Clinical Trial Results:
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
Summary
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EudraCT number |
2020-003403-33 |
Trial protocol |
BE HU |
Global end of trial date |
21 May 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Jun 2023
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First version publication date |
23 Jun 2023
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MIT-Co001-C101
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
NEURALIS SA
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Sponsor organisation address |
Rue Saint Georges 5-7, Liege, Belgium, 4000
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Public contact |
Clinical Study Leader, NEURALIS SA, +32 43492822, Clinical.Trials@mithra.com
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Scientific contact |
Clinical Study Leader, NEURALIS SA, +32 43492822, Clinical.Trials@mithra.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 Sep 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
21 May 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Assess the ability of estetrol (E4) to improve the percentage of patients who recover by Day 28 compared with 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).
Moderate COVID-19 was defined as described below:
i. Positive testing by a standard nationally accepted reverse transcription polymerase chain reaction (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 intensive care unit [ICU] admission)
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Protection of trial subjects |
This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines including the Declaration of Helsinki, International Council for Harmonization Good Clinical Practice (ICH GCP), 21 CFR 50 Protection of Human Rights, Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 21 CFR 56 Institutional Review Boards, and other applicable laws and regulations of the countries in which the study was conducted.
An independent Data Safety Monitoring Board (DSMB) was in place to review and assess the safety data at predefined meetings as required for safety reasons. The DSMB included one voting chairperson and 3 additional voting members and an unblinded statistician.
Due to the increased risk of VTE in COVID-19 infection, all patients were required to take anticoagulants as prophylaxis against VTE for the duration of the study treatment at a dose in accordance with the country's local or national guidelines.
Study MIT-Co001-C101 was designed as a two-part study (Part A and Part B). Part A addressed the primary and secondary objectives; study Part A was completed as planned. Part B was planned to be implemented after the analysis of Part A, as a separate entity and with a distinct cohort of patients. The data of Part B were to contribute to a planned Phase 3 confirmatory study. However, after the analysis of data from Part A of the current study, it was decided not to go ahead with Part B of the study -- and this was in line with the clinical study protocol.
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Background therapy |
Due to increased risk of VTE during COVID-19 infection, all subjects were required to take LMWH (or equivalent) for the duration of the study treatment (including at home after discharge). However, for patients who were already on oral anticoagulants, the addition of LMWH (or equivalent) was made at the discretion of the Investigator. | ||
Evidence for comparator |
Evidence for comparators --- Not applicable LIST OF ABBREVIATIONS IN THIS STUDY ENTRY AE=Adverse event AT III=Antithrombin III CIOMS=Council for International Organizations of Medical Sciences COVID-19=Coronavirus disease 2019 Ct=Cycle threshold DSMB=Data Safety and Monitoring Board E4=Estetrol ECMO=Extracorporeal membrane oxygenation EoT=End of treatment assessment FiO2=Fraction of inspired oxygen Hospt=Hospitalized ICU=Intensive care unit LMWH=Low molecular weight heparin OSCI=Ordinal Scale for Clinical Improvement PCR=Polymerase chain reaction pO2=Partial pressure of oxygen RNA=Ribonucleic acid SARS-CoV-2=Severe acute respiratory syndrome coronavirus type 2 SpO2=Oxygen saturation VTE=Venous thromboembolism WHO=World Health Organization | ||
Actual start date of recruitment |
19 Nov 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Russian Federation: 63
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Country: Number of subjects enrolled |
Poland: 109
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Country: Number of subjects enrolled |
Belgium: 3
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Worldwide total number of subjects |
175
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EEA total number of subjects |
112
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
101
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From 65 to 84 years |
72
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85 years and over |
2
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Recruitment
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Recruitment details |
Male and female subjects recruited according to the Inclusion/Exclusion Criteria. Subjects had to be hospitalized with confirmed SARS-CoV-2 infection and moderate COVID-19. Subjects were excluded from the study if they were ventilated and/or in ICU, had any unexplained vaginal bleeding, had diagnosed protein C, protein S, or AT III deficiency. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
Enrolled in this study were postmenopausal women who had not used hormone replacement therapy within 1 year of study start or men ≥18 years of age who used contraception from screening until 4 weeks after the last dose of study treatment, who were hospitalized with confirmed SARS-CoV-2 infection and moderate COVID-19. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Treatment (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Estetrol (E4) | ||||||||||||||||||||||||
Arm description |
Subjects received Estetrol (E4) 15 mg tablets by mouth once daily for 21 consecutive days, at approximately the same time each day. Patients who were discharged from hospital during the treatment phase completed study treatment at home. Study treatment was stopped if the patient was intubated or unable to swallow the tablets. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Estetrol (E4)
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Investigational medicinal product code |
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Other name |
E4
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Estetrol (E4): 15 mg tablets, taken by mouth once daily for 21 consecutive days.
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
Subjects received placebo by mouth once daily for 21 consecutive days, at approximately the same time each day. Patients who were discharged from hospital during the Treatment Phase completed study treatment at home. Study treatment was stopped if the patient was intubated or unable to swallow the tablets. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo: matching tablets taken by mouth once daily for 21 consecutive days.
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Baseline characteristics reporting groups
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Reporting group title |
Estetrol (E4)
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Reporting group description |
Subjects received Estetrol (E4) 15 mg tablets by mouth once daily for 21 consecutive days, at approximately the same time each day. Patients who were discharged from hospital during the treatment phase completed study treatment at home. Study treatment was stopped if the patient was intubated or unable to swallow the tablets. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo by mouth once daily for 21 consecutive days, at approximately the same time each day. Patients who were discharged from hospital during the Treatment Phase completed study treatment at home. Study treatment was stopped if the patient was intubated or unable to swallow the tablets. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Estetrol (E4)
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Reporting group description |
Subjects received Estetrol (E4) 15 mg tablets by mouth once daily for 21 consecutive days, at approximately the same time each day. Patients who were discharged from hospital during the treatment phase completed study treatment at home. Study treatment was stopped if the patient was intubated or unable to swallow the tablets. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo by mouth once daily for 21 consecutive days, at approximately the same time each day. Patients who were discharged from hospital during the Treatment Phase completed study treatment at home. Study treatment was stopped if the patient was intubated or unable to swallow the tablets. |
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End point title |
1_Improvement in COVID-19 -- Patients reaching a WHO OSCI score of ≤3 on Day 28 | ||||||||||||
End point description |
Improvement in COVID-19 between the placebo and Estetrol (E4) groups measured by the percentage of patients recovered on Day 28.
Recovery was defined as reaching a score of ≤3 on the OSCI WHO (0−10) scale.
Patients were treated for 21 days with either E4 or placebo.
WHO OSCI scale:
Score 0=Uninfected; no viral RNA detected; 1=Asymptomatic, viral RNA detected; 2=Symptomatic, independent; 3=Symptomatic, assistance needed; 4=Hospitalized, no oxygen therapy; 5=Oxygen by mask or nasal prongs; 6=Non-invasive ventilation or high-flow oxygen; 7=Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200; 8=Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressin; 9=Mechanical ventilation pO2/FiO2 <150 and vasopressin, dialysis, or ECMO; 10=Death.
Patient status score: 0=Uninfected; 1-3=Ambulatory, mild disease; 4-5=Hospt, Moderate disease; 6-9=Hospt, Severe disease; 10=Dead.
E4=Estetrol; OSCI=Ordinal Scale for Clinical Improvement; WHO=World Health Org;
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End point type |
Primary
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End point timeframe |
Day 28 after treatment start.
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Notes [1] - ITT population [2] - ITT population |
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Statistical analysis title |
E4 vs Placebo | ||||||||||||
Comparison groups |
Estetrol (E4) v Placebo
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Number of subjects included in analysis |
171
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
Method |
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Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
0.41
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.16 | ||||||||||||
upper limit |
1.07 | ||||||||||||
Notes [3] - Odds Ratio from logistic regression model with randomized treatment included as a class factor, baseline WHO (0-10) score as class factor and age included as covariates and stratified for the randomization stratification factors of gender and antiviral treatment for COVID-19 at baseline at a given timepoint. |
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End point title |
2_Patients with a WHO OSCI score of ≥6 on Day 28 | ||||||||||||
End point description |
Patients with a WHO OSCI Score of ≥6 on Day 28.
Patients were treated for 21 days with either E4 or placebo.
Details of the WHO OSCI scale are shown in the description for end point 1.
E4=Estetrol; OSCI=Ordinal Scale for Clinical Improvement; WHO=World Health Organization;
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End point type |
Secondary
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End point timeframe |
Day 28 after treatment start.
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Notes [4] - ITT population [5] - ITT population |
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Statistical analysis title |
E4 vs Placebo | ||||||||||||
Comparison groups |
Estetrol (E4) v Placebo
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Number of subjects included in analysis |
171
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | ||||||||||||
Method |
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Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.77
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.61 | ||||||||||||
upper limit |
5.16 | ||||||||||||
Notes [6] - Odds Ratio from logistic regression model with randomized treatment included as a class factor, baseline WHO (0-10) score as class factor and age included as covariates and stratified for the randomization stratification factors of gender and antiviral treatment for COVID-19 at baseline. |
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End point title |
3_Time to recovery -- Patients reaching a WHO OSCI score of ≤3 | ||||||||||||
End point description |
Time to recovery, as defined by a score of ≤3 on the WHO OSCI scale.
Patients were treated for 21 days with either E4 or placebo.
Details of the WHO OSCI scale are shown in the description of end point 1.
E4=Estetrol; OSCI=Ordinal Scale for Clinical Improvement; WHO=World Health Organization;
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End point type |
Secondary
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End point timeframe |
From Day 1 (start of treatment) to Day 28 (end of study).
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Notes [7] - ITT population [8] - ITT population |
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No statistical analyses for this end point |
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End point title |
4_Viral load | ||||||||||||||||||||||||
End point description |
Assess changes in SARS-CoV-2 viral load between the E4 and placebo groups.
Patients were treated for 21 days with either E4 or placebo. Assessment was made up to end of treatment (EoT), which was defined as Day 23 or within 2 days of the last dose of study drug if treatment was stopped prior to Day 21 for reasons other than intubation or VTE. Results are presented as change from baseline. The number of patients contributing to the results is indicated under the table.
Viral load (in oropharangeal swabs) was measured by real-time PCR. This method monitors the amplification of the SARS-CoV-2 ribonucleic acid (RNA) that is performed in cycles. The cycle threshold (Ct) result represents the cycle at which the amplification product can be detected by the method; thus, the lower the Ct value the higher the amount of SARS-CoV-2 RNA that is present in the sample, representing a ’high’ viral load.
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End point type |
Secondary
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End point timeframe |
From baseline (before treatment) to EoT (end of treatment assessment).
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Notes [9] - ITT population Baseline N=61 D3 N=47 D7 N=30 D14 N=8 EoT N=15 [10] - ITT population Baseline N=63 D3 N=45 D7 N=36 D14 N=12 EoT N=11 |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
All AEs were followed from the first dose of study drug until 7 days (±2 days) after the last dose of study drug.
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Adverse event reporting additional description |
Safety data are reported for Safety Population as treatment-emergent adverse events (TEAE).
The Safety Population consisted of all patients who took at least one dose of the study medication.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
Estetrol (E4)
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Reporting group description |
Subjects received E4 15 mg orally once daily for 21 consecutive days, at approximately the same time each day. Patients who were discharged from hospital during the Treatment Phase completed study treatment at home. Study treatment was stopped if the patient was intubated or unable to swallow the tablets. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo orally once daily for 21 consecutive days, at approximately the same time each day. Patients who were discharged from hospital during the Treatment Phase completed study treatment at home. Study treatment was stopped if the patient was intubated or unable to swallow the tablets. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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20 Aug 2020 |
Global study protocol amendment:
The inclusion criterion for postmenopausal women was amended to reduce menopausal status and HRT use from 5 years to 1 year prior to study start. Major update based on newly published data on COVID-19.
HRT=Hormone replacement therapy |
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20 Nov 2020 |
Global study protocol amendment:
Protocol update was made to stop treatment for patients with a positive point-of-care test but subsequent negative RT-PCR test.
Inclusion of clinical data from male study; clarifications and updates made to exclusion criteria to exclude patients with thrombophilia or liver disease and cancer, as well as to exclude patients at risk of developing arterial or vein thrombosis/thromboembolia;
Add criterion to exclude hypersensitivity to the active substance. |
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18 Mar 2021 |
Global study protocol amendment:
Amendment was made regarding the sample size for the primary efficacy endpoint of Initially 300 patients; the sample size was adjusted to 162 patients.
The study design was adjusted to be a two-part study. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |