Back to resultsEstetrol (E4) for the Treatment of Patients With Confirmed SARS-COV-2 Infection
Primary Purpose
Covid19
Status
Unknown status
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Estetrol monohydrate 15 mg
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Covid19 focused on measuring SARs-CoV-2 infection, COVID 19 infection, Estetrol
Eligibility Criteria
Inclusion Criteria:
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.
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.
- Hospitalized.
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.
- WHO Ordinal Scale for Clinical Improvement score of 4 or 5.
- Able to provide informed consent.
- Able to comply with the study procedures as defined in this protocol.
Exclusion Criteria:
- Males currently receiving estrogen-based hormonal therapy.
- Current participation in another interventional clinical trial.
- Ventilated and/or in ICU.
- Any unexplained abnormal bleeding including, but not limited to, vaginal bleeding.
- Diagnosed protein C, protein S or antithrombin III deficiency or any other known inherited or acquired thrombophilic abnormalities (e.g. hyperhomocysteinemia, anti-phospholipid antibodies).
- Renal impairment (glomerular filtration rate [GFR] <30 mL/min/1.73 m²).
- Presence or history of severe liver disease or liver cancer (non-malignant or malignant).
- Presence or history (including suspected diagnosis) of breast cancer.
- Presence or history (including suspected diagnosis) of estrogen-sensitive tumors (e.g. endometrial cancer).
- Patients with endometrial hyperplasia.
- Patients with severe hypoxemia at risk of endotracheal intubation.
- Immunocompromised patients
- History of stroke, acute coronary syndromes, or angina pectoris.
- Presence or history of arterial or venous thrombosis/thrombembolia (including deep vein thrombosis and pulmonary emboli).
- 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.
- Use of zanamivir or oseltamivir within 1 week prior to randomization.
- 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).
- Using methyldopa or clonidine containing antihypertensive medication.
- Hypersensitivity to the active substance of the study drug or any other components of the study drug.
Sites / Locations
- ERASME Hospital
- CHR Citadelle
- Koranyi National Institute of Pulmonology
- University of Pecs Medical Center
- University of Szeged Medical Center
- Szent Borbala Korhaz
- Wojewódzki Szpital Specjalistyczny w Białej Podlaskiej Oddział Kardiologiczny Pododdział Kardiologii Zachowawczej
- Zespół Opieki Zdrowotnej w Bolesławcu Oddział Chorób Wewnętrznych
- Arion Med. Sp z o.o. Zespół Opieki Zdrowotnej w Gostyninie Oddział Chorób Wewnętrznych
- Samodzielny Publiczny Zakad Opieki Zdrowotnej w Pulawach Oddział Obserwacyjno-Zakaźny
- Samodzielny Publiczny Zespół Zakładów Opieki Zdrowotnej w Staszowie Oddział Chorób Wewnętrznych
- Wielospecjalistycznego Szpitala im. J. Strusia z Zakładem Opiekuńczo - Leczniczym SP ZOZ Oddział Chorób Wewnętrznych
- Szpital Matki Bożej Nieustającej Pomocy w Wołominie Oddział Chorób Wewnętrznych
- Wojewódzki Szpital Specjalistyczny im. J. Gromkowskiego I Oddział Chorób Zakaźnych
- City Clinical Hospital #15 n.a. Filatov
- State budgetary healthcare institution of Moscow "City Clinical Hospital No 52 of the Department of Healhcare of Moscow"
- State Budgetary Healthcare Institution "Clinical Infectious Disease Hospital No. 1 of the Moscow City Health Department"
- Saint-Petersburg state budgetary healthcare institution "Clinical infectious hospital n.a. S.P. Botkin"
- City Hospital #15
- Saint-Petersburg state budgetary healthcare institution "Pokrovskaya City Hospital"
- Saint-Petersburg state budgetary healthcare institution "Alexandrovskaya City Hospital"
- Saint-Petersburg state budgetary healthcare institution "City hospital No 40 of resort region"
- Budgetary healthcare institution of Voronezh Region "Voronezh regional clinical hospital"
- State budgetary healthcare institution of the Yaroslavl Region "Yaroslavl regional clinical hospital of the war veterans - international center for health problems of aged people "Healthy longevity"
- State budgetary healthcare institution of Moscow Region "Zhukovskaya City Clinical Hospital"
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Treatment Arm
Placebo Arm
Arm Description
Subjects will receive 15 mg E4 orally once daily for 21 consecutive days
Subjects will receive matching placebo orally once daily for 21 consecutive days.
Outcomes
Primary Outcome Measures
Percentage of participants who have recovered 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
Number of participants reaching a score of ≥6 on the WHO (0-10) scale 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]
Time to recovery
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]
SARS-CoV-2 viral load
Number of participants with AEs, SAEs, AESIs, SARs, SUSARs and Laboratory abnormalities as a measure of safety
AEs, Adverse events; SAEs, Serious adverse events; AESIs, Adverse events of special interest; SARs, Serious adverse reactions; SUSARs, Suspected unexpected serious adverse reactions.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04801836
Brief Title
Estetrol (E4) for the Treatment of Patients With Confirmed SARS-COV-2 Infection
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2021
Overall Recruitment Status
Unknown status
Study Start Date
November 19, 2020 (Actual)
Primary Completion Date
March 4, 2022 (Anticipated)
Study Completion Date
August 5, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
NEURALIS s.a.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Covid19
Keywords
SARs-CoV-2 infection, COVID 19 infection, Estetrol
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
162 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment Arm
Arm Type
Experimental
Arm Description
Subjects will receive 15 mg E4 orally once daily for 21 consecutive days
Arm Title
Placebo Arm
Arm Type
Placebo Comparator
Arm Description
Subjects will receive matching placebo orally once daily for 21 consecutive days.
Intervention Type
Drug
Intervention Name(s)
Estetrol monohydrate 15 mg
Other Intervention Name(s)
E4 15 mg
Intervention Description
One Estetrol monohydrate (E4) 15 mg tablet once per day
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
One placebo tablet once per day
Primary Outcome Measure Information:
Title
Percentage of participants who have recovered at Day 28
Description
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]
Time Frame
At Day 28
Secondary Outcome Measure Information:
Title
Number of participants reaching a score of ≥6 on the WHO (0-10) scale at Day 28
Description
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]
Time Frame
At Day 28
Title
Time to recovery
Description
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]
Time Frame
Up to Day 28
Title
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)
Title
Number of participants with AEs, SAEs, AESIs, SARs, SUSARs and Laboratory abnormalities as a measure of safety
Description
AEs, Adverse events; SAEs, Serious adverse events; AESIs, Adverse events of special interest; SARs, Serious adverse reactions; SUSARs, Suspected unexpected serious adverse reactions.
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
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.
Hospitalized.
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.
WHO Ordinal Scale for Clinical Improvement score of 4 or 5.
Able to provide informed consent.
Able to comply with the study procedures as defined in this protocol.
Exclusion Criteria:
Males currently receiving estrogen-based hormonal therapy.
Current participation in another interventional clinical trial.
Ventilated and/or in ICU.
Any unexplained abnormal bleeding including, but not limited to, vaginal bleeding.
Diagnosed protein C, protein S or antithrombin III deficiency or any other known inherited or acquired thrombophilic abnormalities (e.g. hyperhomocysteinemia, anti-phospholipid antibodies).
Renal impairment (glomerular filtration rate [GFR] <30 mL/min/1.73 m²).
Presence or history of severe liver disease or liver cancer (non-malignant or malignant).
Presence or history (including suspected diagnosis) of breast cancer.
Presence or history (including suspected diagnosis) of estrogen-sensitive tumors (e.g. endometrial cancer).
Patients with endometrial hyperplasia.
Patients with severe hypoxemia at risk of endotracheal intubation.
Immunocompromised patients
History of stroke, acute coronary syndromes, or angina pectoris.
Presence or history of arterial or venous thrombosis/thrombembolia (including deep vein thrombosis and pulmonary emboli).
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.
Use of zanamivir or oseltamivir within 1 week prior to randomization.
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).
Using methyldopa or clonidine containing antihypertensive medication.
Hypersensitivity to the active substance of the study drug or any other components of the study drug.
Facility Information:
Facility Name
ERASME Hospital
City
Brussels
ZIP/Postal Code
1070
Country
Belgium
Facility Name
CHR Citadelle
City
Liège
ZIP/Postal Code
4000
Country
Belgium
Facility Name
Koranyi National Institute of Pulmonology
City
Budapest
ZIP/Postal Code
1121
Country
Hungary
Facility Name
University of Pecs Medical Center
City
Pécs
ZIP/Postal Code
7623
Country
Hungary
Facility Name
University of Szeged Medical Center
City
Szeged
ZIP/Postal Code
6725
Country
Hungary
Facility Name
Szent Borbala Korhaz
City
Tatabánya
ZIP/Postal Code
2800
Country
Hungary
Facility Name
Wojewódzki Szpital Specjalistyczny w Białej Podlaskiej Oddział Kardiologiczny Pododdział Kardiologii Zachowawczej
City
Biała Podlaska
ZIP/Postal Code
21-500
Country
Poland
Facility Name
Zespół Opieki Zdrowotnej w Bolesławcu Oddział Chorób Wewnętrznych
City
Boleslawiec
ZIP/Postal Code
59-700
Country
Poland
Facility Name
Arion Med. Sp z o.o. Zespół Opieki Zdrowotnej w Gostyninie Oddział Chorób Wewnętrznych
City
Gorzewo
ZIP/Postal Code
09-500
Country
Poland
Facility Name
Samodzielny Publiczny Zakad Opieki Zdrowotnej w Pulawach Oddział Obserwacyjno-Zakaźny
City
Puławy
ZIP/Postal Code
24-100
Country
Poland
Facility Name
Samodzielny Publiczny Zespół Zakładów Opieki Zdrowotnej w Staszowie Oddział Chorób Wewnętrznych
City
Staszów
ZIP/Postal Code
28-200
Country
Poland
Facility Name
Wielospecjalistycznego Szpitala im. J. Strusia z Zakładem Opiekuńczo - Leczniczym SP ZOZ Oddział Chorób Wewnętrznych
City
Szczecin
ZIP/Postal Code
71-455
Country
Poland
Facility Name
Szpital Matki Bożej Nieustającej Pomocy w Wołominie Oddział Chorób Wewnętrznych
City
Wołomin
ZIP/Postal Code
05-200
Country
Poland
Facility Name
Wojewódzki Szpital Specjalistyczny im. J. Gromkowskiego I Oddział Chorób Zakaźnych
City
Wrocław
ZIP/Postal Code
51-149
Country
Poland
Facility Name
City Clinical Hospital #15 n.a. Filatov
City
Moscow
ZIP/Postal Code
111539
Country
Russian Federation
Facility Name
State budgetary healthcare institution of Moscow "City Clinical Hospital No 52 of the Department of Healhcare of Moscow"
City
Moscow
ZIP/Postal Code
123182
Country
Russian Federation
Facility Name
State Budgetary Healthcare Institution "Clinical Infectious Disease Hospital No. 1 of the Moscow City Health Department"
City
Moscow
ZIP/Postal Code
125367
Country
Russian Federation
Facility Name
Saint-Petersburg state budgetary healthcare institution "Clinical infectious hospital n.a. S.P. Botkin"
City
Saint Petersburg
ZIP/Postal Code
191167
Country
Russian Federation
Facility Name
City Hospital #15
City
Saint Petersburg
ZIP/Postal Code
198205
Country
Russian Federation
Facility Name
Saint-Petersburg state budgetary healthcare institution "Pokrovskaya City Hospital"
City
Saint Petersburg
ZIP/Postal Code
199106
Country
Russian Federation
Facility Name
Saint-Petersburg state budgetary healthcare institution "Alexandrovskaya City Hospital"
City
Saint-Petersburg
ZIP/Postal Code
193312
Country
Russian Federation
Facility Name
Saint-Petersburg state budgetary healthcare institution "City hospital No 40 of resort region"
City
Sestroretsk
ZIP/Postal Code
197706
Country
Russian Federation
Facility Name
Budgetary healthcare institution of Voronezh Region "Voronezh regional clinical hospital"
City
Voronezh
ZIP/Postal Code
394066
Country
Russian Federation
Facility Name
State budgetary healthcare institution of the Yaroslavl Region "Yaroslavl regional clinical hospital of the war veterans - international center for health problems of aged people "Healthy longevity"
City
Yaroslavl
ZIP/Postal Code
150047
Country
Russian Federation
Facility Name
State budgetary healthcare institution of Moscow Region "Zhukovskaya City Clinical Hospital"
City
Zhukovskiy
ZIP/Postal Code
140160
Country
Russian Federation
12. IPD Sharing Statement
Learn more about this trial
Estetrol (E4) for the Treatment of Patients With Confirmed SARS-COV-2 Infection
We'll reach out to this number within 24 hrs