Estradiol and Progesterone in Hospitalized COVID-19 Patients

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04865029

Enrollment

Registered

2021-04-29

Start date

2021-07-22

Completion date

2022-01-25

Last updated

2023-06-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Covid19

Keywords

Estradiol, Progesterone, Covid19, Estrogen, Hormones, Progestogens, Depo-Estradiol, Prometrium, Micronized Progesterone

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.

Interventions

DRUGEstradiol Cypionate 5 mg/ml

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

OTHERPlacebo injection and placebo pill

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

DRUGProgesterone 200 mg Oral Capsule

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Double-blinded clinical trial

Intervention model description

Randomized, placebo-controlled

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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	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

Secondary

Measure	Time frame	Description
Readmission	Baseline to day 60	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.
Number of Patients Requiring Invasive Mechanical Ventilation	Baseline to day 60	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
Number of Days Death Occurred After Admission	Baseline to day 60	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.
Length of Hospital Stay	Baseline to day 60	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.
Grade 3 Adverse Events Occurrence	Baseline to day 60	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.
Serious Adverse Events Occurrence	Baseline to day 60	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.
Number of Participants With Each Cause of Death	Baseline to day 60	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Estradiol and Progesterone 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. Estradiol Cypionate 5 mg/ml: Standard of Care along with Estradiol Cypionate 5mg intramuscular injection at admission. Progesterone 200 mg Oral Capsule: Standard of Care along with Progesterone 200mg by mouth daily for 5 days starting at admission.	5
Normal Saline and Folic Acid Arm Standard of Care along with placebo-equivalent injection (1mL Normal Saline intramuscular injection) at admission and placebo-equivalent pill (folic acid 400 mg pill) daily for 5 days starting at admission. Standard of Care consistent with the National Institutes of Health (NIH) COVID-19 Treatment Guidelines. Placebo injection and placebo pill: Standard of Care consistent with the National Institutes of Health (NIH) COVID-19 Treatment Guidelines	5
Total	10

Baseline characteristics

Characteristic	Total	Estradiol and Progesterone Arm	Normal Saline and Folic Acid Arm
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	1 Participants	0 Participants
Age, Categorical Between 18 and 65 years	9 Participants	4 Participants	5 Participants
Age, Continuous	48.5 Years STANDARD_DEVIATION 12.78	51.4 Years STANDARD_DEVIATION 12.92	45.6 Years STANDARD_DEVIATION 13.41
Alanine transaminase (ALT)	66.4 Units/L STANDARD_DEVIATION 51.19	62.6 Units/L STANDARD_DEVIATION 60.01	70.2 Units/L STANDARD_DEVIATION 47.52
Aspartate aminotransferase (AST)	78.5 Units/L STANDARD_DEVIATION 64.53	78.8 Units/L STANDARD_DEVIATION 74.97	78.2 Units/L STANDARD_DEVIATION 61.22
Body Mass Index	31.63 Kg/m^2 STANDARD_DEVIATION 9.52	24.5 Kg/m^2 STANDARD_DEVIATION 5.47	38.76 Kg/m^2 STANDARD_DEVIATION 6.87
Charlson Comorbidity Index (CCI)	1.9 units on a scale STANDARD_DEVIATION 1.6	2.4 units on a scale STANDARD_DEVIATION 1.82	1.4 units on a scale STANDARD_DEVIATION 1.34
Diastolic blood pressure	83.3 mmHg STANDARD_DEVIATION 17.5	91 mmHg STANDARD_DEVIATION 18	75.6 mmHg STANDARD_DEVIATION 14.76
Heart rate	95.9 Beats per minute (Bpm) STANDARD_DEVIATION 12.04	94.2 Beats per minute (Bpm) STANDARD_DEVIATION 14.67	97.6 Beats per minute (Bpm) STANDARD_DEVIATION 10.19
Neutrophil lymphocyte ratio (NLR)	3.90 Ratio STANDARD_DEVIATION 1.84	3.96 Ratio STANDARD_DEVIATION 0.86	3.85 Ratio STANDARD_DEVIATION 2.61
O2 saturation	90.7 Percentage of O2 saturation STANDARD_DEVIATION 5.29	93 Percentage of O2 saturation STANDARD_DEVIATION 4.8	88.4 Percentage of O2 saturation STANDARD_DEVIATION 5.18
Platelet count	208.9 10^9 cells per liter STANDARD_DEVIATION 74.65	260 10^9 cells per liter STANDARD_DEVIATION 66.49	157.8 10^9 cells per liter STANDARD_DEVIATION 39.88
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	7 Participants	4 Participants	3 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	1 Participants	2 Participants
Region of Enrollment United States	10 participants	5 participants	5 participants
Sex: Female, Male Female	5 Participants	3 Participants	2 Participants
Sex: Female, Male Male	5 Participants	2 Participants	3 Participants
Smoking status Non smokers	4 partipants	1 partipants	3 partipants
Smoking status Smokers	6 partipants	4 partipants	2 partipants
Systolic Blood pressure	140.1 mmHg STANDARD_DEVIATION 17.54	140.8 mmHg STANDARD_DEVIATION 18.21	139.4 mmHg STANDARD_DEVIATION 18.97
Temperature	99.32 Fahrenheit STANDARD_DEVIATION 1.5	98.38 Fahrenheit STANDARD_DEVIATION 1.33	100.26 Fahrenheit STANDARD_DEVIATION 1.07
White blood Cells (WBC)	6.5 10^9 cells per liter. STANDARD_DEVIATION 1.37	6.62 10^9 cells per liter. STANDARD_DEVIATION 0.72	6.38 10^9 cells per liter. STANDARD_DEVIATION 1.91
World Health Organization (WHO) Score of 3 to 5 at randomization	10 Participants	5 Participants	5 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 5	1 / 5
other Total, other adverse events	0 / 5	1 / 5
serious Total, serious adverse events	0 / 5	1 / 5

Outcome results

Primary

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

Time frame: At discharge, measured up to Day 21

Population: Number of participants who achieved WHO score of 1 to 2 at discharge, measured up to Day 21

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Estradiol and Progesterone Arm	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	5 Participants
Normal Saline and Folic Acid Arm	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	4 Participants

Secondary

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.