Canakinumab in Covid-19 Cardiac Injury (The Three C Study)

Canakinumab to Reduce Deterioration of Cardiac and Respiratory Function in SARSCoV2 Associated Acute Myocardial Injury With Heightened Inflammation

TThe purpose of this prospective, Phase 2, single center, blinded, randomized controlled study is to demonstrate as a proof of concept that early treatment with canakinumab prevents progressive heart and respiratory failure in patients with COVID-19 infection. These results will lead to and inform a Phase III randomized placebo-controlled trial.

Study Overview

• Status: Completed
• Conditions: COVID-19; SARS-CoV 2
• Intervention / Treatment: Drug: Canakinumab Injection 600mg; Drug: Canakinumab Injection 300mg; Drug: Placebos

Detailed Description

This is a prospective, Phase 2, single center, blinded randomized-controlled study designed as a proof of concept to demonstrate that early treatment with canakinumab prevents progressive heart and respiratory failure in patients with COVID 19 infection, myocardial injury and hyperinflammation. These results will lead to a Phase III randomized placebo-controlled trial.

The study will be performed in approximately 7 months total, starting from the first patient enrolled with enrollment expected to complete within 2 months. The follow-up period is 5 months for each patient enrolled. The end of the study, including statistical analysis and drafting of the final report is expected within 1 month from the last patient enrolled.

A total of 45 patients will be randomized using a 1:1:1 allocation ratio: 15 subjects will receive 600 mg intravenous canakinumab (8 mg/kg if </= 40 kg), 15 subjects will receive 300 mg intravenous canakinumab (4 mg/kg if </= 40 kg), and 15 patients will receive placebo infusion.

The investigator, clinical team, and subject will be blinded to treatment assignment.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria: Subjects eligible for inclusion in this study must meet all of the following criteria:

1. Written informed consent must be obtained before any assessment is performed
2. Hospitalized due to COVID-19 infection
3. Documented SARS-CoV2 acute myocardial injury: Defined as upper respiratory tract specimen positive for COVID-19 AND Troponin T greater than 99th percentile upper reference range without signs or symptoms of acute myocardial ischemia
4. NT-proBNP greater than the age-adjusted upper reference limit
5. Receiving current standard therapy
6. C-reactive protein (CRP) > 50 mg/L

Exclusion Criteria: Subjects meeting any of the following criteria are not eligible for inclusion in this study.

1. Alternative explanation for acute cardiac injury (Type I or Type II MI according to 4th Universal Definition of Myocardial Infarction, which in addition to a rise and fall of troponin above the 99th percentile upper reference limit, includes symptoms of acute myocardial ischemia, new ischemic ECG changes, development of pathologic Q waves, and imaging evidence of damage in a pattern consistent with an ischemic etiology)
2. Chronic Systolic Heart Failure with EF<35%
3. Age < 18 years-old
4. Uncontrolled systemic bacterial or fungal infection
5. Concomitant viral infection (e.g., Influenza or other respiratory virus)
6. Pregnant. Breast-feeding women are eligible with the decision to continue or discontinue breast-feeding during therapy taking into account the risk of infant exposure, the benefits of breast-feeding to the infant, and benefits of treatment to the mother.
7. On mechanical circulatory support
8. On mechanical ventilation for greater than 48 hours
9. Resuscitated cardiac arrest
10. Has a known hypersensitivity to canakinumab or any of its excipients
11. Neutrophil count <1000/mm3
12. Has a history of myeloproliferative disorder or active malignancy receiving chemotherapy
13. Known active tuberculosis or history of incompletely treated tuberculosis
14. Current treatment with immunosuppressive agents
15. Chronic prednisone use >10 mg/daily (for more than 3 weeks prior to admission)
16. Has a history of solid-organ or bone marrow transplant
17. Severe pre-existing liver disease with clinically significant portal hypertension
18. End-stage renal disease on chronic renal replacement therapy
19. Enrollment in another investigational study using immunosuppressive therapy
20. In the opinion of the investigator and clinical team, should not participate in the study
21. If male and sexually active, must have documented vasectomy or must practice birth control and not donate sperm during the study and for 3 months after study drug administration.

22. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug. Such methods include:

    • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
    • Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Placebo	Drug: Placebos; 250 mL of 5% dextrose infused IV over 2 hours; Other Names: Control
Active Comparator: High Dose Intervention; 600 mg of canakinumab (8 mg/kg for patients </= 40 kg)	Drug: Canakinumab Injection 600mg; Subjects will be given one-time intravenous infusion of 600 mg of canakinumab (8 mg/kg for patients; Other Names: ACZ885
Active Comparator: Low Dose Intervention; 300 mg of canakinumab (4 mg/kg for patients </= 40 kg)	Drug: Canakinumab Injection 300mg; Subjects will be given one-time intravenous infusion of 300 mg of canakinumab (4 mg/kg for patients; Other Names: ACZ885

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinical Improvement at Day 14	Number of patients with either an improvement of two points on a seven category ordinal scale or discharge from the hospital	Up to day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality	Number of patients who expired after treatment	Up to day 28

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: Novartis
• Investigators: Principal Investigator: Paul C Cremer, M. D., The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2020
• Primary Completion (Actual): February 2, 2021
• Study Completion (Actual): April 1, 2021

Study Registration Dates

• First Submitted: April 24, 2020
• First Submitted That Met QC Criteria: April 24, 2020
• First Posted (Actual): April 28, 2020

Study Record Updates

• Last Update Posted (Actual): April 15, 2021
• Last Update Submitted That Met QC Criteria: April 13, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: IND 149328

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No