-asserted-by": "crossref", "first-page": "E242", "journal-title": "CMAJ", "key": "ref_20", "volume": "194", "year": "2022" }, { "DOI": "10.1016/S1473-3099(21)00485-0", "article-title": "Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): A phase 3, randomised, controlled, open-label trial", "author": "Ader", "doi-asserted-by": "crossref", "first-page": "209", "journal-title": "Lancet Infect. Dis.", "key": "ref_21", "volume": "22", "year": "2022" }, { "DOI": "10.1016/S0140-6736(22)00519-0", "doi-asserted-by": "crossref", "key": "ref_22", "unstructured": "WHO Solidarity Trial Consortium (2022). Remdesivir and three other drugs for hospitalised patients with COVID-19: Final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet, 399, 1941–1953." }, { "DOI": "10.1001/jama.2020.16349", "article-title": "Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial", "author": "Spinner", "doi-asserted-by": "crossref", "first-page": "1048", "journal-title": "JAMA", "key": "ref_23", "volume": "324", "year": "2020" }, { "DOI": "10.1056/NEJMoa2015301", "article-title": "Remdesivir for 5 or 10 Days in Patients with Severe COVID-19", "author": "Goldman", "doi-asserted-by": "crossref", "first-page": "1827", "journal-title": "N. Engl. J. Med.", "key": "ref_24", "volume": "383", "year": "2020" }, { "DOI": "10.1056/NEJMoa2021436", "doi-asserted-by": "crossref", "key": "ref_25", "unstructured": "The RECOVERY Collaborative Group (2021). Dexamethasone in Hospitalized Patients with COVID-19. N. Engl. J. Med., 384, 693–704." }, { "DOI": "10.1101/2022.03.02.22271623", "doi-asserted-by": "crossref", "key": "ref_26", "unstructured": "The RECOVERY Collaborative Group (2022). Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial and updated meta-analysis. Lancet, 400, 359–368." }, { "DOI": "10.1016/S2213-2600(21)00331-3", "article-title": "Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): A randomised, double-blind, parallel-group, placebo-controlled phase 3 trial", "author": "Marconi", "doi-asserted-by": "crossref", "first-page": "1407", "journal-title": "Lancet Respir. Med.", "key": "ref_27", "volume": "9", "year": "2021" }, { "DOI": "10.1056/NEJMoa2031994", "article-title": "Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19", "author": "Kalil", "doi-asserted-by": "crossref", "first-page": "795", "journal-title": "N. Engl. J. Med.", "key": "ref_28", "volume": "384", "year": "2021" }, { "DOI": "10.1056/NEJMoa2030340", "article-title": "Tocilizumab in patients hospitalized with COVID-19 pneumonia", "author": "Salama", "doi-asserted-by": "crossref", "first-page": "20", "journal-title": "N. Engl. J. Med.", "key": "ref_29", "volume": "384", "year": "2020" }, { "DOI": "10.1056/NEJMoa2028836", "article-title": "Efficacy of Tocilizumab in Patients Hospitalized with COVID-19", "author": "Stone", "doi-asserted-by": "crossref", "first-page": "2333", "journal-title": "N. Engl. J. Med.", "key": "ref_30", "volume": "383", "year": "2020" }, { "DOI": "10.1007/s00134-021-06507-x", "article-title": "Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: A randomized clinical trial", "author": "Rosas", "doi-asserted-by": "crossref", "first-page": "1258", "journal-title": "Intensive Care Med.", "key": "ref_31", "volume": "47", "year": "2021" }, { "key": "ref_32", "unstructured": "ClinicalTrials.gov (2023, May 19). Estrogen Patch for COVID-19 Symptoms, Available online: https://clinicaltrials.gov/ct2/show/NCT04359329." }, { "key": "ref_33", "unstructured": "ClinicalTrials.gov (2023, May 19). Estrogen Therapy in Non-Severe COVID-19 Patients, Available online: https://clinicaltrials.gov/ct2/show/NCT04539626." }, { "key": "ref_34", "unstructured": "ClinicalTrials.gov (2023, May 19). Oestrogen Treatment for COVID-19 Symptoms, Available online: https://clinicaltrials.gov/ct2/show/NCT04853069." }, { "key": "ref_35", "unstructured": "ClinicalTrials.gov (2023, May 19). Estradiol and Progesterone in Hospitalized COVID-19 Patients, Available online: https://clinicaltrials.gov/ct2/show/NCT04865029." } ], "reference-count": 35, "references-count": 35, "relation": {}, "resource": { "primary": { "URL": "https://www.mdpi.com/2077-0383/12/12/3928" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Estetrol Is Safe and Well Tolerated during Treatment of Hospitalized Men and Women with Moderate COVID-19 in a Randomized, Double-Blind Study", "type": "journal-article", "volume": "12" }