Silmitasertib (CX-4945) in Patients With Severe Coronavirus Disease 2019 (COVID-19) (CX4945)

• ClinicalTrials.gov Identifier: NCT04668209
• Recruitment Status: Completed
• First Posted: December 16, 2020
• Last Update Posted: May 11, 2023
• Sponsor: University of Arizona
• Collaborator: Senhwa Biosciences, Inc.
• Information provided by (Responsible Party): University of Arizona

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Coronavirus	Drug: Silmitasertib	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: January 21, 2021
• Actual Primary Completion Date: June 30, 2022
• Actual Study Completion Date: October 19, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Silmitasertib; Standard of care / supportive care in combination with Silmitasertib (CX-4945)	Drug: Silmitasertib; Standard of care / best supportive care in combination with CX-4945 1000 mg administered orally, two times a day.; Other Name: CX-4945
No Intervention: Standard of Care; Standard of care / supportive care

Outcome Measures

Primary Outcome Measures :

1. Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Through Day 60 ]
   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.

Secondary Outcome Measures :

1. To compare time to clinical recovery in CX-4945 treatment group evaluated from randomization through Day 28 as compared to the control arm. [ Time Frame: Through Day 28 ]
   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.
2. To compare time to clinical recovery in CX-4945 treatment group evaluated from randomization through Day 28 as compared to the control arm. [ Time Frame: Through hospital discharge, an average of 28 days ]
   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.
3. To compare time to clinical recovery in CX-4945 treatment group evaluated from randomization through Day 28 as compared to the control arm. [ Time Frame: Through Day 28 ]

   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.

4. 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. [ Time Frame: Assessed on Day 14 and Day 28 ]
   Difference in percentage of subjects with clinical recovery compared at Day 14 and Day 28.
5. 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. [ Time Frame: Through 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)
6. To evaluate preliminary evidence of anti-viral activity of CX-4945 as compared to the control arm. [ Time Frame: Assessed at Day 1, Day 8, Day 14 and Day 28 ]
   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.
7. To evaluate preliminary evidence of anti-viral activity of CX-4945 as compared to the control arm. [ Time Frame: Through Day 14 ]
   Changes in chest imaging from Screening to Day 5 or 14
8. Number of Days Hospitalized [ Time Frame: Through Day 28 ]
   Days of hospitalization from randomization through Day 28
9. To evaluate changes in IL-6 level [ Time Frame: Assessed on Days 4, 8, 11, and 14 ]
   IL-6 level
10. To evaluate changes in CRP [ Time Frame: Assessed on Days 4, 8, 11, and 14 ]
    CRP level
11. To evaluate changes in LDH [ Time Frame: Assessed on Days 4, 8, 11, and 14 ]
    LDH level
12. To evaluate changes in CPK [ Time Frame: Assessed on Days 4, 8, 11, and 14 ]
    CPK level
13. To evaluate changes in Ferritin [ Time Frame: Assessed on Days 4, 8, 11, and 14 ]
    Ferritin level
14. To evaluate changes in D-dimer [ Time Frame: Assessed on Days 4, 8, 11, and 14 ]
    D-dimer level
15. Number of Days of Supplemental Oxygen Use [ Time Frame: Through Day 28 ]
    Days of supplemental oxygen (if applicable) from randomization through day 28
16. All-cause Mortality Status [ Time Frame: Through Day 60 ]
    The number of deaths occurred in each treatment group from randomization through Day 60
17. Number of days of on-invasive ventilation/high flow oxygen [ Time Frame: Through Day 28 ]
    Days of non-invasive ventilation/high flow oxygen (if applicable) from randomization through day 28
18. Number of days of invasive mechanical ventilation/ECMO [ Time Frame: Through Day 28 ]
    Days of invasive mechanical ventilation/ECMO (if applicable) from randomization through Day 28.
19. Number of patients returned to room air [ Time Frame: Through Day 28 ]
    Number of patients returned to room air after randomization through Day 14 or Day 28.
20. Change in pulse oxygen saturation [ Time Frame: Days 4, 8, 11, 14, and 28 ]
    Change in pulse oxygen saturation (SpO2) from randomization to Day 4, 8, 11, 14 and 28
21. Number of thrombosis events [ Time Frame: Through Day 28 ]
    Number of documented venous thromboembolism (VTE), arterial thrombosis (stroke, myocardial infarction, other) and microthrombosis events from randomization through Day 28
22. Changes in EQ-D5-5L [ Time Frame: Days randomization, 8, 14 and 28 ]
    Changes in EQ-D5-5L (used as an indicator of symptom improvement) from randomization to Day 8, 14 and 28

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or non-pregnant female adult ≥ 18 years of age
2. Diagnosed/confirmed with COVID-19 by standard RT-PCR assay or equivalent testing within 7 days prior to randomization (Day1).

3. 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%

4. Patient (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.

5. Adequate hematopoietic capacity, as defined by the following:

   1. Hemoglobin ≥ 9.0 g/dL and not transfusion dependent
   2. Platelets ≥ 100,000/mm3
   3. Absolute neutrophil count ≥ 1500 cells/mm3

6. Adequate hepatic function, as defined by the following:

   1. AST and ALT ≤ 2.5 times upper limit of normal (ULN)
   2. Total bilirubin ≤ 1.5 x ULN
   3. Albumin ≥ 3.0 g/dL

7. 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).

8. 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:

1. Patient showing signs of respiratory failure necessitating mechanical ventilation
2. 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.
3. 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
4. Active or planned concomitant treatment with other investigational antivirals or immunomodulators
5. Chronic diarrhea (excess of 2-3 stools/day above normal frequency)
6. Current use or anticipated need for drugs that are known strong inhibitors or inducers of major CYP enzymes.

Contacts and Locations

Locations

United States, Arizona

Banner University Medical Center Phoenix

Phoenix, Arizona, United States, 85006

Banner University Medical Center Tucson

Tucson, Arizona, United States, 85724

Sponsors and Collaborators

University of Arizona

Senhwa Biosciences, Inc.

More Information

• Responsible Party: University of Arizona
• ClinicalTrials.gov Identifier: NCT04668209
• Other Study ID Numbers: CX4945-AV02-IIT
• First Posted: December 16, 2020
• Last Update Posted: May 11, 2023
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Study results will be published on clinicaltrials.gov.

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

Keywords provided by University of Arizona:

SARS-CoV-2; COVID-19

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases