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    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
    EudraCT number
    		 2020-003403-33
    Trial protocol
    		 BE   HU  
    Global end of trial date
    21 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jun 2023
    First version publication date
    23 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MIT-Co001-C101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    NEURALIS SA
    Sponsor organisation address
    Rue Saint Georges 5-7, Liege, Belgium, 4000
    Public contact
    Clinical Study Leader, NEURALIS SA, +32 43492822, Clinical.Trials@mithra.com
    Scientific contact
    Clinical Study Leader, NEURALIS SA, +32 43492822, Clinical.Trials@mithra.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    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)
    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.
    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
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 63
    Country: Number of subjects enrolled
    Poland: 109
    Country: Number of subjects enrolled
    Belgium: 3
    Worldwide total number of subjects
    175
    EEA total number of subjects
    112
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    101
    From 65 to 84 years
    72
    85 years and over
    2

    Subject disposition

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    Recruitment
    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
    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
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 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)
    Investigational medicinal product code
    Other name
    E4
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Estetrol (E4): 15 mg tablets, taken by mouth once daily for 21 consecutive days.

    Arm title
    		 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
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo: matching tablets taken by mouth once daily for 21 consecutive days.

    Number of subjects in period 1
    		Estetrol (E4) Placebo
    Started
    87
    88
    Completed
    73
    77
    Not completed
    14
    11
         Adverse event, serious fatal
    2
    2
         Consent withdrawn by subject
    3
    3
         Adverse event, non-fatal
    5
    2
         Disease progression a prespec withdrawal criterion
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Estetrol (E4)
    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
    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.

    Reporting group values
    		 Estetrol (E4) Placebo Total
    Number of subjects
    		 87 88 175
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 50 51 101
        From 65-84 years
    		 36 36 72
        85 years and over
    		 1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.5 ± 12.7 62.2 ± 11.6 -
    Gender categorical
    Units: Subjects
        Female
    		 33 34 67
        Male
    		 54 54 108
    Sex
    Units: Subjects
        Male
    		 54 54 108
        Female
    		 33 34 67
    Race
    Units: Subjects
        White
    		 87 88 175
    Pneumonia
    Pneumonia present
    Units: Subjects
        YES
    		 66 69 135
        NO
    		 21 18 39
        Missing data
    		 0 1 1
    Antiviral medication
    Subjects receiving antiviral medication.
    Units: Subjects
        YES
    		 35 33 68
        NO
    		 50 53 103
        Missing data
    		 2 2 4
    WHO Ordinal Scale for Clinical Improvement (OSCI) score
    WHO Ordinal Scale for Clinical Improvement (OSCI) score. The OSCI score is defined in the section 'Description' for end point 1.
    Units: Subjects
        Score 4
    		 15 14 29
        Score 5
    		 71 74 145
        Score 6
    		 1 0 1
    Body Mass Index -- BMI (kg/m2)
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 29.1 ± 5.3 28.8 ± 5.1 -
    Clinical frailty score
    Clinical Frailty Scale is a nine-point global frailty scale based on clinical evaluation in the domains of mobility, energy, physical activity, and function. Score: 1=Very fit; 2=Well; 3=Managing well; 4=Vulnerable; 5=Mildly frail;6=Moderately frail; 7=Severely frail; 8=Very severely frail; 9=Terminally ill.
    Units: SCORE
        arithmetic mean (standard deviation)
    		 2.9 ± 1.0 2.8 ± 0.9 -

    End points

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    End points reporting groups
    Reporting group title
    Estetrol (E4)
    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
    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.

    Primary: 1_Improvement in COVID-19 -- Patients reaching a WHO OSCI score of ≤3 on Day 28

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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;
    End point type
    Primary
    End point timeframe
    Day 28 after treatment start.
    End point values
    		 Estetrol (E4) Placebo
    Number of subjects analysed
    85 [1]
    86 [2]
    Units: percent
        number (not applicable)
    82.4
    91.9
    Notes
    [1] - ITT population
    [2] - ITT population
    Statistical analysis title
    		 E4 vs Placebo
    Comparison groups
    Estetrol (E4) v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         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.

    Secondary: 2_Patients with a WHO OSCI score of ≥6 on Day 28

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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;
    End point type
    Secondary
    End point timeframe
    Day 28 after treatment start.
    End point values
    		 Estetrol (E4) Placebo
    Number of subjects analysed
    85 [4]
    86 [5]
    Units: percent
        number (not applicable)
    11.8
    7.0
    Notes
    [4] - ITT population
    [5] - ITT population
    Statistical analysis title
    		 E4 vs Placebo
    Comparison groups
    Estetrol (E4) v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         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.

    Secondary: 3_Time to recovery -- Patients reaching a WHO OSCI score of ≤3

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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;
    End point type
    Secondary
    End point timeframe
    From Day 1 (start of treatment) to Day 28 (end of study).
    End point values
    		 Estetrol (E4) Placebo
    Number of subjects analysed
    85 [7]
    86 [8]
    Units: days
        median (confidence interval 95%)
    13 (12 to 14)
    12 (11 to 14)
    Notes
    [7] - ITT population
    [8] - ITT population
    No statistical analyses for this end point

    Secondary: 4_Viral load

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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.
    End point type
    Secondary
    End point timeframe
    From baseline (before treatment) to EoT (end of treatment assessment).
    End point values
    		 Estetrol (E4) Placebo
    Number of subjects analysed
    85 [9]
    86 [10]
    Units: Cycle threshold (Ct)
    median (full range (min-max))
        Day 3
    1.0 (-11 to 10)
    2.1 (-12 to 10)
        Day 7
    8.0 (-6 to 15)
    3.6 (-6 to 18)
        Day 14
    5.8 (1 to 16)
    5.4 (-5 to 16)
        End of treatment (EoT)
    6.4 (-4 to 14)
    3.3 (-1 to 14)
    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
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    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.
    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Estetrol (E4)
    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
    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.

    Serious adverse events
    		 Estetrol (E4) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 87 (12.64%)
    7 / 88 (7.95%)
         number of deaths (all causes)
    8
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    7 / 87 (8.05%)
    2 / 88 (2.27%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 87 (1.15%)
    2 / 88 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract inflammation
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Endotoxic shock
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Estetrol (E4) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 87 (56.32%)
    45 / 88 (51.14%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 87 (10.34%)
    12 / 88 (13.64%)
         occurrences all number
    9
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 87 (6.90%)
    5 / 88 (5.68%)
         occurrences all number
    6
    5
    Fibrin D dimer increased
         subjects affected / exposed
    4 / 87 (4.60%)
    5 / 88 (5.68%)
         occurrences all number
    4
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 87 (2.30%)
    3 / 88 (3.41%)
         occurrences all number
    2
    3
    Hepatic enzyme increased
         subjects affected / exposed
    5 / 87 (5.75%)
    1 / 88 (1.14%)
         occurrences all number
    5
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 87 (6.90%)
    8 / 88 (9.09%)
         occurrences all number
    6
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 87 (3.45%)
    3 / 88 (3.41%)
         occurrences all number
    3
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 87 (4.60%)
    1 / 88 (1.14%)
         occurrences all number
    4
    1
    Neutropenia
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 88 (3.41%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 87 (3.45%)
    0 / 88 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 87 (2.30%)
    4 / 88 (4.55%)
         occurrences all number
    2
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 87 (2.30%)
    5 / 88 (5.68%)
         occurrences all number
    2
    5
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 87 (3.45%)
    0 / 88 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    3 / 87 (3.45%)
    0 / 88 (0.00%)
         occurrences all number
    3
    0
    Pneumonia
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 88 (3.41%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 87 (0.00%)
    4 / 88 (4.55%)
         occurrences all number
    0
    4
    Hyperkalaemia
         subjects affected / exposed
    2 / 87 (2.30%)
    3 / 88 (3.41%)
         occurrences all number
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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
    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.
    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.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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