Estradiol and Progesterone in Hospitalized COVID-19 Patients

NCT ID: NCT04865029

Last Updated: 2023-06-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-22
• Study Completion Date: 2022-01-25

Brief Summary

The purpose of this study is to determine to what extent a short systemic steroid therapy with estradiol and progesterone, administered early to hospitalized and confirmed COVID-19 positive patients of both sexes in addition to standard of care (SOC) can reduce the severity of symptoms and outcomes compared to SOC alone.

Detailed Description

Severe Acute Respiratory Syndrome Associated Corona Virus (SARS-CoV-2), causing COVID-19, has killed over 2.8 million people globally, including 550,000 in the US as of March 2021. Although, the vaccination campaign is ramping up, vaccination hesitancy in the United States represents up to 25-30% of the population, and hospitalizations and deaths are still at the level of 2020. Apart from corticosteroids, most available therapeutic options are at best marginally efficient in reducing disease severity and mortality and extremely expensive. Therefore, the systematic investigation of clinically approved drugs is a priority in order to determine what does improve the disease and invest resources to go to full-scale production. Our current understanding of the disease is that COVID-19 deaths result from an inappropriate immune response with outpouring of pro-inflammatory chemokines leading to lung infiltration and hyperactivation of monocytes and macrophages producing pro-inflammatory cytokines (cytokine storm), resulting in lung edema, reduced gas exchange, and ultimately leading to acute respiratory distress syndrome and multiorgan failure. Men with COVID-19 have a uniformly more severe outcome than women. In series from China, Europe and the U.S., COVID-19 mortality was consistently 1.5 to 2-fold higher in men than in women, suggesting that female biological sex is protecting women from COVID-19 mortality. It is established that women exhibit heightened immune responses to viral infections compared to men, which is at least partially due to the genetic benefit of gene dosage in X-linked immune-response genes. Ovarian steroids, however, also play a protective role. In New York City, among 5700 hospitalized patients, the female protection from COVID-19 mortality was observed at all ages, but was more pronounced in subjects under 50 years of age (18% mortality in women) compared to patients > 50 years of age (40.5% mortality in women), suggesting that ovarian steroids are involved in mitigating COVID-19 mortality in pre-menopausal women. Further, the analysis of electronic health records of over 68,000 COVID-19 patients revealed that estrogen therapy is associated with more than 50% reduction in mortality. The main female steroids, 17β-estradiol and progesterone exhibit potent immuno-modulatory and anti-inflammatory actions via estrogen and progesterone receptors expressed in all immune cells, including epithelial cells, macrophages, dendritic cells, cluster of differentiation 4 (CD4+) and cluster of differentiation 8 (CD8+) lymphocytes, and B cells. Progesterone also acts partially via the glucocorticoid receptor. Together estradiol and progesterone produce a state of decreased innate immune cells production of proinflammatory cytokines, enhanced T cells anti-inflammatory responses and immune tolerance, and enhanced B-cell-mediated antibody production. The National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel recommends the use of dexamethasone 6 mg per day for up to 10 days or until hospital Discharge (whichever comes first) as standard of care (SOC) for the treatment of hospitalized COVID-19 patients who require supplemental oxygen but who are not mechanically ventilated and for the treatment of hospitalized patients who are mechanically ventilated. Remdesivir is SOC at Tulane for COVID-19 patients who require supplemental oxygen but who are not mechanically ventilated. We believe that in hospitalized COVID-19 patients, a short treatment with the combination estradiol and progesterone, administered early and as a prevention in addition to SOC, will prevent or mitigate the cytokine storm while increasing antibody production and prevent severe outcomes, without side effects. Therefore, it will provide steroid immunomodulation without immunosuppression. The advantage of repurposing estradiol and progesterone compounds is the depth of knowledge regarding their clinical efficacy and toxicity that has accumulated from decades of clinical and basic studies. Estradiol and progesterone are widely available in hospitals, inexpensive, manufacturable to scale, and can be prescribed immediately.

Conditions

Covid19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Treatment Arm

Standard of Care along with Estradiol Cypionate 5mg intramuscular injection at admission and Progesterone 200mg by mouth daily for 5 days starting at admission.

Group Type: EXPERIMENTAL

Estradiol Cypionate 5 mg/ml

Intervention Type: DRUG

Standard of Care along with Estradiol Cypionate 5mg intramuscular injection at admission.

Progesterone 200 mg Oral Capsule

Intervention Type: DRUG

Standard of Care along with Progesterone 200mg by mouth daily for 5 days starting at admission.

Control Arm

Standard of Care along with placebo injection and placebo pill

Standard of Care consistent with the National Institutes of Health (NIH) COVID-19 Treatment Guidelines

Group Type: OTHER

Placebo injection and placebo pill

Intervention Type: OTHER

Standard of Care consistent with the National Institutes of Health (NIH) COVID-19 Treatment Guidelines

Interventions

Placebo injection and placebo pill

Standard of Care consistent with the National Institutes of Health (NIH) COVID-19 Treatment Guidelines

Intervention Type: OTHER

Estradiol Cypionate 5 mg/ml

Standard of Care along with Estradiol Cypionate 5mg intramuscular injection at admission.

Intervention Type: DRUG

Progesterone 200 mg Oral Capsule

Standard of Care along with Progesterone 200mg by mouth daily for 5 days starting at admission.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Hospitalization at Tulane Medical Center in the Department of General Internal Medicine and Geriatrics with COVID-19 (WHO Ordinal scale score 3-5) and confirmed by SARS-CoV-2 Polymerase Chain Reaction (PCR).

2. Respiratory symptoms (fever, shortness of breath or cough) or abnormal lung exam or chest imaging characteristic of mild to severe COVID-19 pneumonia.

3. Patient and/or legally authorized representative (LAR) agrees to comply with study procedures and the collection of blood samples per protocol.

4. Patient and/or LAR agrees to be placed on prophylactic dose of anticoagulation for prevention of deep venous thrombosis (DVT) (if necessary).

5. Patient or legally authorized representative has signed informed consent.

6. Women of childbearing age with a negative pregnancy test on admission.

Exclusion Criteria

1. Patient under 18 years of age.

2. Critical COVID-19 (respiratory failure requiring intubation and mechanical ventilation, shock, multi-organ failure).

3. Pregnant women confirmed by pregnancy test.

4. Women who are within six weeks of postpartum.

5. Patient is not hospitalized at Tulane Medical Center with confirmed COVID-19.

6. Patient included in another COVID-19 trial (excluding hydroxychloroquine and dexamethasone).

7. Women already treated by estrogen and or progestogen therapy two weeks prior to admission.

8. Men already treated by testosterone therapy prior to admission.

9. History of breast or endometrial cancer.

10. Abnormal genital bleeding.

11. Active or recent (e.g., within the past year) stroke or myocardial infarction.

12. History of blood clots including deep vein thrombosis related to clotting disease, or pulmonary emboli (prior to hospitalization).

13. History of liver dysfunction or disease.

14. Patients with end-stage renal disease

15. Patients taking inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, and ritonavir.

16. Patients taking St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin.

17. Patients within 6 weeks of major orthopedic surgery.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tulane University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Franck Mauvais-Jarvias, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Tulane University

Locations

Tulane University Medical Center

New Orleans, Louisiana, United States

Countries

United States

References

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.

Reference Type: BACKGROUND

PMID: 32192578 (View on PubMed)

Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020 May 1;130(5):2620-2629. doi: 10.1172/JCI137244.

Reference Type: BACKGROUND

PMID: 32217835 (View on PubMed)

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.

Reference Type: BACKGROUND

PMID: 31986264 (View on PubMed)

Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020 May 28;181(5):1036-1045.e9. doi: 10.1016/j.cell.2020.04.026. Epub 2020 May 15.

Reference Type: BACKGROUND

PMID: 32416070 (View on PubMed)

Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017 Jul;39(5):517-528. doi: 10.1007/s00281-017-0639-8. Epub 2017 May 29.

Reference Type: BACKGROUND

PMID: 28555385 (View on PubMed)

Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ;Cytokine Storm' in COVID-19. J Infect. 2020 Jun;80(6):607-613. doi: 10.1016/j.jinf.2020.03.037. Epub 2020 Apr 10.

Reference Type: BACKGROUND

PMID: 32283152 (View on PubMed)

Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy. 2016 Jul;8(8):959-70. doi: 10.2217/imt-2016-0020.

Reference Type: BACKGROUND

PMID: 27381687 (View on PubMed)

McGonagle D, Sharif K, O'Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020 Jun;19(6):102537. doi: 10.1016/j.autrev.2020.102537. Epub 2020 Apr 3.

Reference Type: BACKGROUND

PMID: 32251717 (View on PubMed)

Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero JJ, DeMeo DL, De Vries GJ, Epperson CN, Govindan R, Klein SL, Lonardo A, Maki PM, McCullough LD, Regitz-Zagrosek V, Regensteiner JG, Rubin JB, Sandberg K, Suzuki A. Sex and gender: modifiers of health, disease, and medicine. Lancet. 2020 Aug 22;396(10250):565-582. doi: 10.1016/S0140-6736(20)31561-0.

Reference Type: BACKGROUND

PMID: 32828189 (View on PubMed)

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.

Reference Type: BACKGROUND

PMID: 32109013 (View on PubMed)

Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW; the Northwell COVID-19 Research Consortium; Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020 May 26;323(20):2052-2059. doi: 10.1001/jama.2020.6775.

Reference Type: BACKGROUND

PMID: 32320003 (View on PubMed)

Klein SL, Dhakal S, Ursin RL, Deshpande S, Sandberg K, Mauvais-Jarvis F. Biological sex impacts COVID-19 outcomes. PLoS Pathog. 2020 Jun 22;16(6):e1008570. doi: 10.1371/journal.ppat.1008570. eCollection 2020 Jun.

Reference Type: BACKGROUND

PMID: 32569293 (View on PubMed)

Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016 Oct;16(10):626-38. doi: 10.1038/nri.2016.90. Epub 2016 Aug 22.

Reference Type: BACKGROUND

PMID: 27546235 (View on PubMed)

Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett. 2005 Feb 15;97(1):107-13. doi: 10.1016/j.imlet.2004.10.007.

Reference Type: BACKGROUND

PMID: 15626482 (View on PubMed)

Straub RH. The complex role of estrogens in inflammation. Endocr Rev. 2007 Aug;28(5):521-74. doi: 10.1210/er.2007-0001. Epub 2007 Jul 19.

Reference Type: BACKGROUND

PMID: 17640948 (View on PubMed)

Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, Progesterone, Immunomodulation, and COVID-19 Outcomes. Endocrinology. 2020 Sep 1;161(9):bqaa127. doi: 10.1210/endocr/bqaa127.

Reference Type: BACKGROUND

PMID: 32730568 (View on PubMed)

Mauvais-Jarvis F, Manson JE, Stevenson JC, Fonseca VA. Menopausal Hormone Therapy and Type 2 Diabetes Prevention: Evidence, Mechanisms, and Clinical Implications. Endocr Rev. 2017 Jun 1;38(3):173-188. doi: 10.1210/er.2016-1146.

Reference Type: BACKGROUND

PMID: 28323934 (View on PubMed)

Mauvais-Jarvis F. Aging, Male Sex, Obesity, and Metabolic Inflammation Create the Perfect Storm for COVID-19. Diabetes. 2020 Sep;69(9):1857-1863. doi: 10.2337/dbi19-0023. Epub 2020 Jul 15.

Reference Type: BACKGROUND

PMID: 32669390 (View on PubMed)

Seeland U, Coluzzi F, Simmaco M, Mura C, Bourne PE, Heiland M, Preissner R, Preissner S. Evidence for treatment with estradiol for women with SARS-CoV-2 infection. BMC Med. 2020 Nov 25;18(1):369. doi: 10.1186/s12916-020-01851-z.

Reference Type: BACKGROUND

PMID: 33234138 (View on PubMed)

O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979 Sep;35(3):549-56.

Reference Type: BACKGROUND

PMID: 497341 (View on PubMed)

Khubchandani J, Sharma S, Price JH, Wiblishauser MJ, Sharma M, Webb FJ. COVID-19 Vaccination Hesitancy in the United States: A Rapid National Assessment. J Community Health. 2021 Apr;46(2):270-277. doi: 10.1007/s10900-020-00958-x. Epub 2021 Jan 3.

Reference Type: BACKGROUND

PMID: 33389421 (View on PubMed)

RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17.

Reference Type: BACKGROUND

PMID: 32678530 (View on PubMed)

Kaka AS, MacDonald R, Greer N, Vela K, Duan-Porter W, Obley A, Wilt TJ. Major Update: Remdesivir for Adults With COVID-19 : A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points. Ann Intern Med. 2021 May;174(5):663-672. doi: 10.7326/M20-8148. Epub 2021 Feb 9.

Reference Type: BACKGROUND

PMID: 33560863 (View on PubMed)

Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, Bruzzi P, Boni F, Braglia L, Turra C, Ballerini PF, Sciascia R, Zammarchi L, Para O, Scotton PG, Inojosa WO, Ravagnani V, Salerno ND, Sainaghi PP, Brignone A, Codeluppi M, Teopompi E, Milesi M, Bertomoro P, Claudio N, Salio M, Falcone M, Cenderello G, Donghi L, Del Bono V, Colombelli PL, Angheben A, Passaro A, Secondo G, Pascale R, Piazza I, Facciolongo N, Costantini M; RCT-TCZ-COVID-19 Study Group. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):24-31. doi: 10.1001/jamainternmed.2020.6615.

Reference Type: BACKGROUND

PMID: 33080005 (View on PubMed)

Janiaud P, Axfors C, Schmitt AM, Gloy V, Ebrahimi F, Hepprich M, Smith ER, Haber NA, Khanna N, Moher D, Goodman SN, Ioannidis JPA, Hemkens LG. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021 Mar 23;325(12):1185-1195. doi: 10.1001/jama.2021.2747.

Reference Type: BACKGROUND

PMID: 33635310 (View on PubMed)

Lovre D, Qadir MMF, Bateman K, Saltzman LY, Sherman M, Mauvais-Jarvis F. Acute estradiol and progesterone therapy in hospitalized adults to reduce COVID-19 severity: a randomized control trial. Sci Rep. 2024 Sep 30;14(1):22732. doi: 10.1038/s41598-024-73263-5.

Reference Type: DERIVED

PMID: 39349554 (View on PubMed)

Ramanadhan S, Hansen K, Henderson JT, Cohen MA, Paynter R, Edelman A. Risk of thromboembolism in patients with COVID-19 who are using hormonal contraception. Cochrane Database Syst Rev. 2023 May 15;5(5):CD014908. doi: 10.1002/14651858.CD014908.pub3.

Reference Type: DERIVED

PMID: 37184292 (View on PubMed)

Cohen MA, Edelman A, Paynter R, Henderson JT. Risk of thromboembolism in patients with COVID-19 who are using hormonal contraception. Cochrane Database Syst Rev. 2023 Jan 9;1(1):CD014908. doi: 10.1002/14651858.CD014908.pub2.

Reference Type: DERIVED

PMID: 36622724 (View on PubMed)

Lovre D, Bateman K, Sherman M, Fonseca VA, Lefante J, Mauvais-Jarvis F. Acute estradiol and progesterone therapy in hospitalised adults to reduce COVID-19 severity: a randomised control trial. BMJ Open. 2021 Nov 30;11(11):e053684. doi: 10.1136/bmjopen-2021-053684.

Reference Type: DERIVED

PMID: 34848523 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2020-939

Identifier Type: -

Identifier Source: org_study_id