E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with moderate COVID-19. |
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E.1.1.1 | Medical 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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053983 |
E.1.2 | Term | Corona virus infection |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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). |
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E.2.2 | Secondary 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). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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, history, or patients at risk of development 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.
16. Use of zanamivir or oseltamivir within 1 week prior to randomization.
17. Vaccinations within 30 days of Screening.
18. 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).
19. Using methyldopa or clonidine containing antihypertensive medication.
20. Hypersensitivity to the active substance of the study drug or any other components of the study drug. |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |