Silmitasertib (CX-4945) in Patients With Severe Coronavirus Disease 2019 (COVID-19)

Study Overview
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Brief Summary
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This multi-center, open-label, 2 arm parallel-group, randomized, interventional prospective exploratory study in 40 patients aimed to evaluate safety and explore putative clinical benefits of Silmitasertib 1000 mg BID dose in patients with severe illness caused be SARS-COV-2. This will be a two-arm trial comparing the SOC/best supportive care alone to the SOC/best supportive care with addition of Silmitasertib (allocation ratio 1:1).

Detailed Description
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This is a phase II multi-center, randomized, open-label, 2 arm parallel-group controlled interventional prospective study of CX-4945 in patients with severe COVID-19. Up to approximately 40 patients will be enrolled into this study. A screening evaluation will occur within 7 days prior to Day 1. All qualified patients will be randomized at Day 1 in a ratio of 1:1 to one of the following two treatment arms: Arm A: SOC/ best supportive care in combination with CX-4945 1000 mg BID PO or Arm B: SOC/ best supportive care alone The standard of care (SOC) is not pre-specified, may vary among patients, and may include agents with anti-viral activity, such as remdesivir, among others. Investigator discretion is to be applied for any established SOC. Active concomitant treatment with other investigational antivirals or immunomodulators are not permitted Best supportive care is defined as intensive care therapy according to current guidelines, evidence, and best practice, including but not limited to lung protective ventilation, thrombosis prophylaxis, renal replacement therapy when indicated, and access to advanced therapies including extracorporeal membrane oxygenation. The total duration of the treatment will be 14 days. Patients will be followed up at 28, 45 and 60 days from the start of the treatment. The total duration for each patient in the study (including the screening) will be up to 67 days.

Official Title
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Phase II, Randomized, Investigator Initiated Trial to Evaluate Safety and to Explore Clinical Benefit of Silmitasertib (CX-4945) in Patients With Severe Coronavirus Disease 2019 (COVID-19)

Conditions
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Coronavirus

Intervention / Treatment
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* Drug: Silmitasertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant female adult ≥ 18 years of age Diagnosed/confirmed with COVID-19 by standard RT-PCR assay or equivalent testing within 7 days prior to randomization (Day1). Hospitalized patient with severe illness caused by SARS-CoV-2 (Note: Prior or current use of remdesivir or dexamethasone (SOC) are allowed under the investigator's discretion. Concomitant treatment with other investigational antiviral drugs or immunomodulators are not permitted from Day1 through Day 28) Symptoms of severe systemic illness/infection with COVID-19: At least 1 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 infection including dyspnea at rest or respiratory distress AND Clinical signs indicative of severe systemic illness/infection with COVID-19 At least 1 of the following: RR ≥ 30, HR ≥ 125, SaO2 <93% on room air or requires > 2L oxygen by nasal cannula in order to maintain SaO2 ≥93% Patient (or legally authorized representative) provides written informed consent prior to initiation of any study procedures. Adequate hematopoietic capacity, as defined by the following: Hemoglobin ≥ 9.0 g/dL and not transfusion dependent Platelets ≥ 100,000/mm3 Absolute neutrophil count ≥ 1500 cells/mm3 Adequate hepatic function, as defined by the following: AST and ALT ≤ 2.5 times upper limit of normal (ULN) Total bilirubin ≤ 1.5 x ULN Albumin ≥ 3.0 g/dL Adequate renal function, as defined by the following: a. Renal: calculated creatinine clearance >45 mL/min for patients with abnormal, increased creatinine levels (Cockcroft-Gault formula). Ability to take oral medication and be willing to adhere to drug administration and premedication requirements (see Section 6.3) throughout study duration. Exclusion Criteria: Patient showing signs of respiratory failure necessitating mechanical ventilation Pregnant or nursing women. NOTE: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation. Should a man father a child, or a woman become pregnant or suspect she is pregnant while participating in this study, he or she should inform the treating physician immediately. Active or uncontrolled infections other than COVID-19 or with serious illnesses or medical conditions which would not permit the patient to receive study treatment Active or planned concomitant treatment with other investigational antivirals or immunomodulators Chronic diarrhea (excess of 2-3 stools/day above normal frequency) Current use or anticipated need for drugs that are known strong inhibitors or inducers of major CYP enzymes.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Silmitasertib<br>Standard of care / supportive care in combination with Silmitasertib (CX-4945) | Drug: Silmitasertib<br>* Standard of care / best supportive care in combination with CX-4945 1000 mg administered orally, two times a day.<br>* Other names: CX-4945;|
| No Intervention: Standard of Care<br>Standard of care / supportive care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] | Adverse Events experienced by the patients from randomization to Day 60 (including vital signs, physical findings, clinical laboratory, and ECG results) as characterized by type, frequency, severity (as graded by Common Terminology Criteria for Adverse Events (CTCAE version 5.0), timing, seriousness, and relationship to study therapy. | Through Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Compare Time to Clinical Recovery in CX-4945 Treatment Group Evaluated From Randomization Through Day 28 as Compared to the Control Arm. | Number of days from randomization to discharge, or to alleviation of cough (defined as mild or absent in a patient reported scale of 0=absent, 1=mild, 2=moderate, and 3=severe). Improvement must be sustained for at least 48 hours. | Through Day 28 | 
| To Compare Time to Clinical Recovery in CX-4945 Treatment Group Evaluated From Randomization Through Day 28 as Compared to the Control Arm. | Number of days from randomization to normalization of fever (defined as <36.6°C from axillary site, or < 37.2°C from oral site or < 37.8°C from rectal or tympanic site), normalization of respiratory rate (< 24 bpm while breathing room air), resolution of hypoxia (defined as SpO2 ≥ 93% in room air or P/F ≥ 300 mmHg). All these improvements must be sustained for at least 48 hours. | Through hospital discharge, an average of 28 days | 
| To Compare Time to Clinical Recovery in CX-4945 Treatment Group Evaluated From Randomization Through Day 28 as Compared to the Control Arm. | Number of days from randomization to the first day on which the subject satisfies one of the following three categories from the ordinal NIAID 8- point Clinical Progression Outcomes scale collected daily from randomization through Day 28: Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized, no limitations on activities. | Through Day 28 | 
| To Compare Changes in Clinical Status of Patients Enrolled to CX-4945 Treatment Arm as Compared to the Control Arm at Day 14 and Day 28. | Difference in percentage of subjects with clinical recovery compared at Day 14 and Day 28. | Assessed on Day 14 and Day 28 | 
| To Compare Changes in Clinical Status of Patients Enrolled to CX-4945 Treatment Arm as Compared to the Control Arm at Day 14 and Day 28. | Percentage of Participants at Each Clinical Status at Day 14 and Day 28 assessed by using the ordinal NIAID 8- point Clinical Progression Outcomes scale (Scale ranges from 1 (Death) to 8 (Not hospitalized, no limitations on activities) | Through Day 28 | 
| To Evaluate Preliminary Evidence of Anti-viral Activity of CX-4945 as Compared to the Control Arm. | Difference in proportions of patients with conversion of positive RT-PCR to negative RT-PCR as assessed at Day 1, Day 8, Day 14 and Day 28. | Assessed at Day 1, Day 8, Day 14 and Day 28 | 
| To Evaluate Preliminary Evidence of Anti-viral Activity of CX-4945 as Compared to the Control Arm. | Changes in chest imaging from Screening to Day 5 or 14 | Through Day 14 | 
| Number of Days Hospitalized | Days of hospitalization from randomization through Day 28 | Through Day 28 | 
| To Evaluate Changes in IL-6 Level | IL-6 level | Assessed on Days 1, 4, 8, 11, and 14 | 
| To Evaluate Changes in CRP | CRP level | Assessed on Days 1, 4, 8, 11, and 14 | 
| To Evaluate Changes in LDH | LDH level | Assessed on Days 1, 4, 8, 11, and 14 | 
| To Evaluate Changes in CPK | CPK level | Assessed on Days 1, 4, 8, 11, and 14 | 
| To Evaluate Changes in Ferritin | Ferritin level | Assessed on Days 1, 4, 8, 11, and 14 | 
| To Evaluate Changes in D-dimer | D-dimer level | Assessed on Days 1, 4, 8, 11, and 14 | 
| Number of Days of Supplemental Oxygen Use | Days of supplemental oxygen (if applicable) from randomization through day 28 | Through Day 28 | 
| All-cause Mortality Status | The number of deaths occurred in each treatment group from randomization through Day 60 | Through Day 60 | 
| Number of Days of On-invasive Ventilation/High Flow Oxygen | Days of non-invasive ventilation/high flow oxygen (if applicable) from randomization through day 28 | Through Day 28 | 
| Number of Days of Invasive Mechanical Ventilation/ECMO | Days of invasive mechanical ventilation/ECMO (if applicable) from randomization through Day 28. | Through Day 28 | 
| Number of Patients Returned to Room Air | Number of patients returned to room air after randomization through Day 14 or Day 28. | Through Day 28 | 
| Change in Pulse Oxygen Saturation | Change in pulse oxygen saturation (SpO2) from randomization to Day 4, 8, 11, 14 and 28 | Days 4, 8, 11, 14, and 28 | 
| Number of Thrombosis Events | Number of documented venous thromboembolism (VTE), arterial thrombosis (stroke, myocardial infarction, other) and microthrombosis events from randomization through Day 28 | Through Day 28 | 
| Changes in EQ-D5-5L | The EuroQol 5 Dimension 5 Level (EQ-5D-5L) is a self-report survey that measures quality of life across 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is scored on a 5-level severity ranking that ranges from no problems (Level 1); slight; moderate; severe; and extreme problems (Level 5). Higher values indicate worse outcomes, while lower indicate better outcomes. The subscales are combined to compute a total score and averaged to produce the mean and SD. Changes in EQ-D5-5L (used as an indicator of symptom improvement) from randomization to Day 8, 14 and 28 | Days randomization, 8, 14 and 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, COVID-19