Evaluating Safety, Pharmacokinetics and Clinical Benefit of Silmitasertib (CX-4945) in Subjects With Moderate COVID-19

Study Overview
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Brief Summary
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This single-center, open-label, 2 arm parallel-group, randomized, interventional prospective exploratory study in 20 subjects aimed to evaluate safety and explore putative clinical benefits of Silmitasertib 1000 mg BID dose in patients with moderate COVID-19. Two-arm trial comparing the SOC/supportive care alone to the SOC/supportive care with addition of Silmitasertib (allocation ratio 1:1).

Detailed Description
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Silmitasertib is a first-in-class small molecule drug that targets Casein Kinase 2 (CK2). Protein kinase CK2 phosphorylates key proteins required to trigger mechanisms vital for viral replication and also is involved in development of host anti-viral immune response. SARS-CoV-2 viral proteins interacting with many human host proteins affect multiple innate immune pathways. One of these key proteins dysregulated by SARS-CoV-2 is the protein kinase CK2. SARS-COV-2 upregulates CK2 to support viral replication, avoid innate immune response and spread virus to nearby cells. Overactivation of CK2 indirectly contribute to successful viral replication and development of cytokine storm.SARs-Cov-2-induced overexpression of CK2, while pharmacological inhibition of CK2 suppresses virus proliferation. CK2 signaling appears to be an important pathway hijacked by SARS-CoV-2. Emerging pre-clinical and clinical data and results of independent efficacy evaluation conducted by Utah State University and UCSF COVID-19 research group and Senhwa Biosciences hypothesize that Silmitasertib (CX-4945) could potentially quell virus-provoked aberrant hyperactivation of the innate immune system by inhibition of upregulated CK2 protein kinase, preferentially restoring normal host cell cytokine regulation, and attenuating viral replication in patients with moderate to severe COVID-19, thereby preventing disease progression and improving clinical outcomes. Intended target patient population for treatment with Silmitasertib (CX-4945) are SARS-COV-2 positive patients with moderate to severe COVID-19, since in the moderate to severe stage of the disease infected cells actively produce viral proteins that dysregulate signaling pathways to allow viruses to manipulate host immune responses to create an environment more favorable for infection, that may not be observed in the initial or mild stage of the disease. CX-4945 demonstrated remarkable clinical benefits under emergency IND authorization in a patient with COVID-19 pneumonia not responsive to remdesivir, dexamethasone and antibiotics and requiring supplemental oxygen. The patient recovered and was discharged from the hospital in five days of treatment with CX-4945. The purpose of this open-label, randomized, 2 arm parallel-group controlled, interventional prospective exploratory study in 20 subjects is to evaluate safety, tolerability and pharmacokinetics of Silmitasertib (CX-4945) 1000 mg BID dose, to compare time to clinical recovery, and putative clinical benefit across treatment groups, and to evaluate anti-viral activities in COVID-19 patients. Silmitasertib is a generally well-tolerated medication. Most adverse events reported were mild to moderate in severity. The most common toxicities associated with CX-4945 were gastrointestinal disorders, manageable with drug discontinuation or use of anti-diarrheal medication. Based on the currently available data, the identified or potential risks of the product do not outweigh its identified or potential benefits.

Official Title
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A Phase II, Randomized and Controlled Investigator Initiated Trial Evaluating Safety, Pharmacokinetics and Clinical Benefit of Silmitasertib (CX-4945) in Outpatient Adult Subjects With Moderate Coronavirus Disease 2019 (COVID-19)

Conditions
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Covid19

Intervention / Treatment
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* Drug: Silmitasertib
* Drug: SOC


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 with COVID-19 by standard RT-PCR assay or equivalent testing Outpatient subjects with moderate illness caused by SARS-CoV-2 infection as defined below, Symptoms of moderate systemic illness/infection with COVID-19: At least two of the key COVID-19-related symptoms with score 2 or higher (0=none, 1=mild, 2=moderate, and 3=severe): cough, sore throat, malaise, headache, muscle pain, fever, neurological symptoms such as brain fog/concentration challenges, gastrointestinal symptoms or shortness of breath with exertion AND Clinical signs indicative of moderate systemic illness/infection with COVID-19 At least 1 of the following: respiratory rate ≥ 20 breaths per minute, heart rate ≥ 90 beats per minute AND No clinical signs indicative of Severe or Critical Illness Severity required hospitalization (see exclusion criterion #1) 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: Any signs indicative of Severe or Critical Illness Severity required hospitalization as defined below: Severe COVID-19: Shortness of breath in rest, or respiratory distress, respiratory rate (RR) >/= 30 per minute, heart rate (HR) >/=125 bpm, SpO2</=93% on room air at sea level or PaO2/FiO2<300 Critical COVID-19: respiratory failure required mechanical ventilation, oxygen delivered by high-flow nasal cannula, ESMO; shock or multi-organ dysfunction/failure 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 Chronic diarrhea (excess of 2-3 stools/day above normal frequency) Concomitant treatment with another investigational drug from Day 1 through Day 28. 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 |
| --- | --- |
| Experimental: Group A<br>Group A will receive the best supportive care and/or recommended standard of care (at this point no standard of care drugs are recommended by CDC for patients with moderate COVID-19) in combination with the study drug Silmitasertib | Drug: Silmitasertib<br>* Capsules<br>* Other names: CX-4945;|
| Active Comparator: Group B<br>Group B (control) that will receive the same care as the Group A but without Silmitasertib | Drug: SOC<br>* Some therapeutics for COVID-19 are available through EUA. SOC treatment availability is expected to change during the course of this trial.<br>* Other names: SOC/ Best 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]) within the CX-4945 Treatment Group assessed by CTCAE v5.0 | To assess adverse events associated with the administration of CX-4945 orally, twice daily to patients with moderate COVID-19. | From the first day that CX-4945 is taken until the end of the study i.e. 60 days or 46 days after the last dose of CX-4945 is taken. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Recovery associated with COVID-19 within the CX-4945 Treatment Group | To compare the number of days to clinical recovery specifically associated with COVID-19 in the CX-4945 treatment group as compared to the control arm by Day 14 of the study. | First 14 days of the study. | 
| Anti-Viral Activity of CX-4945 | To evaluate preliminary evidence of anti-viral activity of CX-4945 as compared to the control arm. | Quantitative changes in viral load from Day 1 to Day 28. | 
| Maximum Plasma Concentration [Cmax] of CX-4945 | To evaluate the maximum plasma concentration of CX-4945 when given at 1000 mg BID PO (Experimental Arm taking CX-4945 only i.e. Group A). | Plasma sample of CX-4945 are collected at the following timepoints: Day 1 pre-dose, 0.5, 1, 2, 3, 6 and 24 hours post Day 1 morning dose and Day 14: pre-dose, 0.5, 1, 2, 3, 6, 24, 48 and 72 hours post Day 14 morning dose. | 
| Clinical Benefit of CX-4945 i.e. All-Cause Mortality | Between the experimental arm with CX-4945 and the control arm, moderate COVID-19 patients' health status will be evaluated in terms of all-cause mortality. Mortality status and cause will be assessed by study staff and the information will be documented on a Clinical Status questionnaire. The data collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in all-cause mortality between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Day 1, Day 4, Day 8, Day 11, Day 14, Day 15, Day 16, Da y17, Day 28, Day 45 and Day 60. | 
| Clinical Benefit of CX-4945 i.e. Number of Respiratory Failures | Between the experimental arm with CX-4945 and the control arm, moderate COVID-19 patients' health status will be evaluated in terms of the number of respiratory failures. Respiratory failures will be assessed by study staff and the information will be documented on a Clinical Status questionnaire. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in number of respiratory failures between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1, Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45. | 
| Clinical Benefit of CX-4945 i.e. Number of Hospitalized Days | Between the experimental arm with CX-4945 and the control arm, moderate COVID-19 patients' health status will be evaluated in terms of the number of hospitalized days. The number of hospitalized days will be assessed by study staff and the information will be documented on a Clinical Status questionnaire. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in number of hospitalized days between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1, Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45. | 
| Clinical Benefit of CX-4945 i.e. Changes in Pulse Oxygen Saturation | Between the experimental arm with CX-4945 and the control arm, moderate COVID-19 patients' health status will be evaluated in terms of changes in pulse oxygen saturation. The levels of oxygen saturation will be assessed by study staff measuring the subject's oxygen saturation level, non-invasively and recording the oxygen saturation reading on a Clinical Recovery log. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in pulse oxygen saturation between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1, Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45. | 
| Clinical Benefit of CX-4945 i.e. Changes in Clinical Status | Between the experimental arm with CX-4945 and the control arm, moderate COVID-19 patients' health status will be evaluated in terms of changes in clinical status. Clinical status (ranging from deceased to not hospitalized/no limitations on activities) will be assessed by study staff and the information will be documented on a Clinical Status questionnaire. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in clinical status between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1, Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45. | 
| Clinical Benefit of CX-4945 i.e. Self-Reported Quality of Life | Between the experimental arm with CX-4945 and the control arm, moderate COVID-19 patients' health status will be evaluated in terms of subject reported quality of life. Quality of life will be assessed by the subject in relation to Covid-19 related symptoms. The information will be documented on a Clinical Symptom questionnaire. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in self-reported quality of life between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1 - Day 14, Day 28 and Day 45. | 
| CX-4945 Inflammatory Marker Outcomes i.e. Plasma IL-6 | Labs to evaluate changes in plasma IL-6 (interleukin-6 in pg/mL) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma IL-6 levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Day 1, Day 4, Day 8, Day 11 and Day 14. | 
| CX-4945 Inflammatory Marker Outcomes i.e. Plasma CRP | Labs to evaluate changes in plasma CRP (C-reactive protein in mg/DL) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma CRP levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1, Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45. | 
| CX-4945 Inflammatory Marker Outcomes i.e. Plasma LDH | Labs to evaluate changes in plasma LDH (lactic acid dehydrogenase in U/L) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma LDH levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1, Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45. | 
| CX-4945 Inflammatory Marker Outcomes i.e. Plasma CPK | Labs to evaluate changes in plasma CPK (creatine phosphokinase in mcg/L) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma CPK levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1, Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45. | 
| CX-4945 Inflammatory Marker Outcomes i.e. Plasma Ferritin | Labs to evaluate changes in plasma ferritin (mcg/L) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma ferritin levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1, Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45. | 
| CX-4945 Inflammatory Marker Outcomes i.e. Plasma D-Dimer | Labs to evaluate changes in plasma D-dimer (ng/mL) levels between the patients within the experimental arm with CX-4945 and the control arm, of patients with moderate COVID-19. The information collected will be analyzed at the conclusion of the study to determine if there is a statistically significant difference in plasma D-dimer levels between those whose treatment included CX-4945 and those whose treatment did not include CX-4945. | Various time points i.e. Screening, Day 1, Day 4, Day 8, Day 11, Day 14, Day 28 and Day 45. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate Covid19