Canakinumab to Reduce Deterioration of Cardiac and Respiratory Function Due to COVID-19

• ClinicalTrials.gov Identifier: NCT04365153
• Recruitment Status: Recruiting
• First Posted: April 28, 2020
• Last Update Posted: May 21, 2020
• Sponsor: The Cleveland Clinic
• Information provided by (Responsible Party): The Cleveland Clinic

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
COVID-19; SARS-CoV 2	Drug: Canakinumab Injection 600mg; Drug: Canakinumab Injection 300mg; Drug: Placebos	Phase 2

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 canakinmab (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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Canakinumab to Reduce Deterioration of Cardiac and Respiratory Function in SARSCoV2 Associated Acute Myocardial Injury and Hyperinflammation
• Actual Study Start Date: April 24, 2020
• Estimated Primary Completion Date: December 31, 2020
• Estimated Study Completion Date: December 31, 2020

Arms and Interventions

Arm	Intervention/treatment
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 </= 40 kg) in 250 mL of 5% dextrose infused IV over 2 hours; Other Name: 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 </= 40 kg) in 250 mL of 5% dextrose infused IV over 2 hours; Other Name: ACZ885
Placebo Comparator: Control; Placebo	Drug: Placebos; 250 mL of 5% dextrose infused IV over 2 hours; Other Name: Control

Outcome Measures

Primary Outcome Measures :

1. Time to clinical improvement up to day 14, defined as the time in days from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever occurs first. [ Time Frame: Up to day 14 ]
   Number of days

Secondary Outcome Measures :

1. Mortality at day 28 [ Time Frame: Up to day 28 ]
   Number of days

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: 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 tropnonin 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

Contacts and Locations

Contacts

Contact: Paul C Cremer, M. D.; 216-445-6765; cremerp@ccf.org

Contact: Yuki Kuramochi, RN BSN; 216-445-4063; kuramoy@ccf.org

Locations

United States, Ohio

Cleveland Clinic; Recruiting

Cleveland, Ohio, United States, 44195

Contact: Paul C Cremer, M. D. 216-445-6765 cremerp@ccf.org

Contact: Yuki Kuramochci, RN BSN 216-445-4063 kuramoy@ccf.org

Principal Investigator: Paul C Cremer, M. D.

Sub-Investigator: Venu Menon, M. D.

Sub-Investigator: Ossama Abou Hassan, M. D.

Sub-Investigator: Calvin Sheng, M. D.

Sub-Investigator: Tom Wang, M. D.

Sub-Investigator: Sidhharth Dugar, M. D.

Sub-Investigator: Debases Sahoo, M. D.

Sub-Investigator: Alice Goyanes, M. D.

Sub-Investigator: Narendrakumar Alappan, M. D.

Sub-Investigator: Ravi Sunderkrishnan, M. D.

Sub-Investigator: Robier Aguillon-Prada, M. D.

Sponsors and Collaborators

The Cleveland Clinic

Investigators

• Principal Investigator: Paul C Cremer, M. D.; The Cleveland Clinic

More Information

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT04365153
• Other Study ID Numbers: IND 149328
• First Posted: April 28, 2020
• Last Update Posted: May 21, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs