Estrogen Therapy in Non-severe COVID-19 Patients

Estrogen Therapy in Non-severe COVID-19 Patients: Proposed Treatment Scheme in a Tertiary Hospital

The primary objective of this study is to evaluate the effect of additional estradiol estrogen therapy on clinical response and mortality in non-severe COVID-19 patients

Study Overview

• Status: Active, not recruiting
• Conditions: Covid-19
• Intervention / Treatment: Drug: Estrogen Therapy

Detailed Description

Actually, there is not treatment or vaccine that can prevent or control the evolution of COVID-19. The epidemiological data reported in China by the Center for Disease Control (CDC) on February 2020, reported that 87% of the patients have been adults in an age range of 30-69 years. In addition, different studies have shown that male gender are more vulnerable for the contagion of the virus (60%-80%), as well as the clinical evolution of COVID-19 (including mortality) compared to the female sex (20-40%), independently of individual such as diabetes, cardiovascular diseases, obesity, mainly.

The mechanism of SARS-CoV-2 infection has been shown to occur with the interaction of angiotensin converting enzyme 2 (ACE2), this enzyme is expressed in lungs, brain, heart, kidneys and gastrointestinal tract. Also, has been shown that older people have higher levels of ACE2 expression. Among the different molecular functions of ACE2 are the regulation of cell proliferation, cytokine production, and inflammatory response.

It has been proposed that exogenous human recombinant ACE2 could be an alternative treatment for COVID-19, however, this treatment is not yet highly available and could entail high costs. Other molecules as estrogens have been proposed in different research groups, for its capacity to increase the gene expression of ACE2/Ang 1-7. This mechanism could reduce lung and endothelial damage and coagulopathy in COVID-19 patients.

So, it is relevant to evaluate the effect of additional estradiol estrogen (as adjuvant therapeutic element) therapy on clinical response and mortality in non-severe COVID-19 patients.

A controlled clinical trial will be conducted in a tertiary hospital in Mexico City, Mexico. Participants will be divide in two groups; 1) intervention: who will receive EVRA skin patches (1 patch every week during 21 days) with norelgesetromin 6mg / ethinyl estradiol 0.60mg and 2) control: who will receive conventional treatment

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Mexico
  • Benito Juárez
    • Mexico City, Benito Juárez, Mexico, 03100
      • CMN "20 de Noviembre"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male ≥ 18 years of age and female ≥ 55 years of age
• Diagnosis of positive SARS-CoV-2 infection confirmed by clinical diagnosis and / or RT-PCR test
• Hospitalized patients in acute disease* stages of the disease
• Agree to participate in the study prior to signing an informed consent.

• Patients with conventional treatment with anticoagulants (Noxaparin)

  • Acute disease: patients who are hospitalized, conscious, not intubated, with biochemical values of D-Dimer> 2, Ferritin> 1000 u.

Exclusion Criteria:

• Patients with abnormal genital bleeding
• Patients with protein C or protein S deficiency
• Patients with liver failure (cirrhosis, hepatitis C)
• Patients with history of allergic reaction to estrogens use
• Patients receiving lamotrigine therapy
• Patients with a history of breast cancer and / or endometrial cancer
• Patients with severe hypoxia at risk of acute intubation in ED
• Patients with a history of cerebrovascular history
• Male patients with testosterone treatment
• Patients with a history of myocardial infarction, who have cardiac stents and / or unstable angina pectoris
• Patients with previous hormonal treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Estrogen Therapy; Drug: Norelgesetromin 6mg / Ethinyl estradiol 0.60mg Dosage form: EVRA skin patches with norelgesetromin 6mg / ethinyl estradiol 0.60mg, (1 patch will be placed every week during 21 days)	Drug: Estrogen Therapy; EVRA skin patches with norelgesetromin 6mg / ethinyl estradiol 0.60mg, (1 patch will be placed every week during 21 days); Other Names: Norelgesetromin; Ethinyl estradiol
No Intervention: Control Group; Patients who will receive conventional COVID-19 treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical improve to estrogen therapy in non-severe COVID-19 patients Clinical improve to estrogen therapy in non-severe COVID-19 patients	Success rate in reducing hospitalization days; Success rate in no oxygen therapy use (low or high-flow oxygen); Success rate in no intubation and/or mechanical ventilation; Success rate in non mortality occurrence	Day 7
Clinical improve to estrogen therapy in non-severe COVID-19 patients	Success rate in reducing hospitalization days; Success rate in no oxygen therapy use (low or high-flow oxygen); Success rate in no intubation and/or mechanical ventilation; Success rate in non mortality occurrence	Day 14
Clinical improve to estrogen therapy in non-severe COVID-19 patients	Success rate in reducing hospitalization days; Success rate in no oxygen therapy use (low or high-flow oxygen); Success rate in no intubation and/or mechanical ventilation; Success rate in non mortality occurrence	Day 21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic improve to estrogen therapy in non-severe COVID-19 patients	According to the National Committee for Epidemiological Surveillance (CONAVE) in Mexico, COVID-19 symptomatic onset rate defined as the presence of cough, fever or headache during the last 7 days, accompanied at least one of the following symptoms: dyspnea, arthralgia, myalgia, odynophagia / pharyngeal burning, rhinorrhea, conjunctivitis or chest pain.	Day 7
Symptomatic improve to estrogen therapy in non-severe COVID-19 patients	According to the National Committee for Epidemiological Surveillance (CONAVE) in Mexico, COVID-19 symptomatic onset rate defined as the presence of cough, fever or headache during the last 7 days, accompanied at least one of the following symptoms: dyspnea, arthralgia, myalgia, odynophagia / pharyngeal burning, rhinorrhea, conjunctivitis or chest pain.	Day 14
Symptomatic improve to estrogen therapy in non-severe COVID-19 patients	According to the National Committee for Epidemiological Surveillance (CONAVE) in Mexico, COVID-19 symptomatic onset rate defined as the presence of cough, fever or headache during the last 7 days, accompanied at least one of the following symptoms: dyspnea, arthralgia, myalgia, odynophagia / pharyngeal burning, rhinorrhea, conjunctivitis or chest pain.	Day 21
Biochemical improve to estrogen therapy in non-severe COVID-19 patients	Percentage change from hemoglobin, hematocrit, leukocytes, erythrocytes, platelets, prothrombin, partial thromboplastin activation time, anti-thrombin activity, fibrinogen, fibrin degradation products, D-Dimer, ALT, AST, ALP, GGT, LD, albumin, cholesterol, triglycerides, HDL, LDL, C-reactive protein, estrogens and progesterone levels, pro inflammatory cytokine and nitric oxide profile.	Day 7
Biochemical improve to estrogen therapy in non-severe COVID-19 patients	Percentage change from hemoglobin, hematocrit, leukocytes, erythrocytes, platelets, prothrombin, partial thromboplastin activation time, anti-thrombin activity, fibrinogen, fibrin degradation products, D-Dimer, ALT, AST, ALP, GGT, LD, albumin, cholesterol, triglycerides, HDL, LDL, C-reactive protein, estrogens and progesterone levels, pro inflammatory cytokine and nitric oxide profile.	Day 14
Angiotensin 1-7 change after estrogen therapy in non-severe COVID-19 patientsCOVID-19 patients	Percentage change from Angiotensin 1-7, measured with the Human Angiotensin 1-7 ELISA kit (colorimetric) [pg/mL]	Day 21

Collaborators and Investigators

• Sponsor: CMN "20 de Noviembre"
• Investigators: Study Chair: Rodrigo Ruz Barros, MD, CMN "20 de Noviembre"; Study Chair: Daniel Santillán Cortés, MSc, CMN "20 de Noviembre"; Study Chair: Mónica Escamilla Tilch, PhD, CMN "20 de Noviembre"; Study Chair: Juan A Pineda Juárez, PhD, CMN "20 de Noviembre"; Study Chair: Sandra Muñoz López, MD, CMN "20 de Noviembre"; Study Chair: Maricela Escarela Serrano, MD, CMN "20 de Noviembre"; Study Chair: Paul Mondragón Terán, PhD, CMN "20 de Noviembre"; Study Chair: Alberto H De la Vega Bravo, MD, CMN "20 de Noviembre"; Principal Investigator: Alfredo L Cortés Algara, MD, MSc, CMN "20 de Noviembre"; Study Chair: Samuel Reyes-Long, MSc, Neurociencias básicas, Instituto Nacional de Rehabilitación LGII; Study Chair: Cindy Bandala, MD MSc PhD, Neurociencias básicas, Instituto Nacional de Rehabilitación LGII; Escuela Superior de Medicina, Instituto Politécnico Nacional

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2020
• Primary Completion (Actual): April 3, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: September 3, 2020
• First Submitted That Met QC Criteria: September 3, 2020
• First Posted (Actual): September 7, 2020

Study Record Updates

• Last Update Posted (Actual): April 5, 2023
• Last Update Submitted That Met QC Criteria: April 3, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: COVID-19; Estrogens; Severe Acute Respiratory Syndrome Coronavirus-2
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Hormonal; Estradiol; Ethinyl Estradiol; Estrogens
• Other Study ID Numbers: 03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No