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    Clinical Trial Results:
    A Phase 2 Randomized Single-Blind Study to Evaluate the Activity and Safety of Low Dose Oral Selinexor (KPT-330) in Patients with Severe COVID-19 Infection

    Summary
    EudraCT number
    		 2020-001411-25
    Trial protocol
    		 DE   FR   AT   GB   ES   IT  
    Global end of trial date
    05 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2021
    First version publication date
    23 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    XPORT-COV-1001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04349098
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Karyopharm Therapeutics Inc.
    Sponsor organisation address
    85 Wells Avenue, Newton, MA, United States, 02459
    Public contact
    Clinical Trials Information, Karyopharm Therapeutics Inc., +1 617658 0600, clinicaltrials@karyopharm.com
    Scientific contact
    Clinical Trial Information, Karyopharm Therapeutics Inc., +1 617658 0600, clinicaltrials@karyopharm.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
    05 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine if low-dose oral selinexor could expedite the clinical recovery, suppress the viral load, shorten the hospitalization, and reduce morbidity and mortality in subjects with severe COVID-19 compared with placebo.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki in place at the time of study conduct. The study was conducted in compliance with the International Council for Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP) (Committee for Proprietary Medicinal Products [CPMP] guideline CPMP/ICH/135/95), United States Code of Federal Code of Regulations, and all applicable local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Apr 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
    United States: 175
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    France: 1
    Worldwide total number of subjects
    190
    EEA total number of subjects
    10
    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)
    130
    From 65 to 84 years
    49
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 20 sites in the United States of America, 3 sites in France, 3 sites in Israel, 2 sites in Spain, and 4 sites in the United Kingdom from 17 Apr 2020 to 05 Oct 2020.

    Pre-assignment
    Screening details
    		 A total of 190 subjects were enrolled and randomised, of which 188 subjects received study treatment in this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Study design was changed as double-blinded (subjects and principal investigator) as per protocol version 4.1.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Selinexor 20 mg
    Arm description
    		 Subjects received a single dose of Selinexor 20 milligrams (mg) tablets orally on Days 1, 3 and 5 of each week for up to 2 weeks. The subject tolerated therapy and showed clinical benefit, dosing continued for an additional 2 weeks (on Days 15, 17, 19, 22, 24, and 26) along with standard of care (SoC). As the treatment for COVID-19 is rapidly evolving, the SoC varied over time and across regions of the world.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selinexor
    Investigational medicinal product code
    KPT-330
    Other name
    XPOVIO®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of Selinexor 20 mg tablets orally on Days 1, 3 and 5.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received a single dose of placebo matched to selinexor tablets orally on Days 1, 3 and 5 of each week for up to 2 weeks. The subject tolerated therapy and showed clinical benefit, dosing continued for an additional 2 weeks (on Days 15, 17, 19, 22, 24, and 26) along with SoC. As the treatment for COVID-19 is rapidly evolving, the SoC varied over time and across regions of the world.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of placebo matched to selinexor tablets orally on Days 1, 3 and 5.

    Number of subjects in period 1
    		Selinexor 20 mg Placebo
    Started
    103
    87
    Completed
    65
    61
    Not completed
    38
    26
         Consent withdrawn by subject
    8
    5
         Death
    16
    8
         Unspecified
    3
    5
         Lost to follow-up
    11
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selinexor 20 mg
    Reporting group description
    		 Subjects received a single dose of Selinexor 20 milligrams (mg) tablets orally on Days 1, 3 and 5 of each week for up to 2 weeks. The subject tolerated therapy and showed clinical benefit, dosing continued for an additional 2 weeks (on Days 15, 17, 19, 22, 24, and 26) along with standard of care (SoC). As the treatment for COVID-19 is rapidly evolving, the SoC varied over time and across regions of the world.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a single dose of placebo matched to selinexor tablets orally on Days 1, 3 and 5 of each week for up to 2 weeks. The subject tolerated therapy and showed clinical benefit, dosing continued for an additional 2 weeks (on Days 15, 17, 19, 22, 24, and 26) along with SoC. As the treatment for COVID-19 is rapidly evolving, the SoC varied over time and across regions of the world.

    Reporting group values
    		 Selinexor 20 mg Placebo Total
    Number of subjects
    		 103 87 190
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.5 ( 16.12 ) 56.5 ( 14.64 ) -
    Gender categorical
    Units: Subjects
        Female
    		 43 39 82
        Male
    		 60 48 108
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 41 32 73
        Not Hispanic or Latino
    		 59 53 112
        Unknown or Not Reported
    		 3 2 5
    Race
    Units: Subjects
        Asian
    		 6 4 10
        Native Hawaiian or Other Pacific Islander
    		 2 0 2
        Black or African American
    		 23 24 47
        White
    		 44 34 78
        More than one race
    		 19 14 33
        Unknown or Not Reported
    		 9 11 20

    End points

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    End points reporting groups
    Reporting group title
    Selinexor 20 mg
    Reporting group description
    		 Subjects received a single dose of Selinexor 20 milligrams (mg) tablets orally on Days 1, 3 and 5 of each week for up to 2 weeks. The subject tolerated therapy and showed clinical benefit, dosing continued for an additional 2 weeks (on Days 15, 17, 19, 22, 24, and 26) along with standard of care (SoC). As the treatment for COVID-19 is rapidly evolving, the SoC varied over time and across regions of the world.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a single dose of placebo matched to selinexor tablets orally on Days 1, 3 and 5 of each week for up to 2 weeks. The subject tolerated therapy and showed clinical benefit, dosing continued for an additional 2 weeks (on Days 15, 17, 19, 22, 24, and 26) along with SoC. As the treatment for COVID-19 is rapidly evolving, the SoC varied over time and across regions of the world.

    Primary: Percentage of Subjects With At-least a 2-Point Improvement in Ordinal Scale

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    End point title
    		 Percentage of Subjects With At-least a 2-Point Improvement in Ordinal Scale
    End point description
    Ordinal Scale 2-Point improvement defined as percentage of subjects with at least 2 points improvement (increase from baseline) by Day 14. Baseline score defined as last score measured before first dosing. The 8-point ordinal scale ranges from 1 to 8: where, 1=death, 2=hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 3=hospitalized, on non-invasive ventilation or high flow oxygen devices; 4=hospitalized, requiring supplemental oxygen; 5=hospitalized, not requiring supplemental oxygen-requiring ongoing medical care (COVID-19) related or otherwise; 6=hospitalized, not requiring supplemental oxygen-no longer requires ongoing medical care; 7=not hospitalized, limitation on activities and/or requiring home oxygen; 8=not hospitalized, no limitations on activities. ITT population: all subjects who randomised with confirmed SARS-CoV2 infection under protocol V6.0 and above, regardless of receive study treatment.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 14
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    66
    51
    Units: Percentage of subjects
        number (confidence interval 95%)
    60.6 (47.8 to 72.4)
    60.8 (46.1 to 74.2)
    Statistical analysis title
    		 At least 2-point improvement in ordinal scale
    Comparison groups
    Selinexor 20 mg v Placebo
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.675
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.79

    Secondary: Percentage of Subjects With at Least a 2-Point Improvement in the Ordinal Scale up to Day 7

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    End point title
    		 Percentage of Subjects With at Least a 2-Point Improvement in the Ordinal Scale up to Day 7
    End point description
    Ordinal Scale 2-points improvement was defined as percentage of subjects with at least a 2 points improvement (increase from baseline) by Day 7. Baseline score was defined as the last score measured before first dosing. The 8-point ordinal scale ranges from 1 to 8: where, 1= death, 2= hospitalized, on invasive mechanical ventilation or ECMO; 3= hospitalized, on non-invasive ventilation or high flow oxygen devices; 4= hospitalized, requiring supplemental oxygen; 5= hospitalized, not requiring supplemental oxygen – requiring ongoing medical care (COVID-19 related or otherwise); 6= hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7= not hospitalized, limitation on activities and/or requiring home oxygen; 8= not hospitalized, no limitations on activities. PV 1-6 population included subjects randomised into the study under protocol versions 1-6.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 7
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    103
    87
    Units: Percentage of subjects
        number (confidence interval 95%)
    30.1 (21.5 to 39.9)
    32.2 (22.6 to 43.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With at Least a 1-Point Improvement in the Ordinal Scale

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    End point title
    		 Percentage of Subjects With at Least a 1-Point Improvement in the Ordinal Scale
    End point description
    Ordinal Scale 1-point improvement was defined as percentage of subjects with at least 1 point improvement (increase from baseline) by Day 7 and 14. Baseline score was defined as the last score measured before first dosing. The 8-point ordinal scale ranges from 1 to 8: where 1= death, 2= hospitalized, on invasive mechanical ventilation or ECMO; 3= hospitalized, on non-invasive ventilation or high flow oxygen devices; 4= hospitalized, requiring supplemental oxygen; 5= hospitalized, not requiring supplemental oxygen – requiring ongoing medical care (COVID-19 related or otherwise); 6= hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7= not hospitalized, limitation on activities and/or requiring home oxygen; 8= not hospitalized, no limitations on activities. PV 1-6 population included subjects randomised into the study under protocol versions 1-6.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 7 and 14
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    103
    87
    Units: Percentage of subjects
    number (confidence interval 95%)
        Day 7
    51.5 (41.4 to 61.4)
    50.6 (39.6 to 61.5)
        Day 14
    72.8 (63.2 to 81.1)
    72.4 (61.8 to 81.5)
    No statistical analyses for this end point

    Secondary: Time to Clinical Improvement of 2-Points Using Ordinal Scale (TTCI-2)

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    End point title
    		 Time to Clinical Improvement of 2-Points Using Ordinal Scale (TTCI-2)
    End point description
    TTCI-2 was defined as the time from randomisation to an improvement of 2 points using 8-points Ordinal Scale. The 8-point ordinal scale ranges from 1 to 8: where 1= death, 2= hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3= hospitalized, on non-invasive ventilation or high flow oxygen devices; 4= hospitalized, requiring supplemental oxygen; 5= hospitalized, not requiring supplemental oxygen – requiring ongoing medical care (coronavirus disease 2019 [COVID-19] related or otherwise); 6= hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7= not hospitalized, limitation on activities and/or requiring home oxygen; 8= not hospitalized, no limitations on activities. ITT Population included all subjects who were randomised in the study with confirmed SARS-CoV2 infection under protocol version 6.0 and above, regardless of whether or not they receive study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 28
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    66
    51
    Units: Days
        median (confidence interval 95%)
    10.0 (8.0 to 14.0)
    10.0 (8.0 to 14.0)
    No statistical analyses for this end point

    Secondary: Overall Death Rate

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    End point title
    		 Overall Death Rate
    End point description
    Overall death rate was defined as the percentage of subjects who died on or before Day 28. ITT population included all subjects who were randomised in the study with confirmed SARS-CoV2 infection under protocol version 6.0 and above, regardless of whether or not they receive study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 28
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    66
    51
    Units: Percentage of subjects
        number (confidence interval 95%)
    15.2 (7.5 to 26.1)
    3.9 (0.5 to 13.5)
    No statistical analyses for this end point

    Secondary: Rate of Mechanical Ventilation (RMV)

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    End point title
    		 Rate of Mechanical Ventilation (RMV)
    End point description
    The rate of RMV was defined as the percentage of subjects who ever used invasive mechanical ventilation or ECMO during the hospital stay. ITT population included all subjects who were randomised in the study with confirmed SARS-CoV2 infection under protocol version 6.0 and above, regardless of whether or not they receive study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 28
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    66
    51
    Units: Percentage of subjects
        number (confidence interval 95%)
    13.6 (6.4 to 24.3)
    11.8 (4.4 to 23.9)
    No statistical analyses for this end point

    Secondary: Rate of Intensive Care Unit (ICU) Admission

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    End point title
    		 Rate of Intensive Care Unit (ICU) Admission
    End point description
    The rate of ICU admission was defined as the percentage of subjects with ICU admissions. ITT population included all subjects who were randomised in the study with confirmed SARS-CoV2 infection under protocol version 6.0 and above, regardless of whether or not they receive study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 28
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    66
    51
    Units: Percentage of subjects
        number (confidence interval 95%)
    48.5 (36.0 to 61.1)
    41.2 (27.6 to 55.8)
    No statistical analyses for this end point

    Secondary: Length of Hospitalization

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    End point title
    		 Length of Hospitalization
    End point description
    Length of hospitalization (days) was defined as (first hospital discharge date – date of randomisation + 1). ITT population included all subjects who were randomised in the study with confirmed SARS-CoV2 infection under protocol version 6.0 and above, regardless of whether or not they receive study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 67
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    66
    51
    Units: Days
        median (full range (min-max))
    9.0 (3 to 39)
    9.0 (3 to 67)
    No statistical analyses for this end point

    Secondary: Change From Baseline in C-reactive Protein (CRP) Levels

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    End point title
    		 Change From Baseline in C-reactive Protein (CRP) Levels
    End point description
    The anti-inflammatory and immune effects of selinexor were assessed by CRP levels. Baseline was defined as the most recent non-missing measurement prior to the first administration of study treatment. Change from Baseline at the indicated time points was calculated as the value at the indicated time points minus the value at Baseline. PV 1-6 population included subjects randomised into the study under protocol versions 1-6. Here “n= number of subjects” who were evaluable for this end point at a specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 3, 5, 8, 12, 15, 19, 22 and 26
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    103
    87
    Units: milligram per liter (mg/L)
    arithmetic mean (standard deviation)
        Change at Day 3 (n= 88, 74)
    -47.9660 ( 99.06082 )
    -42.9658 ( 89.09341 )
        Change at Day 5 (n= 83, 69)
    -74.4735 ( 114.52388 )
    -68.6191 ( 108.19671 )
        Change at Day 8 (n= 57, 45)
    -83.3460 ( 93.83500 )
    -74.4669 ( 117.66505 )
        Change at Day 12 (n= 31, 27)
    -86.9158 ( 123.54705 )
    -93.2744 ( 131.56709 )
        Change at Day 15 (n= 10, 15)
    -87.9800 ( 121.19999 )
    -98.7940 ( 87.65276 )
        Change at Day 19 (n= 7, 9)
    -66.2143 ( 86.55049 )
    -124.3233 ( 102.04161 )
        Change at Day 22 (n= 10, 5)
    -90.7100 ( 149.25579 )
    -47.5620 ( 171.49171 )
        Change at Day 26 (n= 5, 5)
    -37.2800 ( 141.41390 )
    -129.5020 ( 46.26178 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Ferritin Levels

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    End point title
    		 Change From Baseline in Ferritin Levels
    End point description
    The anti-inflammatory and immune effects of selinexor were assessed by ferritin levels. Baseline was defined as the most recent non-missing measurement prior to the first administration of study treatment. Change from Baseline at the indicated time points was calculated as the value at the indicated time points minus the value at Baseline. PV 1-6 population included subjects randomised into the study under protocol versions 1-6. Here “n= number of subjects” who were evaluable for this end point at a specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 3, 5, 8, 12, 15, 19, 22 and 26
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    103
    87
    Units: microgram/liter (mcg/L)
    arithmetic mean (standard deviation)
        Change at Day 3 (n= 82, 70)
    80.8415 ( 759.10075 )
    -61.9843 ( 542.09460 )
        Change at Day 5 (n= 79, 63)
    -25.7000 ( 856.16619 )
    -155.3111 ( 773.76777 )
        Change at Day 8 (n= 53, 39)
    226.6113 ( 1673.46162 )
    -292.2462 ( 738.07874 )
        Change at Day 12 (n= 29, 25)
    193.5793 ( 1203.33385 )
    -352.5280 ( 741.13673 )
        Change at Day 15 (n= 10, 14)
    204.3900 ( 557.29217 )
    -356.8429 ( 476.04151 )
        Change at Day 19 (n= 6, 8)
    -15.9333 ( 462.40358 )
    -231.2374 ( 599.98919 )
        Change at Day 22 (n= 10, 4)
    -103.9900 ( 636.89555 )
    -102.0000 ( 417.51247 )
        Change at Day 26 (n= 6, 4)
    -150.1167 ( 535.94141 )
    -25.7500 ( 231.43232 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lactate Dehydrogenase (LDH) Levels

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    End point title
    		 Change From Baseline in Lactate Dehydrogenase (LDH) Levels
    End point description
    The anti-inflammatory and immune effects of selinexor were assessed by LDH levels. Baseline was defined as the most recent non-missing measurement prior to the first administration of study treatment. Change from Baseline at the indicated time points was calculated as the value at the indicated time points minus the value at Baseline. PV 1-6 population included subjects randomised into the study under protocol versions 1-6. Here “n= number of subjects” who were evaluable for this end point at a specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 3, 5, 8, 12, 15, 19, 22 and 26
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    103
    87
    Units: units/liter (U/L)
    arithmetic mean (standard deviation)
        Change at Day 3 (n= 76, 63)
    -13.86 ( 148.231 )
    -11.86 ( 151.630 )
        Change at Day 5 (n= 74, 62)
    -49.12 ( 175.722 )
    31.85 ( 326.281 )
        Change at Day 8 (n= 52, 40)
    -75.85 ( 264.840 )
    -10.93 ( 166.876 )
        Change at Day 12 (n= 28, 25)
    -107.39 ( 198.092 )
    -16.84 ( 232.605 )
        Change at Day 15 (n= 11, 14)
    -71.82 ( 193.543 )
    -51.50 ( 148.063 )
        Change at Day 19 (n= 8, 7)
    -96.38 ( 200.164 )
    -74.14 ( 114.271 )
        Change at Day 22 (n= 10, 5)
    -129.70 ( 177.454 )
    -75.40 ( 43.569 )
        Change at Day 26 (n= 6, 4)
    -169.50 ( 213.481 )
    4.50 ( 130.733 )
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Blood Plasma Cytokines Levels-Interleukin-6 (IL-6)

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    End point title
    		 Changes From Baseline in Blood Plasma Cytokines Levels-Interleukin-6 (IL-6)
    End point description
    The anti-inflammatory and immune effects of selinexor were assessed by blood plasma cytokines like IL-6. Baseline was defined as the most recent non-missing measurement prior to the first administration of study treatment. Change from Baseline at the indicated time points was calculated as the value at the indicated time points minus the value at Baseline. PV 1-6 population included subjects randomised into the study under protocol versions 1-6. Here “n= number of subjects” who were evaluable for this end point at a specified time points. Here, '99999' indicates standard deviation was not estimated due to single subject and '9999' indicates no subject was estimated at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 3, 5, 8, 12, 15, 22 and 26
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    103
    87
    Units: nanograms/milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Change at Day 3 (n= 38, 23)
    -19.931 ( 51.2072 )
    2.046 ( 49.0258 )
        Change at Day 5 (n= 38, 26)
    -10.786 ( 102.9160 )
    -77.509 ( 408.0085 )
        Change at Day 8 (n= 28, 15)
    -13.909 ( 161.6803 )
    183.728 ( 662.7908 )
        Change at Day 12 (n= 13, 9)
    276.289 ( 1541.3692 )
    223.637 ( 715.5904 )
        Change at Day 15 (n= 4, 4)
    -34.850 ( 28.6357 )
    207.625 ( 408.5783 )
        Change at Day 22 (n= 3, 0)
    -8.600 ( 11.8072 )
    9999 ( 9999 )
        Change at Day 26 (n= 1, 0)
    -23.400 ( 99999 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
    End point description
    Adverse events are defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are defined as those AEs that develop or worsen after the first dose of study drug. TEAEs included both serious and non-serious TEAEs. All-treated population consisted of the subset of ITT subjects who took at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to Day 58
    End point values
    		 Selinexor 20 mg Placebo
    Number of subjects analysed
    102
    86
    Units: Subjects
        Subjects with TEAEs
    75
    49
        Subjects with Serious TEAEs
    23
    14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to Day 58
    Adverse event reporting additional description
    All-treated population consisted of the subset of ITT subjects who took at least one dose of study treatment on this study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Selinexor 20 mg
    Reporting group description
    		 Subjects received a single dose of Selinexor 20 mg tablets orally on Days 1, 3 and 5 of each week for up to 2 weeks. The subject tolerated therapy and showed clinical benefit, dosing continued for an additional 2 weeks (on Days 15, 17, 19, 22, 24, and 26).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a single dose of placebo matched to selinexor tablets orally on Days 1, 3 and 5 of each week for up to 2 weeks. The subject tolerated therapy and showed clinical benefit, dosing continued for an additional 2 weeks (on Days 15, 17, 19, 22, 24, and 26).

    Serious adverse events
    		 Selinexor 20 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 102 (22.55%)
    14 / 86 (16.28%)
         number of deaths (all causes)
    16
    8
         number of deaths resulting from adverse events
    16
    7
    Injury, poisoning and procedural complications
    Procedural pneumothorax
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Cardiac arrest
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Cardiac failure
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Long QT syndrome
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Myocardial infarction
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 102 (1.96%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Hypoxia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Pneumonia aspiration
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Pneumothorax
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Pulmonary embolism
         subjects affected / exposed
    4 / 102 (3.92%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Respiratory distress
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Respiratory failure
         subjects affected / exposed
    6 / 102 (5.88%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Psychiatric disorders
    Catatonia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 102 (1.96%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Renal failure
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    13 / 16
    5 / 7
    Pneumonia
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Sepsis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Viral myocarditis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 16
    0 / 8
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Selinexor 20 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 102 (67.65%)
    45 / 86 (52.33%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 102 (7.84%)
    4 / 86 (4.65%)
         occurrences all number
    8
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 102 (8.82%)
    7 / 86 (8.14%)
         occurrences all number
    9
    7
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 102 (2.94%)
    5 / 86 (5.81%)
         occurrences all number
    3
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 102 (8.82%)
    1 / 86 (1.16%)
         occurrences all number
    9
    1
    Leukopenia
         subjects affected / exposed
    5 / 102 (4.90%)
    1 / 86 (1.16%)
         occurrences all number
    5
    1
    Lymphopenia
         subjects affected / exposed
    5 / 102 (4.90%)
    2 / 86 (2.33%)
         occurrences all number
    5
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    14 / 102 (13.73%)
    9 / 86 (10.47%)
         occurrences all number
    14
    9
    Diarrhoea
         subjects affected / exposed
    10 / 102 (9.80%)
    4 / 86 (4.65%)
         occurrences all number
    10
    4
    Nausea
         subjects affected / exposed
    13 / 102 (12.75%)
    6 / 86 (6.98%)
         occurrences all number
    13
    6
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    6 / 102 (5.88%)
    2 / 86 (2.33%)
         occurrences all number
    6
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    5 / 102 (4.90%)
    0 / 86 (0.00%)
         occurrences all number
    5
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    7 / 102 (6.86%)
    3 / 86 (3.49%)
         occurrences all number
    7
    3
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 102 (3.92%)
    5 / 86 (5.81%)
         occurrences all number
    4
    5
    Hypokalaemia
         subjects affected / exposed
    5 / 102 (4.90%)
    3 / 86 (3.49%)
         occurrences all number
    5
    3
    Hyponatraemia
         subjects affected / exposed
    24 / 102 (23.53%)
    5 / 86 (5.81%)
         occurrences all number
    24
    5
    Hypophosphataemia
         subjects affected / exposed
    5 / 102 (4.90%)
    0 / 86 (0.00%)
         occurrences all number
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2020
    Protocol Version 4: • Amended the objectives and endpoints to add established World Health Organization (WHO) ordinal score and additional secondary endpoints to capture all relevant endpoints to facilitate interpretation and combination of results across studies and trials. • Added criteria to provide clarity for stopping criteria based on specific adverse events associated study drug or lack of activity and worsening clinical outcomes. • Specific criteria for early stopping rule was clarified to provide guidance based on increase mortality. • Clarified role and responsibilities of the Data Safety Monitoring Board.
    08 May 2020
    Protocol Version 6.0: • Primary endpoint changed to the proportion of subjects with at least a 2-point increase in Ordinal Scale from baseline to Day 14. • Added secondary endpoints: - Time to recovery defined as improvement from baseline score of 3 greater than or equal to (>=) 4 or from a baseline score of 4 to >=5 - Proportion of subjects with at least a 2 point improvement (increase) in the Ordinal Scale from baseline to Day 7 - Proportion of subjects with at least a 1-point improvement (increase) in the Ordinal Scale from baseline to Day 7 - Proportion of subjects with at least a 1-point improvement (increase) in the Ordinal Scale from baseline to Day 14 - Time to an improvement of 2 point using WHO Ordinal Scale Improvement TTCI-2 - Time to clinical improvement (TTCI-1): defined as the time from randomisation, to an improvement of 1-point on the Ordinal Scale • Deleted secondary endpoint of Time to mechanical ventilation. • Deleted the following additional secondary endpoints: - Time to ICU admission - Proportion of subjects discharged - Duration of oxygen supplementation - TTCI in subjects less than or equal to (<=) 70 years old - TTCI in subjects greater than (>) 70 years old - TTCI in subjects that are immune compromised, have hypertension, or have pulmonary disease (smoking history or moderate to severe chronic obstructive pulmonary disease [COPD)], cardiac disease - Time to an improvement of one point using WHO Ordinal Scale Improvement - Proportion of subjects experiencing WHO Ordinal Scale Improvement of >1 point

    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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