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.
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
mg intravenous canakinumab (4 mg/kg if
infusion.
The investigator, clinical team, and subject will be blinded to treatment assignment.
Drug: Canakinumab Injection 600mg
Subjects will be given one-time intravenous infusion of 600 mg of canakinumab (8 mg/kg for patients Other Name: ACZ885
Drug: Canakinumab Injection 300mg
Subjects will be given one-time intravenous infusion of 300 mg of canakinumab (4 mg/kg for patients Other Name: ACZ885
Drug: Placebos
250 mL of 5% dextrose infused IV over 2 hours
Other Name: Control
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
Cleveland Clinic Florida
Weston, Florida, United States
Cleveland Clinic
Cleveland, Ohio, United States
Paul C Cremer, M. D., Principal Investigator
The Cleveland Clinic