Evaluation of Activity and Safety of Oral Selinexor in Participants With Severe COVID-19 Infection (Coronavirus)

• ClinicalTrials.gov Identifier: NCT04349098
• Recruitment Status: Completed
• First Posted: April 16, 2020
• Results First Posted: November 1, 2021
• Last Update Posted: January 20, 2023
• Sponsor: Karyopharm Therapeutics Inc
• Information provided by (Responsible Party): Karyopharm Therapeutics Inc

Tracking Information

• First Submitted Date: April 14, 2020
• First Posted Date: April 16, 2020
• Results First Submitted Date: October 5, 2021
• Results First Posted Date: November 1, 2021
• Last Update Posted Date: January 20, 2023
• Actual Study Start Date: April 17, 2020
• Actual Primary Completion Date: October 5, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 5, 2021)

Percentage of Participants With At-least a 2-Point Improvement in Ordinal Scale [ Time Frame: Baseline up to Day 14 ]

Ordinal Scale 2-Point improvement was defined as percentage of participants with at least a 2-points improvement (increase from baseline) by Day 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 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.

• Original Primary Outcome Measures (submitted: April 14, 2020): Percentage of Participants with at Least a 2 Point Improvement in the Ordinal Scale [ Time Frame: Baseline to Day 14 ]

Current Secondary Outcome Measures (submitted: October 5, 2021)

• Percentage of Participants With at Least a 2-Point Improvement in the Ordinal Scale up to Day 7 [ Time Frame: Baseline up to Day 7 ]
  Ordinal Scale 2-points improvement was defined as percentage of participants 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.
• Percentage of Participants With at Least a 1-Point Improvement in the Ordinal Scale [ Time Frame: Baseline up to Day 7 and 14 ]
  Ordinal Scale 1-point improvement was defined as percentage of participants 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.
• Time to Clinical Improvement of 2-points Using Ordinal Scale (TTCI-2) [ Time Frame: Baseline up to Day 28 ]
  TTCI-2 was defined as the time from randomization 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.
• Overall Death Rate [ Time Frame: Baseline up to Day 28 ]
  Overall death rate was defined as the percentage of participants who died on or before Day 28.
• Rate of Mechanical Ventilation (RMV) [ Time Frame: Baseline up to Day 28 ]
  The rate of RMV was defined as the percentage of participants who ever used invasive mechanical ventilation or ECMO during the hospital stay.
• Rate of Intensive Care Unit (ICU) Admission [ Time Frame: Baseline up to Day 28 ]
  The rate of ICU admission was defined as the percentage of participants with ICU admissions.
• Length of Hospitalization [ Time Frame: Baseline up to Day 67 ]
  Length of hospitalization (days) was defined as (first hospital discharge date - date of randomization + 1).
• Change From Baseline in C-reactive Protein (CRP) Levels [ Time Frame: Baseline, Day 3, 5, 8, 12, 15, 19, 22 and 26 ]
  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.
• Change From Baseline in Ferritin Levels [ Time Frame: Baseline, Day 3, 5, 8, 12, 15, 19, 22 and 26 ]
  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.
• Change From Baseline in Lactate Dehydrogenase (LDH) Levels [ Time Frame: Baseline, Day 3, 5, 8, 12, 15, 19, 22 and 26 ]
  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.
• Changes From Baseline in Blood Plasma Cytokines Levels-Interleukin-6 (IL-6) [ Time Frame: Baseline, Day 3, 5, 8, 12, 15, 22 and 26 ]
  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.
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: From start of study drug administration up to Day 58 ]
  Adverse events are defined as any untoward medical occurrence in a participant or clinical investigation participant 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, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. 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.

Original Secondary Outcome Measures (submitted: April 14, 2020)

• Time to Clinical Improvement (TTCI) [ Time Frame: Up to Day 28 ]
• Number of Participants with Overall Death Rate [ Time Frame: Day 14, Day 28 ]
• Number of Participants With Rate of Mechanical Ventilation [ Time Frame: Up to Day 28 ]
• Time to Mechanical Ventilation [ Time Frame: Up to Day 28 ]
• Overall survival [ Time Frame: Up to Day 28 ]
• Time to Improvement (2 points) in Clinical Measures Using the Ordinal Scale [ Time Frame: Baseline, Day 28 ]
• Time to Intensive Care Unit (ICU) Admission [ Time Frame: Up to Day 28 ]
• Rate of Intensive Care Unit (ICU) Admission [ Time Frame: Up to Day 28 ]
• Length of Stay in Hospital [ Time Frame: Up to Day 28 ]
• Percentage of Participants Discharged from Hospital [ Time Frame: Up to Day 28 ]
• Length of Stay in Intensive Care Unit (ICU) [ Time Frame: Up to Day 28 ]
• Duration of Oxygen Supplementation [ Time Frame: Up to Day 28 ]
• Duration of Mechanical Ventilation [ Time Frame: Up to Day 28 ]
• Change in Vienna Vaccine Safety Initiative (ViVI) Disease Severity Score [ Time Frame: Up to Day 28 ]
• Time to Clinical Improvement in Participants ≤ 70 Years Old [ Time Frame: Up to Day 28 ]
• Time to Clinical Improvement in Participants > 70 Years Old [ Time Frame: Up to Day 28 ]
• Time to Clinical Improvement in Participants with Pre-existing Diseases [ Time Frame: Up to Day 28 ]
• Change in Oxygenation Index [ Time Frame: Up to Day 28 ]
• Time to Improvement of One Point Using WHO Ordinal Scale Improvement [ Time Frame: Up to Day 28 ]
• Percentage of Participants Experiencing WHO Ordinal Scale Improvement of >1 point [ Time Frame: Up to Day 28 ]
• Change from Baseline in C-reactive protein (CRP) Levels [ Time Frame: Up to Day 28 ]
• Change from Baseline in Ferritin Levels [ Time Frame: Up to Day 28 ]
• Change from Baseline in Lactate Dehydrogenase (LDH) Levels [ Time Frame: Up to Day 28 ]
• Changes from Baseline in Blood Plasma Cytokines Levels [ Time Frame: Up to Day 28 ]
• Number of Participants with Adverse Events (AE) [ Time Frame: From start of study drug administration up to Day 28 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Activity and Safety of Oral Selinexor in Participants With Severe COVID-19 Infection
• Official Title: 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
• Brief Summary: The main purpose of this study is to evaluate the activity of low dose oral selinexor (KPT-330) and to evaluate the clinical recovery, the viral load, length of hospitalization and the rate of morbidity and mortality in participants with severe COVID-19 compared to placebo. The study had 2 arms and evaluated selinexor 20 mg + standard of care (SoC) and placebo + SoC. As the treatment for COVID-19 is rapidly evolving, the SoC varied over time and across regions of the world.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: Coronavirus Infection

Intervention

• Drug: Selinexor
  Participants will receive 20 mg of selinexor.
  Other Names:

  • KPT-330
  • XPOVIO
• Other: Placebo
  Participants will receive 20 mg of placebo matched to selinexor.

Study Arms

• Experimental: Selinexor 20 mg
  Participants will receive 20 milligram (mg) of selinexor oral tablet on Days 1, 3, and 5 of each week for up to 2 weeks (14 days). If the participant is tolerating therapy and clinically benefitting, dosing can continue for an additional 2 weeks (28 days).
  Intervention: Drug: Selinexor
• Placebo Comparator: Placebo
  Participants will receive 20 mg of placebo matched to selinexor oral tablet on Days 1, 3, and 5 of each week for up to 2 weeks (14 days). If the participant is tolerating therapy and clinically benefitting, dosing can continue for an additional 2 weeks (28 days).
  Intervention: Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 5, 2021): 190
• Original Estimated Enrollment (submitted: April 14, 2020): 230
• Actual Study Completion Date: October 5, 2020
• Actual Primary Completion Date: October 5, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Confirmed laboratory diagnosis of SARS-CoV2 by standard FDA-approved reverse transcription polymerase chain reaction (RT-PCR) assay or equivalent FDA-approved testing (local labs).
• Currently hospitalized.
• Informed consent provided as above (it is recommended that participants are dosed with study drug within 12 hours of consent).

• Has symptoms of severe COVID-19 as demonstrated by:

  • At least one of the following: fever, cough, sore throat, malaise, headache, muscle pain, shortness of breath at rest or with exertion, confusion, or symptoms of severe lower respiratory symptoms including dyspnea at rest or respiratory distress.
  • Clinical signs indicative of lower respiratory infection with COVID-19, with at least one of the following: SaO2 <92% on room air in last 12 hours or requires > 4 liters per minute (LPM) oxygen by nasal canula, non-rebreather/Ventimask or high flow nasal canula in order maintain SaO2 ≥92%, PaO2/FiO2 <300 millimeter per mercury (mm/hg).
• Elevated C-reactive protein (CRP) > 2 x upper limit of normal (ULN).
• Concurrent anti-viral and/or anti-inflammatory agents (e.g., biologics, hydroxychloroquine) are permitted. If in the physician's judgment, it is in the best interest of the participant to use anti-viral or anti-inflammatory treatments, these treatments are to be documented in the participant's chart and entered in the electronic case report form.
• Female participants of childbearing potential must have a negative serum pregnancy test at Screening. Female participants of childbearing potential and fertile male participants must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.

Exclusion Criteria:

• Evidence of critical COVID-19 based on:

  • Respiratory failure (defined by endotracheal intubation and mechanical ventilation, oxygen delivered by noninvasive positive pressure ventilation, or clinical diagnosis of respiratory failure in setting of resource limitations)
  • Septic shock (defined by Systolic blood pressure [BP] < 90 mm Hg, or Diastolic BP < 60 mm Hg)
  • Multiple organ dysfunction/failure
• In the opinion of the investigator, unlikely to survive for at least 48 hours from screening or anticipate mechanical ventilation within 48 hours.

• Inadequate hematologic parameters as indicated by the following labs:

  • Participants with severe neutropenia (ANC <1000 x 10^9/L) or
  • Thrombocytopenia (e.g., platelets <100,000 per microliter of blood)

• Inadequate renal and liver function as indicated by the following labs:

  • Creatinine clearance (CrCL) <20 mL/min using the formula of Cockcroft and Gault
  • Aspartate transaminase (AST) or alanine transaminase (ALT) > 5 x ULN
• Hyponatremia defined as sodium < 135 milliequivalents per liter (mEq/L).
• Unable to take oral medication when informed consent is obtained.
• Participants with a legal guardian or who are incarcerated.
• Treatment with strong CYP3A inhibitors or inducers.
• Pregnant and breastfeeding women.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, France, Israel, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04349098
• Other Study ID Numbers: XPORT-CoV-1001; 2020-001411-25 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Karyopharm Therapeutics Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: Karyopharm Therapeutics Inc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Karyopharm Therapeutics Inc
• Verification Date: January 2023