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
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EudraCT number |
2020-001411-25 |
Trial protocol |
DE FR AT GB ES IT |
Global end of trial date |
05 Oct 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Oct 2021
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First version publication date |
23 Oct 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
XPORT-COV-1001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04349098 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Karyopharm Therapeutics Inc.
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Sponsor organisation address |
85 Wells Avenue, Newton, MA, United States, 02459
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Public contact |
Clinical Trials Information, Karyopharm Therapeutics Inc., +1 617658 0600, clinicaltrials@karyopharm.com
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Scientific contact |
Clinical Trial Information, Karyopharm Therapeutics Inc., +1 617658 0600, clinicaltrials@karyopharm.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
05 Oct 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Oct 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
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.
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 Apr 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 175
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Country: Number of subjects enrolled |
Israel: 1
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Country: Number of subjects enrolled |
Spain: 9
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
France: 1
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Worldwide total number of subjects |
190
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EEA total number of subjects |
10
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
130
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From 65 to 84 years |
49
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85 years and over |
11
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Recruitment
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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
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Screening details |
A total of 190 subjects were enrolled and randomised, of which 188 subjects received study treatment in this study. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||
Blinding implementation details |
Study design was changed as double-blinded (subjects and principal investigator) as per protocol version 4.1.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
KPT-330
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Other name |
XPOVIO®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of Selinexor 20 mg tablets orally on Days 1, 3 and 5.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of placebo matched to selinexor tablets orally on Days 1, 3 and 5.
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Baseline characteristics reporting groups
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Reporting group title |
Selinexor 20 mg
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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
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Selinexor 20 mg
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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
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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. |
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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.
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End point type |
Primary
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End point timeframe |
Baseline up to Day 14
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Statistical analysis title |
At least 2-point improvement in ordinal scale | ||||||||||||
Comparison groups |
Selinexor 20 mg v Placebo
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Number of subjects included in analysis |
117
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.675 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
0.84
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.39 | ||||||||||||
upper limit |
1.79 |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 7
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 7 and 14
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 28
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 28
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 28
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 28
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 67
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 3, 5, 8, 12, 15, 19, 22 and 26
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 3, 5, 8, 12, 15, 19, 22 and 26
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 3, 5, 8, 12, 15, 19, 22 and 26
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 3, 5, 8, 12, 15, 22 and 26
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
From start of study drug administration up to Day 58
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From start of study drug administration up to Day 58
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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.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Selinexor 20 mg
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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
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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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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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 |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |