Estradiol and Progesterone in Hospitalized COVID-19 Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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Acute Estradiol and Progesterone Therapy in Hospitalized Adults to Reduce Coronavirus Disease (COVID-19) Severity: A Randomized Control Trial

Conditions
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Covid19

Intervention / Treatment
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* Other: Placebo injection and placebo pill
* Drug: Estradiol Cypionate 5 mg/ml
* Drug: Progesterone 200 mg Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Respiratory symptoms (fever, shortness of breath or cough) or abnormal lung exam or chest imaging characteristic of mild to severe COVID-19 pneumonia. Patient and/or legally authorized representative (LAR) agrees to comply with study procedures and the collection of blood samples per protocol. Patient and/or LAR agrees to be placed on prophylactic dose of anticoagulation for prevention of deep venous thrombosis (DVT) (if necessary). Patient or legally authorized representative has signed informed consent. Women of childbearing age with a negative pregnancy test on admission. Exclusion Criteria: Patient under 18 years of age. Critical COVID-19 (respiratory failure requiring intubation and mechanical ventilation, shock, multi-organ failure). Pregnant women confirmed by pregnancy test. Women who are within six weeks of postpartum. Patient is not hospitalized at Tulane Medical Center with confirmed COVID-19. Patient included in another COVID-19 trial (excluding hydroxychloroquine and dexamethasone). Women already treated by estrogen and or progestogen therapy two weeks prior to admission. Men already treated by testosterone therapy prior to admission. History of breast or endometrial cancer. Abnormal genital bleeding. Active or recent (e.g., within the past year) stroke or myocardial infarction. History of blood clots including deep vein thrombosis related to clotting disease, or pulmonary emboli (prior to hospitalization). History of liver dysfunction or disease. Patients with end-stage renal disease Patients taking inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, and ritonavir. Patients taking St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin. Patients within 6 weeks of major orthopedic surgery.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Standard of Care along with Estradiol Cypionate 5mg intramuscular injection at admission and Progesterone 200mg by mouth daily for 5 days starting at admission. | Drug: Estradiol Cypionate 5 mg/ml<br>* Standard of Care along with Estradiol Cypionate 5mg intramuscular injection at admission.<br>Drug: Progesterone 200 mg Oral Capsule<br>* Standard of Care along with Progesterone 200mg by mouth daily for 5 days starting at admission.<br>|
| Other: Control Arm<br>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 | Other: Placebo injection and placebo pill<br>* Standard of Care consistent with the National Institutes of Health (NIH) COVID-19 Treatment Guidelines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Scores 1 or 2 on the 9-point World Health Organization (WHO) Ordinal Scale at Discharge, Measured up to Day 21 | The proportion will be calculated based on WHO ordinal scale for clinical improvement. The scale is from 0 to 8, with a higher score indicating worse clinical status. Uninfected: No clinical or virological evidence of infection 0 Ambulatory: No limitation of activities 1 Limitation of activities 2 Hospitalized Mild Disease Hospitalized, no oxygen therapy 3 Oxygen by mask or nasal prongs 4 Hospitalized Severe Disease Non-invasive ventilation or high flow oxygen 5 Intubation and mechanical ventilation 6 Ventilation + additional organ support - 7 pressors, Renal Replacement Therapy (RRT), Extracorporeal Membrane Oxygenation (ECMO) Dead Death 8 | At discharge, measured up to Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of Hospital Stay | The investigators will review patients' medical records on day 14 and day 28. Then, the investigators will call patients on day 60. This will be done to determine the efficiency of treatment on length of hospital stay. | Baseline to day 60 | 
| Readmission | The investigators will review patients' medical records on day 14 and day 28. Then, the investigators will call patients on day 60. This will be done to determine the readmission rates. | Baseline to day 60 | 
| Number of Patients Requiring Invasive Mechanical Ventilation | The investigators will review patients' medical records on day 14 and day 28. Then, the investigators will call patients on day 60. This will be done to determine the number of patients requiring invasive mechanical ventilation | Baseline to day 60 | 
| Number of Days Death Occurred After Admission | The investigators will review patients' medical records on day 14 and day 28 and calculate number of deaths that occurred after admission. Then, the investigators will call patients on day 60. This will be done to determine the number of days death occurred after admission. | Baseline to day 60 | 
| Number of Participants With Each Cause of Death | The investigators will review patients' medical records on day 14 and day 28 and determine the cause of death. Then, the investigators will call patients on day 60. This will be done to determine the cause of death. | Baseline to day 60 | 
| Grade 3 Adverse Events Occurrence | Subjects will be followed daily for 7 days after initiation of treatment for adverse events. The investigators will review patients' medical records on day 14 and day 28. Then, the investigators will call patients on day 60. This will be done to determine the frequency and severity of adverse events in treatment arm vs. control arm. | Baseline to day 60 | 
| Serious Adverse Events Occurrence | Subjects will be followed daily for 7 days after initiation of treatment for serious adverse events. The investigators will review patients' medical records on day 14 and day 28. Then, the investigators will call patients on day 60. This will be done to determine the frequency of serious adverse events in treatment arm vs. control arm. | Baseline to day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Progesterone, Estradiol, Covid19, Estrogen, Hormones, Progestogens, Depo-Estradiol, Prometrium, Micronized Progesterone