Evaluation of Activity and Safety of Oral Selinexor in Participants With Severe COVID-19 Infection
- Registration Number
- NCT04349098
- Lead Sponsor
- Karyopharm Therapeutics Inc
- 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 available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 190
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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).
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Currently hospitalized.
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Informed consent provided as above (it is recommended that participants are dosed with study drug within 12 hours of consent).
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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).
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Elevated C-reactive protein (CRP) > 2 x upper limit of normal (ULN).
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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.
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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.
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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
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In the opinion of the investigator, unlikely to survive for at least 48 hours from screening or anticipate mechanical ventilation within 48 hours.
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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)
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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
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Hyponatremia defined as sodium < 135 milliequivalents per liter (mEq/L).
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Unable to take oral medication when informed consent is obtained.
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Participants with a legal guardian or who are incarcerated.
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Treatment with strong CYP3A inhibitors or inducers.
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Pregnant and breastfeeding women.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Selinexor 20 mg Selinexor 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). Placebo 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).
- Primary Outcome Measures
Name Time Method Percentage of Participants With At-least a 2-Point Improvement in Ordinal Scale 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With at Least a 2-Point Improvement in the Ordinal Scale up to Day 7 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.
Time to Clinical Improvement of 2-points Using Ordinal Scale (TTCI-2) 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 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) 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 Baseline up to Day 28 The rate of ICU admission was defined as the percentage of participants with ICU admissions.
Percentage of Participants With at Least a 1-Point Improvement in the Ordinal Scale 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.
Changes From Baseline in Blood Plasma Cytokines Levels-Interleukin-6 (IL-6) 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.
Length of Hospitalization 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 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 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 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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs 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.
Trial Locations
- Locations (32)
Emory University
🇺🇸Atlanta, Georgia, United States
Boston Medical Center
🇺🇸Boston, Massachusetts, United States
Lehigh Valley Hospital
🇺🇸Allentown, Pennsylvania, United States
Princess Royal University Hospital
🇬🇧Kent, United Kingdom
UCLA
🇺🇸Los Angeles, California, United States
CHU Nantes
🇫🇷Nantes, France
Hadassah MC
🇮🇱Jerusalem, Israel
Miami Cancer Institute at Baptist Health
🇺🇸Miami, Florida, United States
UC Davis Health
🇺🇸Sacramento, California, United States
Servicio de Medicina Interna, Hospital Universitario de Salamanca, Universidad de Salamanca
🇪🇸Salamanca, Spain
Hasharon Medical Center
🇮🇱Petah Tiqva, Israel
Sheba Medical Center
🇮🇱Tel HaShomer, Israel
CHU Bordeaux
🇫🇷Bordeaux, France
The Royal Marsden Hospital
🇬🇧London, United Kingdom
Kings College Hospital
🇬🇧London, United Kingdom
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
CHU Lyon
🇫🇷Lyon, France
University Hospitals Plymouth NHS Trust
🇬🇧Plymouth, United Kingdom
Kaiser Permanente Oakland
🇺🇸Oakland, California, United States
Kaiser Permanente Sacramento
🇺🇸Sacramento, California, United States
Kaiser Permanente San Francisco
🇺🇸San Francisco, California, United States
Advocate Christ Medical Center
🇺🇸Oak Lawn, Illinois, United States
Norton Healthcare
🇺🇸Louisville, Kentucky, United States
Karmanos
🇺🇸Detroit, Michigan, United States
Michigan Center of Medical Research
🇺🇸Royal Oak, Michigan, United States
Columbia University
🇺🇸New York, New York, United States
Weill Cornell Medical College
🇺🇸New York, New York, United States
MultiCare Institute for Research & Innovation (Puget Sound)
🇺🇸Tacoma, Washington, United States
Levine Cancer Institute-Atrium Health University City
🇺🇸Charlotte, North Carolina, United States
Baylor Scott & White Dallas
🇺🇸Dallas, Texas, United States
Hospital Hietzing, 2. Medical department - Center for Diagnosis and Therapy of Rheumatic Diseases
🇦🇹Vienna, Austria
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States