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    Summary
    EudraCT Number:2020-003403-33
    Sponsor's Protocol Code Number:MIT-Co001-C101
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-12-16
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2020-003403-33
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the ability of E4 to improve the percentage of patients who recover by Day 28 compared to placebo in those with confirmed SARS-CoV-2 infection who are hospitalized with moderate COVID-19 (i.e. not on high flow oxygen or mechanical ventilation).
    A.4.1Sponsor's protocol code numberMIT-Co001-C101
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNEURALIS s.a.
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNEURALIS s.a.
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNEURALIS s.a.
    B.5.2Functional name of contact pointAnastassia Karageorgis
    B.5.3 Address:
    B.5.3.1Street AddressRue St-Georges 5/7
    B.5.3.2Town/ cityLiège
    B.5.3.3Post code4000
    B.5.3.4CountryBelgium
    B.5.4Telephone number+324353 37 00
    B.5.6E-mailakarageorgis@mithra.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEstetrol (E4)
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEstetrol
    D.3.9.1CAS number 2055649-81-3
    D.3.9.2Current sponsor codeE4
    D.3.9.3Other descriptive nameEstetrol monohydrate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with moderate COVID-19.
    E.1.1.1Medical condition in easily understood language
    Moderate COVID-19 patients hospitalized with confirmed SARS-CoV-2 infection who are at risk of deterioration due to lack of estrogen.
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10053983
    E.1.2Term Corona virus infection
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the ability of E4 to improve the percentage of patients who recover by Day 28 compared to placebo in those with confirmed SARS-CoV-2 infection who are hospitalized with moderate COVID-19 (i.e. not on high flow oxygen or mechanical ventilation).
    E.2.2Secondary objectives of the trial
    • To evaluate and compare the efficacy of E4 versus placebo treatment to prevent severe COVID-19 disease or worsening COVID-19 disease in patients with confirmed SARS-CoV-2 infection who are hospitalized with moderate COVID-19 (i.e. not on high flow oxygen or mechanical ventilation).
    • To assess the ability of E4 to improve the time to recovery compared to placebo in patients with confirmed SARS-CoV-2 infection who are hospitalized with moderate COVID-19 (i.e. not on high flow oxygen or mechanical ventilation).
    • Assess changes in viral load between the E4 and placebo groups.
    • To assess the general safety and tolerability of E4 compared to placebo when administered to patients with confirmed SARS-CoV-2 infection who are hospitalized with moderate COVID-19 (i.e. not on high flow oxygen or mechanical ventilation).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Postmenopausal women who have not used HRT (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 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.

    The definition of moderate COVID-19 is:
    i. Positive testing by standard RT-PCR assay.
    ii. Symptoms of moderate illness with COVID-19, which could include any symptom of mild illness (including fever, cough, anosmia, dysgeusia, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms) or shortness of breath with exertion.
    iii. Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥20 breaths per minute, heart rate ≥90 beats per minute.
    iv. No clinical signs indicative of severe or critical illness (i.e. need for ventilation or ICU admission).
    3. Hospitalized.
    4. Clinical Frailty Score ≤5.
    5. World Health Organization (WHO) Ordinal Scale for Clinical Improvement score of 4 or 5.
    6. Able to provide IC.
    7. Able to comply with the study procedures as defined in the protocol.
    E.4Principal 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 <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/
    thromboembolia (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 SoC).
    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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint for this trial is the improvement in COVID-19 between the placebo and E4 groups measured by the percentage of patients recovered at Day 28. Recovery will be defined as reaching a score of ≤3 on the WHO (0-10) scale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 28 (±2 days) or 7 days (±2 days) after the last dose of study drug if treatment is stopped prior to Day 21.
    E.5.2Secondary end point(s)
    1. The percentage of patients reaching a score of WHO ordinal scales (0-10) of ≥6 at 28 days.
    2. The improvement in time to recovery between the placebo and E4 groups (≤3 on the WHO (0-10) scale).
    3. Changes in viral load between the E4 and placebo groups.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • WHO Ordinal Scale for Clinical Improvement score will be recorded daily at the same time each day (±3 hours) at Screening, on Treatment Days 1−21 whilst the patient is hospitalized and at the End of Treatment and End of Study visits.
    • Oropharyngeal swabs for viral load assessment will be taken on Treatment Day 1 (immediately before taking the dose of study drug), on Days 3, 7, and 14 when the patient is in hospital, and at the End of Treatment visit.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Georgia
    Russian Federation
    Belgium
    Hungary
    Poland
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 81
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 81
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 81
    F.4.2.2In the whole clinical trial 162
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-01-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-09-24
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