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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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COVID-19, SARS-CoV 2

Intervention / Treatment
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* Drug: Canakinumab Injection 600mg
* Drug: Canakinumab Injection 300mg
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects eligible for inclusion in this study must meet all of the following criteria: Written informed consent must be obtained before any assessment is performed Hospitalized due to COVID-19 infection 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 NT-proBNP greater than the age-adjusted upper reference limit Receiving current standard therapy C-reactive protein (CRP) > 50 mg/L Exclusion Criteria: Subjects meeting any of the following criteria are not eligible for inclusion in this study. 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) Chronic Systolic Heart Failure with EF<35% Age < 18 years-old Uncontrolled systemic bacterial or fungal infection Concomitant viral infection (e.g., Influenza or other respiratory virus) 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. On mechanical circulatory support On mechanical ventilation for greater than 48 hours Resuscitated cardiac arrest Has a known hypersensitivity to canakinumab or any of its excipients Neutrophil count <1000/mm3 Has a history of myeloproliferative disorder or active malignancy receiving chemotherapy Known active tuberculosis or history of incompletely treated tuberculosis Current treatment with immunosuppressive agents Chronic prednisone use >10 mg/daily (for more than 3 weeks prior to admission) Has a history of solid-organ or bone marrow transplant Severe pre-existing liver disease with clinically significant portal hypertension End-stage renal disease on chronic renal replacement therapy Enrollment in another investigational study using immunosuppressive therapy In the opinion of the investigator and clinical team, should not participate in the study 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. 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

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: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 |