E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe COVID-19 Infection |
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E.1.1.1 | Medical condition in easily understood language |
Severe infection caused by a novel coronavirus COVID-19 |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051905 |
E.1.2 | Term | Coronavirus infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Day 14 Ordinal Scale Improvement (OSI) |
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E.2.2 | Secondary objectives of the trial |
Key secondary objectives:
-To evaluate improvement in clinical measures across the 2 treatment arms
Additional secondary objectives:
-To evaluate improvement in additional clinical measures across the 2 treatment arms
-To determine the anti-inflammatory and immune effect of selinexor
-To assess safety and tolerability of selinexor [time frame: up to 28 days] |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all the following criteria:
1.Age ≥18 years
2.Confirmed laboratory diagnosis of SARS-CoV2 by standard - approved RT-PCR assay (local labs) within 7 days of enrollment
3.Currently hospitalized
4.Informed consent
5.Has symptoms of severe COVID-19 as demonstrated by:
a.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
AND
b. 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 LPM oxygen by nasal canula, non-rebreather/Ventimask (or similar device) or high flow nasal canula in order to maintain SaO2≥92%, PaO2/FiO2 <300 mm/hg. Patients with COPD or chronic lung disease must demonstrate evidence of increased oxygen needs above baseline.
6.Elevated CRP > 2 x ULN
7.Concurrent anti-viral and/or anti-inflammatory agents (e.g., biologics, hydroxychloroquine) are permitted. If in the physician’s judgement, it is in the best interest of the patient to use anti-viral or anti-inflammatory treatments, these treatments are to be documented in the patient’s chart and entered in the electronic case report form.
Note: Patients who may have received plasma convalescent therapy > 48 hours prior to enrollment with no clinical improvement and who still meet criteria for severe COVID-19 may enroll. On study plasma convalescent therapy is not permitted. Patient who receive plasma convalescent therapy within 48 hours may be permitted to enroll based on discussion with sponsor.
8.Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment. Highly effective methods of contraception are listed in Section 8.3.1 of the protocol.
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E.4 | Principal exclusion criteria |
1.Evidence of critical COVID-19 based on:
a.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)
b.Septic shock (defined by investigator assessment or requiring vasopressors)
c.Multiple organ dysfunction/failure
2.In the opinion of the investigator, unlikely to survive for at least 48 hours from screening
3.Inadequate hematologic parameters as indicated by the following labs:
a.Patients with severe neutropenia (ANC <1,000 x 109/L) or
b.Thrombocytopenia (e.g., platelets <100,000 per microliter of blood )
4.Inadequate renal function and liver function as indicated by the following labs:
a.creatinine clearance (CrCL) <20 mL/min using the formula of Cockcroft and Gault.
b.Aspartate transaminase (AST) or alanine transaminase (ALT) >5x the upper limit of normal
5.Unable to take oral medication when inform consent is obtained.
6.Patients with a legal guardian or who are incarcerated.
7.Pregnant and breastfeeding women
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients with at least a 2 point improvement (increase) in the Ordinal Scale from baseline to Day 14.
The Ordinal Scale is an assessment of the clinical status at the first assessment on each day of hospitalization.
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 (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.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key secondary endpoints:
•Time to recovery defined as improvement from baseline score of 3 to ≥4 or from a baseline score of 4 to ≥5
•Proportion of patients with at least a 2 point improvement (increase) in the Ordinal Scale from baseline to Day 7.
•Proportion of patients with at least a 1 point improvement (increase) in the Ordinal Scale from baseline to Day 7
•Proportion of patients 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 randomization, or lower score within 24 hours, to an improvement of 1 point on the Ordinal Scale)
•Overall death rate on Day 28
•Rate of mechanical ventilation
Additional secondary endpoints:
•Overall Survival
•Overall death rate on Day 14
•Rate of ICU admission
•Length of hospitalization
•Length of ICU stay
•Duration of mechanical ventilation
•PaO2:FiO2 and/or oxygenation index over time
•Reduction of C-reactive protein (CRP)
•Reduction in ferritin levels
•LDH
•Measure changes from baseline of blood plasma cytokines: IL-1β, IL-1Rα, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IFNγ, IP10, TNFα
•Listing and documentation of frequency and severity of adverse effects |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall death rate on Day 14 and Day 28
Rest of endpoints during the course of the study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
enrollment stratified by: Use of concomitant therapies and High Risk Comorbidities |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Canada |
France |
Germany |
India |
Israel |
Italy |
Malaysia |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of Study will occur when the last patient has completed the 30-day
Safety follow up period (after their last dose of study treatment), has
withdrawn consent or has died, whichever comes first. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |