Estrogen Therapy in Non-severe COVID-19 Patients

• ClinicalTrials.gov Identifier: NCT04539626
• Recruitment Status: Active, not recruiting
• First Posted: September 7, 2020
• Last Update Posted: July 11, 2022
• Sponsor: CMN "20 de Noviembre"
• Information provided by (Responsible Party): Alfredo Cortés Algara, CMN "20 de Noviembre"

Tracking Information

• First Submitted Date: September 3, 2020
• First Posted Date: September 7, 2020
• Last Update Posted Date: July 11, 2022
• Actual Study Start Date: October 1, 2020
• Actual Primary Completion Date: July 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 3, 2020)

• Clinical improve to estrogen therapy in non-severe COVID-19 patients Clinical improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 7 ]
  • 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
• Clinical improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 14 ]
  • 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
• Clinical improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 21 ]
  • 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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 27, 2022)

• Symptomatic improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 7 ]
  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.
• Symptomatic improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 14 ]
  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.
• Symptomatic improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 21 ]
  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.
• Biochemical improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 7 ]
  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.
• Biochemical improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 14 ]
  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.
• Angiotensin 1-7 change after estrogen therapy in non-severe COVID-19 patientsCOVID-19 patients [ Time Frame: Day 21 ]
  Percentage change from Angiotensin 1-7, measured with the Human Angiotensin 1-7 ELISA kit (colorimetric) [pg/mL]

Original Secondary Outcome Measures (submitted: September 3, 2020)

• Symptomatic improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 7 ]
  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.
• Symptomatic improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 14 ]
  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.
• Symptomatic improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 21 ]
  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.
• Biochemical improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 7 ]
  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.
• Biochemical improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 14 ]
  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.
• Biochemical improve to estrogen therapy in non-severe COVID-19 patients [ Time Frame: Day 21 ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Estrogen Therapy in Non-severe COVID-19 Patients
• Official Title: Estrogen Therapy in Non-severe COVID-19 Patients: Proposed Treatment Scheme in a Tertiary Hospital
• Brief Summary: 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

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
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description:

The Outcome Assessor will be an external member of the Gynecology Service, which will be blinded to the intervention.

Primary Purpose: Treatment

• Condition: Covid-19

Intervention

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

Study Arms

• 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)

  Intervention: Drug: Estrogen Therapy
• No Intervention: Control Group
  Patients who will receive conventional COVID-19 treatment

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 27, 2022): 44
• Original Estimated Enrollment (submitted: September 3, 2020): 60
• Estimated Study Completion Date: December 2022
• Actual Primary Completion Date: July 30, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Mexico

Administrative Information

• NCT Number: NCT04539626
• Other Study ID Numbers: 03
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Alfredo Cortés Algara, CMN "20 de Noviembre"
• Original Responsible Party: Same as current
• Current Study Sponsor: CMN "20 de Noviembre"
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

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

• PRS Account: CMN "20 de Noviembre"
• Verification Date: July 2022