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    Clinical Trial Results:
    Multicenter, adaptive, randomized, placebo-controlled, double blind, parallel-group Phase 2/3 trial, to study efficacy and safety of two doses of raloxifene in adult paucisymptomatic COVID-19 patients.

    Summary
    EudraCT number
    		 2020-003936-25
    Trial protocol
    		 IT   FR  
    Global end of trial date
    12 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2022
    First version publication date
    11 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RLX0120
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05172050
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dompé Farmaceutici S.p.A.
    Sponsor organisation address
    Via Santa Lucia, 6, Milano, Italy, 20122
    Public contact
    Clinical Trial Transparency Manager, Dompé farmaceutici S.p.A., +39 02583831, clinops@pec.dompe.it
    Scientific contact
    Clinical Trial Transparency Manager, Dompé farmaceutici S.p.A., +39 02583831, clinops@pec.dompe.it
    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
    12 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate the efficacy and safety of two different doses of raloxifene orally administered compared to placebo in patients with early diagnosis of paucisymptomatic COVID-19. Efficacy was assessed based on the proportion of patients with undetectable SARS-CoV-2 at day 7 after randomization and the proportion of patients who required supplemental oxygen therapy and/or mechanical ventilation by day 14 after randomization. Safety was also assessed.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonization (ICH) Consolidated Guideline on Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jan 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 61
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    47
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Actual recruitment was greatly slower than expected and this determined a significant delay in study conduction, which in turn reflected on a study completion forecast that was not in line with Sponsor's planning.

    Pre-assignment
    Screening details
    		 Due to the premature study interruption, the sample size was smaller than originally planned due to several reason that caused difficulties in patients enrollment.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Appearance, including packaging and labelling, of the IMP (capsules, packaging) did not allow to recognize actual treatment (either raloxifene or placebo).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Raloxifene 60 mg
    Arm description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 60 mg was administered; the treatment was taken by the patients for two weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Raloxifene
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Raloxifene: Raloxifene was administered as 60 mg hard gelatine capsule(s) once a day. Starting from day 2 of treatment: one single capsule (plus one of placebo to guarantee the blinding) containing 60 mg raloxifene was administered in Group 1, and 2 capsules 60 mg each for a total of 120 mg in Group 2.

    Arm title
    		 Raloxifene 120 mg
    Arm description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 120 mg was administered; the treatment was taken by the patients for two weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Raloxifene
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Raloxifene: Raloxifene was administered as 60 mg hard gelatine capsule(s) once a day. Starting from day 2 of treatment: one single capsule (plus one of placebo to guarantee the blinding) containing 60 mg raloxifene was administered in Group 1, and 2 capsules 60 mg each for a total of 120 mg in Group 2.

    Arm title
    		 Placebo
    Arm description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing placebo), a single daily oral dose of placebo (2 capsules guarantee the blinding design) was administered; the treatment was taken by the patients for two weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    control
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo: Placebo was administered orally once a day as 2 capsules (for maintaining the blinding design)

    Number of subjects in period 1
    		Raloxifene 60 mg Raloxifene 120 mg Placebo
    Started
    22
    20
    19
    Completed
    10
    9
    8
    Not completed
    12
    11
    11
         Negative Nasopharingeal swab
    5
    5
    3
         Development of AE or unacceptable toxicity
    5
    4
    7
         Unknown
    2
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Raloxifene 60 mg
    Reporting group description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 60 mg was administered; the treatment was taken by the patients for two weeks.

    Reporting group title
    Raloxifene 120 mg
    Reporting group description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 120 mg was administered; the treatment was taken by the patients for two weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing placebo), a single daily oral dose of placebo (2 capsules guarantee the blinding design) was administered; the treatment was taken by the patients for two weeks.

    Reporting group values
    		 Raloxifene 60 mg Raloxifene 120 mg Placebo Total
    Number of subjects
    		 22 20 19 61
    Age categorical
    The Full Analysis Set (FAS) population, which included all randomized patients who received at least one dose of the study medication (either Raloxifene or Placebo). The FAS population was used for primary and secondary efficacy analyses, all the demographics and baseline characteristics. Patients were analysed according to the treatment they were randomized.
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 18 15 15 48
        From 65-84 years
    		 4 5 4 13
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.1 ( 10.88 ) 58.9 ( 10.03 ) 54.6 ( 9.33 ) -
    Gender categorical
    The Full Analysis Set (FAS) population, which included all randomized patients who received at least one dose of the study medication (either Raloxifene or Placebo). The FAS population was used for primary and secondary efficacy analyses, all the demographics and baseline characteristics. Patients were analysed according to the treatment they were randomized.
    Units: Subjects
        Female
    		 11 8 9 28
        Male
    		 11 12 10 33
    Subject analysis sets

    Subject analysis set title
    Raloxifene 60 mg - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) population included all randomized patients who received at least one dose of the study medication. The FAS population was used for primary and secondary efficacy analyses.

    Subject analysis set title
    Raloxifene 120 mg - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) population included all randomized patients who received at least one dose of the study medication. The FAS population was used for primary and secondary efficacy analyses.

    Subject analysis set title
    Placebo - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) population included all randomized patients who received at least one dose of the study medication. The FAS population was used for primary and secondary efficacy analyses.

    Subject analysis set title
    Raloxifene 60 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) population included all randomized patients who received at least one dose of the study medication and did not have any Major Protocol Deviations. The PP population was used for sensitivity analyses of the efficacy endpoints.

    Subject analysis set title
    Raloxifene 120 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) population, which included all randomized patients who received at least one dose of the study medication and did not have any Major Protocol Deviations. The PP population was used for sensitivity analyses of the efficacy endpoints.

    Subject analysis set title
    Placebo - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) population included all randomized patients who received at least one dose of the study medication and did not have any Major Protocol Deviations. The PP population was used for sensitivity analyses of the efficacy endpoints.

    Subject analysis sets values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS Raloxifene 60 mg - PP Raloxifene 120 mg - PP Placebo - PP
    Number of subjects
    22
    20
    19
    18
    17
    17
    Age categorical
    The Full Analysis Set (FAS) population, which included all randomized patients who received at least one dose of the study medication (either Raloxifene or Placebo). The FAS population was used for primary and secondary efficacy analyses, all the demographics and baseline characteristics. Patients were analysed according to the treatment they were randomized.
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    18
    15
    15
        From 65-84 years
    4
    5
    4
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.1 ( 10.88 )
    58.9 ( 10.03 )
    54.6 ( 9.33 )
    ( )
    ( )
    ( )
    Gender categorical
    The Full Analysis Set (FAS) population, which included all randomized patients who received at least one dose of the study medication (either Raloxifene or Placebo). The FAS population was used for primary and secondary efficacy analyses, all the demographics and baseline characteristics. Patients were analysed according to the treatment they were randomized.
    Units: Subjects
        Female
    11
    8
    9
        Male
    11
    12
    10

    End points

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    End points reporting groups
    Reporting group title
    Raloxifene 60 mg
    Reporting group description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 60 mg was administered; the treatment was taken by the patients for two weeks.

    Reporting group title
    Raloxifene 120 mg
    Reporting group description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 120 mg was administered; the treatment was taken by the patients for two weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing placebo), a single daily oral dose of placebo (2 capsules guarantee the blinding design) was administered; the treatment was taken by the patients for two weeks.

    Subject analysis set title
    Raloxifene 60 mg - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) population included all randomized patients who received at least one dose of the study medication. The FAS population was used for primary and secondary efficacy analyses.

    Subject analysis set title
    Raloxifene 120 mg - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) population included all randomized patients who received at least one dose of the study medication. The FAS population was used for primary and secondary efficacy analyses.

    Subject analysis set title
    Placebo - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) population included all randomized patients who received at least one dose of the study medication. The FAS population was used for primary and secondary efficacy analyses.

    Subject analysis set title
    Raloxifene 60 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) population included all randomized patients who received at least one dose of the study medication and did not have any Major Protocol Deviations. The PP population was used for sensitivity analyses of the efficacy endpoints.

    Subject analysis set title
    Raloxifene 120 mg - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) population, which included all randomized patients who received at least one dose of the study medication and did not have any Major Protocol Deviations. The PP population was used for sensitivity analyses of the efficacy endpoints.

    Subject analysis set title
    Placebo - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) population included all randomized patients who received at least one dose of the study medication and did not have any Major Protocol Deviations. The PP population was used for sensitivity analyses of the efficacy endpoints.

    Primary: Number of Participants With Undetectable SARS-CoV-2 at PCR at Day 7 After Randomization in the FAS

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    End point title
    		 Number of Participants With Undetectable SARS-CoV-2 at PCR at Day 7 After Randomization in the FAS
    End point description
    Number of participants who, after an approved molecular test (PCR), were not detected as SARS-CoV2 positive. Based on Approved molecular test (PCR) result at day 7, the responses were considered as “detectable” if PCR result was “Positive” otherwise “undetectable” if PCR result was “Negative” .
    End point type
    Primary
    End point timeframe
    At Day 7
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    19 [1]
    18 [2]
    14
    Units: count of participants
    7
    4
    4
    Notes
    [1] - No. of patients considered in the model
    [2] - No. of patients considered in the model
    Statistical analysis title
    		 Raloxifene 60 mg vs placebo [3]
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0109 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    9.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.781
         upper limit
    		 -
    Notes
    [3] - A low or upper value for the confidence interval may be missing. Values for both the lower and upper limit are expected to be provided with a 2-sided confidence interval.
    Justification: The upper limit was not estimable due to the low number of events
    [4] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects.
    [5] - Please note that the upper limit of the IC is not estimable (NE), due to the low number of events; hence no digit was reported.
    Statistical analysis title
    		 Raloxifene 120 mg vs placebo [6]
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0673 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.414
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.858
         upper limit
    		 -
    Notes
    [6] - A low or upper value for the confidence interval may be missing. Values for both the lower and upper limit are expected to be provided with a 2-sided confidence interval.
    Justification: The upper limit was not estimable due to the low number of events
    [7] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects.
    [8] - Please note that the upper limit of the IC is not estimable (NE), due to the low number of events; hence no digit was reported.

    Primary: Number of Participants Not Requiring Oxygen Therapy and/or Mechanical Ventilation at Day 14 After Randomization in the FAS

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    End point title
    		 Number of Participants Not Requiring Oxygen Therapy and/or Mechanical Ventilation at Day 14 After Randomization in the FAS
    End point description
    Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) and/or mechanical ventilation. NEWS is a system for scoring the physiological measurements that are routinely recorded at the patient's bedside. NEWS uses six physiological measurements. An additional two points are added if the patient is receiving oxygen therapy. The total possible score ranges from 0 to 20. If collected NEWS score > 2 or mechanical ventilation with result “Yes” then the response was considered as “Required”. If collected NEWS score ≤ 2 and mechanical ventilation with result “No” then the response was considered as “Not Required” (if both NEWS score and mechanical ventilation were missing, patient was considered as missing).
    End point type
    Primary
    End point timeframe
    At Day 14
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    18 [9]
    16
    17
    Units: count of participants
    10
    8
    8
    Notes
    [9] - No. of patients considered in the model
    Statistical analysis title
    		 Raloxifene 60 mg vs placebo
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.7121
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.663
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.337
         upper limit
    		 9.053
    Notes
    [10] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects.
    Statistical analysis title
    		 Raloxifene 120 mg vs placebo
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 > 0.999
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.963
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.185
         upper limit
    		 4.977
    Notes
    [11] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects

    Primary: Number of Participants With Undetectable SARS-CoV-2 at PCR at Day 7 After Randomization in the PP population

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    End point title
    		 Number of Participants With Undetectable SARS-CoV-2 at PCR at Day 7 After Randomization in the PP population
    End point description
    Number of participants who, after an approved molecular test (PCR), were not detected as SARS-CoV2 positive. Based on Approved molecular test (PCR) result at day 7, the responses were considered as “detectable” if PCR result was “Positive” otherwise “undetectable” if PCR result was “Negative” .
    End point type
    Primary
    End point timeframe
    At day 7
    End point values
    		 Raloxifene 60 mg - PP Raloxifene 120 mg - PP Placebo - PP
    Number of subjects analysed
    17 [12]
    17 [13]
    14 [14]
    Units: number of subjects
    9
    13
    14
    Notes
    [12] - No. of patients considered in the model
    [13] - No. of patients considered in the model
    [14] - No. of patients considered in the model
    Statistical analysis title
    		 Raloxifene 60 mg vs placebo [15]
    Statistical analysis description
    This sensitivity analysis is conducted on the subjects analyzed in per protocol (PP) population.
    Comparison groups
    Placebo - PP v Raloxifene 60 mg - PP
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.0061 [17]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    12.186
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.147
         upper limit
    		 -
    Notes
    [15] - A low or upper value for the confidence interval may be missing. Values for both the lower and upper limit are expected to be provided with a 2-sided confidence interval.
    Justification: The upper limit was not estimable due to the low number of events
    [16] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects
    [17] - Please note that the upper limit of the IC was not estimable due to the low number of events; hence no digit was reported.
    Statistical analysis title
    		 Raloxifene 120 mg vs placebo [18]
    Statistical analysis description
    This sensitivity analysis is conducted on the subjects analyzed in per protocol (PP) population.
    Comparison groups
    Raloxifene 120 mg - PP v Placebo - PP
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.0567 [20]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.936
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.938
         upper limit
    		 -
    Notes
    [18] - A low or upper value for the confidence interval may be missing. Values for both the lower and upper limit are expected to be provided with a 2-sided confidence interval.
    Justification: The upper limit was not estimable due to the low number of events
    [19] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects.
    [20] - Please note that the upper limit of the IC was not estimable due to the low number of events; hence no digit was reported.

    Primary: Number of Participants Not Requiring Oxygen Therapy and/or Mechanical Ventilation at Day 14 After Randomization in the PP population

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    End point title
    		 Number of Participants Not Requiring Oxygen Therapy and/or Mechanical Ventilation at Day 14 After Randomization in the PP population
    End point description
    Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) and/or mechanical ventilation. NEWS is a system for scoring the physiological measurements that are routinely recorded at the patient's bedside. NEWS uses six physiological measurements. An additional two points are added if the patient is receiving oxygen therapy. The total possible score ranges from 0 to 20. If collected NEWS score > 2 or mechanical ventilation with result “Yes” then the response was considered as “Required”. If collected NEWS score ≤ 2 and mechanical ventilation with result “No” then the response was considered as “Not Required” (if both NEWS score and mechanical ventilation were missing, patient was considered as missing).
    End point type
    Primary
    End point timeframe
    At Day 14
    End point values
    		 Raloxifene 60 mg - PP Raloxifene 120 mg - PP Placebo - PP
    Number of subjects analysed
    14 [21]
    14 [22]
    15 [23]
    Units: number of subjects
    8
    8
    8
    Notes
    [21] - No. of patients considered in the model
    [22] - No. of patients considered in the model
    [23] - No. of patients considered in the model
    Statistical analysis title
    		 Raloxifene 60 mg vs placebo
    Statistical analysis description
    This sensitivity analysis is conducted on the subjects analyzed in per protocol (PP) population.
    Comparison groups
    Raloxifene 60 mg - PP v Placebo - PP
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.5378
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 20.153
    Notes
    [24] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects
    Statistical analysis title
    		 Raloxifene 120 mg vs placebo
    Statistical analysis description
    This sensitivity analysis is conducted on the subjects analyzed in per protocol (PP) population:
    Comparison groups
    Raloxifene 120 mg - PP v Placebo - PP
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 > 0.999
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.209
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.185
         upper limit
    		 8.589
    Notes
    [25] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects.

    Secondary: Number of Participants With Undetectable SARS-CoV-2 at PCR at Days 14 and 28 After Randomization in the FAS

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    End point title
    		 Number of Participants With Undetectable SARS-CoV-2 at PCR at Days 14 and 28 After Randomization in the FAS
    End point description
    Number of participants with undetectable SARS-CoV-2 at PCR at day 14 after randomization, and at day 28 after randomization. Based on Approved molecular test (PCR) result at days 14 and 28 after randomization, the responses were considered as “detectable” if PCR result was “Positive” otherwise “undetectable” if PCR result was “Negative”.
    End point type
    Secondary
    End point timeframe
    At days 14 and 28 after randomization
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    20 [26]
    18 [27]
    16
    Units: count of participants
        at Day 14
    10
    14
    7
        at Day 28
    17
    17
    12
    Notes
    [26] - No. of patients considered in the model
    [27] - No. of patients considered in the model
    Statistical analysis title
    		 Raloxifene 60 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    at Day 14
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 > 0.999
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.114
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.219
         upper limit
    		 5.708
    Notes
    [28] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects.
    Statistical analysis title
    		 Raloxifene 120 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    at Day 14
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.2553
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.202
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.541
         upper limit
    		 22.116
    Notes
    [29] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects.
    Statistical analysis title
    		 Raloxifene 60 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    at Day 28
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.6189
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.294
         upper limit
    		 18.532
    Notes
    [30] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects.
    Statistical analysis title
    		 Raloxifene 120 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    at Day 28
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.1662
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.586
         upper limit
    		 413.499
    Notes
    [31] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects.

    Secondary: Number of Participants Not Requiring Oxygen Therapy and/or Mechanical Ventilation at Day 7 an d at Day 28 in the FAS

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    End point title
    		 Number of Participants Not Requiring Oxygen Therapy and/or Mechanical Ventilation at Day 7 an d at Day 28 in the FAS
    End point description
    Proportion of participants who does not require supplemental oxygen therapy (NEWS ≤ 2) and/or mechanical ventilation after randomization;
    End point type
    Secondary
    End point timeframe
    At days 7 and 28
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    22 [32]
    18
    17 [33]
    Units: count of participants
        at Day 7
    12
    12
    11
        at Day 28
    9
    12
    7
    Notes
    [32] - No. of patients considered in the model
    [33] - No. of patients considered in the model
    Statistical analysis title
    		 Raloxifene 60 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    at Day 7
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 > 0.999
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.972
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.193
         upper limit
    		 4.906
    Notes
    [34] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects
    Statistical analysis title
    		 Raloxifene 120 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    at Day 7
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 > 0.999
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.156
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 6.822
    Notes
    [35] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects
    Statistical analysis title
    		 Raloxifene 60 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    at Day 28
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 > 0.999
    Method
    		 Regression, Linear
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.066
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.208
         upper limit
    		 5.478
    Notes
    [36] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects
    Statistical analysis title
    		 Raloxifene 120 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    at Day 28
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.5465
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.068
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.369
         upper limit
    		 12.58
    Notes
    [37] - Analysis is based on Exact Binary logistic regression model with treatment group, age group and status as main effects

    Secondary: Number of Patients in Each National Early Warning Score (NEWS) Category in the FAS

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    End point title
    		 Number of Patients in Each National Early Warning Score (NEWS) Category in the FAS
    End point description
    Proportion of patients in each National Early Warning Score (NEWS) category after randomization. NEWS is a system for scoring the physiological measurements that are routinely recorded at the patient's bedside. NEWS uses six physiological measurements: respiratory rate; oxygen saturation; temperature; systolic blood pressure; heart rate and level of consciousness. Each scores 0–3 and individual scores are added together for an overall score. An additional two points are added if the patient is receiving oxygen therapy. The total possible score ranges from 0 to 20. The higher the score, the worse the outcome.
    End point type
    Secondary
    End point timeframe
    At days 7, 14, 28
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    22
    20
    19
    Units: count of participants
        Day 7 - Score 0
    6
    5
    6
        Day 7 - Score 1
    3
    4
    5
        Day 7 - Score 2
    3
    3
    0
        Day 7 - Score 3
    1
    2
    0
        Day 7 - Score 4
    2
    0
    3
        Day 7 - Score 5
    1
    1
    0
        Day 7 - Score 7
    2
    1
    0
        Day 7 - Missing
    4
    4
    5
        Day 14 - Score 0
    5
    4
    5
        Day 14 - Score 1
    5
    2
    3
        Day 14 - Score 2
    1
    3
    0
        Day 14 - Score 3
    1
    5
    2
        Day 14 - Score 4
    2
    1
    1
        Day 14 - Score 5
    0
    0
    1
        Day 14 - Score 6
    1
    0
    1
        Day 14 - Missing
    7
    5
    6
        Day 28 - Score 0
    5
    8
    5
        Day 28 - Score 1
    4
    5
    3
        Day 28 - Score 2
    1
    0
    1
        Day 28 - Score 3
    0
    0
    1
        Day 28 - Score 4
    2
    0
    1
        Day 28 - Missing
    10
    7
    8
    No statistical analyses for this end point

    Secondary: Mean Value of National Early Warning Score (NEWS) Category in the FAS

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    End point title
    		 Mean Value of National Early Warning Score (NEWS) Category in the FAS
    End point description
    Mean value of National Early Warning Score (NEWS) category after randomization. NEWS is a system for scoring the physiological measurements that are routinely recorded at the patient's bedside. The total possible score ranges from 0 to 20. The higher the score the greater the clinical risk. Higher scores indicate the need for escalation, medical review and possible clinical intervention and more intensive monitoring
    End point type
    Secondary
    End point timeframe
    At days 7, 14, 28
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    22
    20
    19
    Units: number of patients
    arithmetic mean (standard deviation)
        Day 7
    2.2 ( 2.36 )
    1.8 ( 1.98 )
    1.2 ( 1.58 )
        Day 14
    1.6 ( 1.84 )
    1.8 ( 1.37 )
    1.8 ( 2.12 )
        Day 28
    1.2 ( 1.47 )
    0.4 ( 0.51 )
    1.1 ( 1.38 )
    No statistical analyses for this end point

    Secondary: Number of Hospitalized Participants Who at the Beginning of the Study Were at Domicile Isolation After Randomization in the FAS

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    End point title
    		 Number of Hospitalized Participants Who at the Beginning of the Study Were at Domicile Isolation After Randomization in the FAS
    End point description
    Proportion of hospitalized participants at Day 7, Day 14 and Day 28 after randomization among subjects who at the beginning of the study were at domicile isolation.
    End point type
    Secondary
    End point timeframe
    At days 7, 14, 28
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    22
    20
    19
    Units: count of participants
        Day 7
    20
    18
    15
        Day 14
    20
    18
    15
        Day 28
    20
    18
    16
    Statistical analysis title
    		 Raloxifene 60 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    At Day 7
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.3899 [39]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [38] - The proportion of hospitalized participants who at the beginning of the study were at domicile isolation at Day 7, Day 14 and Day 28 after randomization was analysed using comparison of proportions (i.e. comparisons of each active treatment group versus placebo at each assessment day) through Fisher’s exact test and was summarized using frequency and percent by treatment and visit.
    [39] - P-Value comparing % among treatment groups Raloxifene 60mg versus Placebo using Fisher's Exact test.
    Statistical analysis title
    		 Raloxifene 120 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    At Day 7
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 = 0.4075 [41]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [40] - The proportion of hospitalized participants who at the beginning of the study were at domicile isolation at Day 7, Day 14 and Day 28 after randomization was analysed using comparison of proportions (i.e. comparisons of each active treatment group versus placebo at each assessment day) through Fisher’s exact test and was summarized using frequency and percent by treatment and visit.
    [41] - P-Value comparing % among treatment groups Raloxifene 120 mg versus Placebo using Fisher's Exact test.
    Statistical analysis title
    		 Raloxifene 60 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    At Day 14
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [42]
    P-value
    		 = 0.3899 [43]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [42] - The proportion of hospitalized participants who at the beginning of the study were at domicile isolation at Day 7, Day 14 and Day 28 after randomization was analysed using comparison of proportions (i.e. comparisons of each active treatment group versus placebo at each assessment day) through Fisher's exact test and was summarized using frequency and percent by treatment and visit.
    [43] - P-Value comparing % among treatment groups Raloxifene 60mg versus Placebo using Fisher's Exact test.
    Statistical analysis title
    		 Raloxifene 120 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    At Day 14
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [44]
    P-value
    		 = 0.4075 [45]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [44] - The proportion of hospitalized participants who at the beginning of the study were at domicile isolation at Day 7, Day 14 and Day 28 after randomization was analysed using comparison of proportions (i.e. comparisons of each active treatment group versus placebo at each assessment day) through Fisher's exact test and was summarized using frequency and percent by treatment and visit.
    [45] - P-Value comparing % among treatment groups Raloxifene 120mg versus Placebo using Fisher's Exact test.
    Statistical analysis title
    		 Raloxifene 60 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    At Day 28
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [46]
    P-value
    		 = 0.6846 [47]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [46] - The proportion of hospitalized participants who at the beginning of the study were at domicile isolation at Day 7, Day 14 and Day 28 after randomization was analysed using comparison of proportions (i.e. comparisons of each active treatment group versus placebo at each assessment day) through Fisher's exact test and was summarized using frequency and percent by treatment and visit.
    [47] - P-Value comparing % among treatment groups Raloxifene 60mg versus Placebo using Fisher's Exact test.
    Statistical analysis title
    		 Raloxifene 120 mg (FAS) vs placebo (FAS)
    Statistical analysis description
    At Day 28
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [48]
    P-value
    		 = 0.6614 [49]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [48] - The proportion of hospitalized participants who at the beginning of the study were at domicile isolation at Day 7, Day 14 and Day 28 after randomization was analysed using comparison of proportions (i.e. comparisons of each active treatment group versus placebo at each assessment day) through Fisher's exact test and was summarized using frequency and percent by treatment and visit.
    [49] - P-Value comparing % among treatment groups Raloxifene 120mg versus Placebo using Fisher's Exact test.

    Secondary: Number of Participants Admitted to Intensive Care After Randomization in the FAS

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    End point title
    		 Number of Participants Admitted to Intensive Care After Randomization in the FAS
    End point description
    End point type
    Secondary
    End point timeframe
    At days 7, 14, 28
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    22
    20
    19
    Units: count of participants
        Day 7
    0
    0
    0
        Day 14
    0
    0
    0
        Day 28
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Survivors in the FAS

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    End point title
    		 Number of Survivors in the FAS
    End point description
    End point type
    Secondary
    End point timeframe
    At days 7, 14, 28
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    22
    20
    19
    Units: count of participants
        Day 7
    22
    20
    19
        Day 14
    22
    20
    19
        Day 28
    22
    20
    19
    Statistical analysis title
    		 Raloxifene 60 mg (FAS) vs placebo (FAS)
    Comparison groups
    Raloxifene 60 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1
    Statistical analysis title
    		 Raloxifene 120 mg (FAS) vs placebo (FAS)
    Comparison groups
    Raloxifene 120 mg - FAS v Placebo - FAS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1

    Secondary: Quality of Life Questionnaire (EQ-5D-5L) at 3 Months After Randomization - EQ-5D Descriptive System

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    End point title
    		 Quality of Life Questionnaire (EQ-5D-5L) at 3 Months After Randomization - EQ-5D Descriptive System
    End point description
    The EQ-5D-5L consists of: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS).The EQ-5D system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit number describing the patient's health state. In the EQ VAS - quantitative measure of health outcome - the patient records a self-rates health on a vertical, visual analogue scale which goes from 'Best imaginable health state' to 'Worst imaginable health state'. Both for total and partial scores, the higher the score, the worse is the outcome.
    End point type
    Secondary
    End point timeframe
    At month 3
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    22
    20
    19
    Units: count of participants
        mobility -no problems in walking about
    18
    12
    15
        mobility - slight problems in walking abou
    1
    5
    2
        mobility - moderate problems in walking about
    0
    0
    1
        mobility-severe problems in walking about
    0
    0
    0
        mobility - unable to walk about
    0
    0
    0
        self care - no problems washing or dressing myself
    18
    17
    18
        self care - slight problems washing or dressing my
    0
    0
    0
        self care - moderate problems washing or dressing
    1
    0
    0
        self care - severe problems washing or dressing my
    0
    0
    0
        self care - unable to wash or dress myself
    0
    0
    0
        usual activities - no problems doing my usual acti
    14
    14
    12
        usual activities - slight problems doing my usual
    3
    3
    5
        usual activities - moderate problems doing my usua
    1
    0
    1
        usual activities - severe problems doing my usual
    1
    0
    0
        usual activities - unable to do my usual activitie
    0
    0
    0
        Pain/discomfort - no pain or discomfort
    17
    13
    15
        Pain/discomfort - slight pain or discomfort
    0
    4
    2
        Pain/discomfort - moderate pain or discomfort
    1
    0
    0
        Pain/discomfort - severe pain or discomfort
    1
    0
    1
        Pain/discomfort - extreme pain or discomfort
    0
    0
    0
        Anxiety / Depression - I am not anxious or depress
    13
    10
    13
        Anxiety / Depression - I am slightly anxious or de
    1
    5
    4
        Anxiety / Depression - I am moderately anxious or
    5
    2
    1
        Anxiety / Depression - I am severely anxious or de
    0
    0
    0
        Anxiety / Depression - I am extremely anxious or d
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Quality of Life Questionnaire (EQ-5D-5L) at 3 Months After Randomization - EQ VAS

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    End point title
    		 Quality of Life Questionnaire (EQ-5D-5L) at 3 Months After Randomization - EQ VAS
    End point description
    The EQ-5D-5L consists of: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS).The EQ-5D system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit number describing the patient's health state. In the EQ VAS - quantitative measure of health outcome - the patient records a self-rates health on a vertical, visual analogue scale which goes from 'Best imaginable health state' to 'Worst imaginable health state'. Both for total and partial scores, the higher the score, the worse is the outcome.
    End point type
    Secondary
    End point timeframe
    At month 3
    End point values
    		 Raloxifene 60 mg - FAS Raloxifene 120 mg - FAS Placebo - FAS
    Number of subjects analysed
    22
    20
    19
    Units: score on a scale
        arithmetic mean (standard deviation)
    85.6 ( 13.7 )
    72.5 ( 21.9 )
    84.1 ( 11.5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The specific period of time over which adverse events data were collected was within Day 7, 14 and 28 after randomization.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Raloxifene 60 mg - SAF
    Reporting group description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 60 mg was administered; the treatment was taken by the patients for two weeks. Raloxifene: Raloxifene was administered as 60 mg hard gelatine capsule(s) once a day. Starting from day 2 of treatment: one single capsule (plus one of placebo to guarantee the blinding) containing 60 mg raloxifene was administered in Group 1, and 2 capsules 60 mg each for a total of 120 mg in Group 2.

    Reporting group title
    Raloxifene 120 mg - SAF
    Reporting group description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing 60 mg of the active substance or placebo), a single daily oral dose of raloxifene 120 mg was administered; the treatment was taken by the patients for two weeks. Raloxifene: Raloxifene was administered as 60 mg hard gelatine capsule(s) once a day. Starting from day 2 of treatment: one single capsule (plus one of placebo to guarantee the blinding) containing 60 mg raloxifene was administered in Group 1, and 2 capsules 60 mg each for a total of 120 mg in Group 2.

    Reporting group title
    Placebo - SAF
    Reporting group description
    		 After an administration of two oral doses in the first day of treatment (one dose in the morning and one dose in the evening, each dose administered with 2 capsules containing placebo), a single daily oral dose of placebo (2 capsules guarantee the blinding design) was administered; the treatment was taken by the patients for two weeks. Placebo: Placebo was administered orally once a day as 2 capsules (for maintaining the blinding design)

    Serious adverse events
    		 Raloxifene 60 mg - SAF Raloxifene 120 mg - SAF Placebo - SAF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 20 (10.00%)
    5 / 19 (26.32%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma of liver
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4.5%
    Non-serious adverse events
    		 Raloxifene 60 mg - SAF Raloxifene 120 mg - SAF Placebo - SAF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 22 (27.27%)
    8 / 20 (40.00%)
    6 / 19 (31.58%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Peripheral swelling
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    2
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pneumonitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory failure
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Lipids increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Fall
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Thrombocytosis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    Dyspepsia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Gastric disorder
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    Gastrintestinal disorder
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    1
    0
    Nausea
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    1
    0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The 95%IC upper limit for some endpoints was not estimable due to the low number of events
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