Clinical trial NCT04801836: 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
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Covid19
Keywords: SARs-CoV-2 infection
COVID 19 infection
Estetrol
Lead sponsor: NEURALIS s.a.
Sponsor class: INDUSTRY
First posted: 2021-03-17
Enrollment: 162
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Percentage of participants who have recovered at Day 28
timeFrame: At Day 28
Secondary outcomes:
measure: Number of participants reaching a score of ≥6 on the WHO (0-10) scale at Day 28
timeFrame: At Day 28
measure: Time to recovery
timeFrame: Up to Day 28
measure: SARS-CoV-2 viral load
timeFrame: 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)
measure: Number of participants with AEs, SAEs, AESIs, SARs, SUSARs and Laboratory abnormalities as a measure of safety
timeFrame: 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)
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: ERASME Hospital
city: Liège
country: Belgium
facility: CHR Citadelle
city: Budapest
country: Hungary
facility: Koranyi National Institute of Pulmonology
city: Pécs
country: Hungary
facility: University of Pecs Medical Center
city: Szeged
country: Hungary
facility: University of Szeged Medical Center
city: Tatabánya
country: Hungary
facility: Szent Borbala Korhaz
city: Biała Podlaska
country: Poland
facility: Wojewódzki Szpital Specjalistyczny w Białej Podlaskiej Oddział Kardiologiczny Pododdział Kardiologii Zachowawczej
city: Boleslawiec
country: Poland
facility: Zespół Opieki Zdrowotnej w Bolesławcu Oddział Chorób Wewnętrznych
city: Gorzewo
country: Poland
facility: Arion Med. Sp z o.o. Zespół Opieki Zdrowotnej w Gostyninie Oddział Chorób Wewnętrznych
city: Puławy
country: Poland
facility: Samodzielny Publiczny Zakad Opieki Zdrowotnej w Pulawach Oddział Obserwacyjno-Zakaźny
city: Staszów
country: Poland
facility: Samodzielny Publiczny Zespół Zakładów Opieki Zdrowotnej w Staszowie Oddział Chorób Wewnętrznych
city: Szczecin
country: Poland
facility: Wielospecjalistycznego Szpitala im. J. Strusia z Zakładem Opiekuńczo - Leczniczym SP ZOZ Oddział Chorób Wewnętrznych
city: Wołomin
country: Poland
facility: Szpital Matki Bożej Nieustającej Pomocy w Wołominie Oddział Chorób Wewnętrznych
city: Wrocław
country: Poland
facility: Wojewódzki Szpital Specjalistyczny im. J. Gromkowskiego I Oddział Chorób Zakaźnych
city: Moscow
country: Russian Federation
facility: City Clinical Hospital #15 n.a. Filatov
city: Moscow
country: Russian Federation
facility: State budgetary healthcare institution of Moscow "City Clinical Hospital No 52 of the Department of Healhcare of Moscow"
city: Moscow
country: Russian Federation
facility: State Budgetary Healthcare Institution "Clinical Infectious Disease Hospital No. 1 of the Moscow City Health Department"
city: Saint Petersburg
country: Russian Federation
facility: Saint-Petersburg state budgetary healthcare institution "Clinical infectious hospital n.a. S.P. Botkin"
city: Saint Petersburg
country: Russian Federation
facility: City Hospital #15
city: Saint Petersburg
country: Russian Federation
facility: Saint-Petersburg state budgetary healthcare institution "Pokrovskaya City Hospital"
city: Saint-Petersburg
country: Russian Federation
facility: Saint-Petersburg state budgetary healthcare institution "Alexandrovskaya City Hospital"
city: Sestroretsk
country: Russian Federation
facility: Saint-Petersburg state budgetary healthcare institution "City hospital No 40 of resort region"
city: Voronezh
country: Russian Federation
facility: Budgetary healthcare institution of Voronezh Region "Voronezh regional clinical hospital"
city: Yaroslavl
country: Russian Federation
facility: 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: Zhukovskiy
country: Russian Federation
facility: State budgetary healthcare institution of Moscow Region "Zhukovskaya City Clinical Hospital"
Study officials:
References: