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Estetrol (E4) for the Treatment of Patients With Confirmed SARS-COV-2 Infection

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04801836
Recruitment Status : Active, not recruiting
First Posted : March 17, 2021
Last Update Posted : August 2, 2021
Sponsor:
Information provided by (Responsible Party):
NEURALIS s.a.

Brief Summary:

It has been reported in several research studies that men are almost twice as likely to progress to severe COVID 19 disease and die than women. Some researchers have suggested this is due to the activity of estrogen which is produced by the ovaries in pre-menopausal women. Men and post-menopausal women produce very low levels of estrogen. This study will look whether E4, a natural estrogen, can help men and post-menopausal women that are hospitalized with COVID 19 infection but for whom help breathing is not yet needed.

The study has 2 parts. In Part A, 162 patients will be randomized (81 patients in the E4 treatment arm and 81 patients in the placebo treatment arm). The data collected from patients in Part A will address the primary and secondary objectives of the study. Once all patients in Part A have been randomized and Part A analysis is complete, assuming positive data, recruitment and double-blind randomization of patients will continue into Part B, unchanged, on 1:1 basis to E4 and placebo.


Condition or disease Intervention/treatment Phase
Covid19 Drug: Estetrol monohydrate 15 mg Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 162 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled Trial to Determine the Safety and Efficacy of Estetrol (E4) for the Treatment of Patients With Confirmed SARS-COV-2 Infection
Actual Study Start Date : November 19, 2020
Estimated Primary Completion Date : March 4, 2022
Estimated Study Completion Date : August 5, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment Arm
Subjects will receive 15 mg E4 orally once daily for 21 consecutive days
Drug: Estetrol monohydrate 15 mg
One Estetrol monohydrate (E4) 15 mg tablet once per day
Other Name: E4 15 mg

Placebo Comparator: Placebo Arm
Subjects will receive matching placebo orally once daily for 21 consecutive days.
Drug: Placebo
One placebo tablet once per day




Primary Outcome Measures :
  1. Percentage of participants who have recovered at Day 28 [ Time Frame: At Day 28 ]

    Participants have recovered if they have reached a score ≤3 on the World Health Organization (WHO) (0-10) scale.

    The WHO Ordinal Scale for Clinical Improvement is as follows: 0) uninfected; 1) ambulatory, asymptomatic; 2) ambulatory, symptomatic, independent; 3) ambulatory, symptomatic, assistance needed; 4) hospitalized, no oxygen therapy; 5) hospitalized, oxygen by mask or nasal prongs; 6) hospitalized, non-invasive ventilation or high-flow oxygen; 7) hospitalized, intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200; 8) hospitalized, mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressin; 9) hospitalized, mechanical ventilation, pO2/FiO2 <150 and vasopressin, dialysis, or extracorporeal membrane oxygenation (ECMO); 10) dead.

    [FiO2, fraction of inspired oxygen; pO2, partial pressure of oxygen; SpO2, oxygen saturation]



Secondary Outcome Measures :
  1. Number of participants reaching a score of ≥6 on the WHO (0-10) scale at Day 28 [ Time Frame: At Day 28 ]

    The WHO Ordinal Scale for Clinical Improvement is as follows: 0) uninfected; 1) ambulatory, asymptomatic; 2) ambulatory, symptomatic, independent; 3) ambulatory, symptomatic, assistance needed; 4) hospitalized, no oxygen therapy; 5) hospitalized, oxygen by mask or nasal prongs; 6) hospitalized, non-invasive ventilation or high-flow oxygen; 7) hospitalized, intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200; 8) hospitalized, mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressin; 9) hospitalized, mechanical ventilation, pO2/FiO2 <150 and vasopressin, dialysis, or extracorporeal membrane oxygenation (ECMO); 10) dead.

    [FiO2, fraction of inspired oxygen; pO2, partial pressure of oxygen; SpO2, oxygen saturation]


  2. Time to recovery [ Time Frame: Up to Day 28 ]

    Participants have recovered if they have reached a score ≤3 on the World Health Organization (WHO) (0-10) scale.

    The WHO Ordinal Scale for Clinical Improvement is as follows: 0) uninfected; 1) ambulatory, asymptomatic; 2) ambulatory, symptomatic, independent; 3) ambulatory, symptomatic, assistance needed; 4) hospitalized, no oxygen therapy; 5) hospitalized, oxygen by mask or nasal prongs; 6) hospitalized, non-invasive ventilation or high-flow oxygen; 7) hospitalized, intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200; 8) hospitalized, mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressin; 9) hospitalized, mechanical ventilation, pO2/FiO2 <150 and vasopressin, dialysis, or extracorporeal membrane oxygenation (ECMO); 10) dead.

    [FiO2, fraction of inspired oxygen; pO2, partial pressure of oxygen; SpO2, oxygen saturation]


  3. SARS-CoV-2 viral load [ Time Frame: At Days 1, 3, 7, and 14, and end of treatment visit (on Day 23 or within 48 hours of the last dose of study drug if treatment is stopped prior to Day 21) ]
  4. Number of participants with AEs, SAEs, AESIs, SARs, SUSARs and Laboratory abnormalities as a measure of safety [ Time Frame: Up to end of study (on Day 28 (±2 days) or 7 days (±2 days) after the last dose of study drug if treatment is stopped prior to Day 21) ]
    AEs, Adverse events; SAEs, Serious adverse events; AESIs, Adverse events of special interest; SARs, Serious adverse reactions; SUSARs, Suspected unexpected serious adverse reactions.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Postmenopausal women who have not used hormone replacement therapy (including oral, transdermal, topical, or vaginal preparations) within 1 year prior to study start. Menopause is defined as women who have at least 12 months of spontaneous amenorrhea without another medical cause.

    OR Men ≥18 years of age who are willing to use adequate contraception from Screening until 4 weeks after the last dose of study treatment.

  2. Patients with SARS-CoV-2 infection confirmed by a nationally accepted RT-PCR assay and moderate COVID-19.

    Patients with a strong clinical suspicion of moderate COVID-19 and a positive point-of-care test for viral infection can also be entered while the result of a nationally accepted RT-PCR assay is awaited; if the RT-PCR assay result is negative, the treatment must be stopped and the patient must be discontinued from the study.

    To meet the definition of moderate COVID-19, it is sufficient for a patient to have been hospitalized due to COVID-19 illness.

  3. Hospitalized.
  4. Clinical Frailty Score ≤5.

    The Clinical Frailty Scale is a nine-point global frailty scale (ranging from 1: "very fit" to 9: "terminally ill") based on clinical evaluation in the domains of mobility, energy, physical activity, and function. People scoring at 5: "mildly frail" often have more evident slowing and need help in high order Instrumental Activities of Daily Living (IADLs) (finances, transportation, heavy housework, medications). Typically, mild frailty progressively impairs shopping and walking outside alone, meal preparation and housework.

  5. WHO Ordinal Scale for Clinical Improvement score of 4 or 5.
  6. Able to provide informed consent.
  7. Able to comply with the study procedures as defined in this protocol.

Exclusion Criteria:

  1. Males currently receiving estrogen-based hormonal therapy.
  2. Current participation in another interventional clinical trial.
  3. Ventilated and/or in ICU.
  4. Any unexplained abnormal bleeding including, but not limited to, vaginal bleeding.
  5. Diagnosed protein C, protein S or antithrombin III deficiency or any other known inherited or acquired thrombophilic abnormalities (e.g. hyperhomocysteinemia, anti-phospholipid antibodies).
  6. Renal impairment (glomerular filtration rate [GFR] <30 mL/min/1.73 m²).
  7. Presence or history of severe liver disease or liver cancer (non-malignant or malignant).
  8. Presence or history (including suspected diagnosis) of breast cancer.
  9. Presence or history (including suspected diagnosis) of estrogen-sensitive tumors (e.g. endometrial cancer).
  10. Patients with endometrial hyperplasia.
  11. Patients with severe hypoxemia at risk of endotracheal intubation.
  12. Immunocompromised patients
  13. History of stroke, acute coronary syndromes, or angina pectoris.
  14. Presence or history of arterial or venous thrombosis/thrombembolia (including deep vein thrombosis and pulmonary emboli).
  15. Patients with any condition, including findings in the patients' medical history or in the screening study assessments that in the opinion of the Investigator, constitute a risk or a contraindication for the participation of the patient into the study or that could interfere with the study objectives, conduct or evaluation, including patients with suspected genital cancer or suspected breast cancer and patients with increased risk of development of venous thrombosis/thromboembolia for reasons other than COVID-19 disease.
  16. Use of zanamivir or oseltamivir within 1 week prior to randomization.
  17. Patients who have received prior investigational or off-label agents for COVID-19. (Note: use of antivirals and corticosteroids is allowed if part of Standard of Care).
  18. Using methyldopa or clonidine containing antihypertensive medication.
  19. Hypersensitivity to the active substance of the study drug or any other components of the study drug.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04801836


Locations
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Sponsors and Collaborators
NEURALIS s.a.
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Responsible Party: NEURALIS s.a.
ClinicalTrials.gov Identifier: NCT04801836    
Other Study ID Numbers: MIT-Co001-C101
2020-003403-33 ( EudraCT Number )
First Posted: March 17, 2021    Key Record Dates
Last Update Posted: August 2, 2021
Last Verified: May 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by NEURALIS s.a.:
SARs-CoV-2 infection
COVID 19 infection
Estetrol
Additional relevant MeSH terms:
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Infections
COVID-19
Respiratory Tract Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases