COVID-19, SARS-CoV 2
Conditions
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.
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.
Interventions
DRUGCanakinumab 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
DRUGCanakinumab 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
DRUGPlacebos
250 mL of 5% dextrose infused IV over 2 hours
Sponsors
Novartis
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Improvement at Day 14 | Up to day 14 | Number of patients with either an improvement of two points on a seven category ordinal scale or discharge from the hospital |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality | Up to day 28 | Number of patients who expired after treatment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Dose Intervention 600 mg of canakinumab (8 mg/kg for patients \</= 40 kg)
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 | 15 |
| Low Dose Intervention 300 mg of canakinumab (4 mg/kg for patients \</= 40 kg)
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 | 14 |
| Control Placebo
Placebos: 250 mL of 5% dextrose infused IV over 2 hours | 16 |
| Total | 45 |
Baseline characteristics
| Characteristic | High Dose Intervention | Low Dose Intervention | Control | Total |
|---|---|---|---|---|
| Age, Continuous | 66.4 years | 70.7 years | 68.2 years | 68.8 years |
| Atrial fibrillation or flutter | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Baseline PaO2/FiO2 ratio | 148 ratio | 160 ratio | 117 ratio | 148 ratio |
| Baseline SOFA scores (SOFA: Sequential organ failure assessment) | 3 score on a scale | 2 score on a scale | 4 score on a scale | 3 score on a scale |
| BMI | 29.2 kg/m^2 | 28.3 kg/m^2 | 29.2 kg/m^2 | 28.8 kg/m^2 |
| Chronic kidney disease | 6 Participants | 2 Participants | 7 Participants | 15 Participants |
| COPD | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
| Coronary Artery Disease | 2 Participants | 4 Participants | 4 Participants | 10 Participants |
| Corticosteroids | 8 Participants | 3 Participants | 10 Participants | 21 Participants |
| C reactive protein (mg/dL) (reference range 0.0-0.4 mg/dL) | 12.7 mg/dL | 12.2 mg/dL | 17.6 mg/dL | 15.3 mg/dL |
| Current or former smoker | 5 Participants | 4 Participants | 6 Participants | 15 Participants |
| D-dimer (ng/mL)(reference range <500 ng/mL) | 1795 ng/mL | 950 ng/mL | 1500 ng/mL | 1320 ng/mL |
| Diabetes mellitus | 10 Participants | 4 Participants | 7 Participants | 21 Participants |
| Dyspnea | 11 Participants | 11 Participants | 14 Participants | 36 Participants |
| Ferritin (ng/mL)(reference range 14.7-205.1 ng/mL) | 740 ng/mL | 998 ng/mL | 1246 ng/mL | 1015 ng/mL |
| High sensitivity troponin T (ng/L) (reference range <12 ng/L) | 21 ng/L | 25 ng/L | 32 ng/L | 22 ng/L |
| Hospitalized, not requiring supplemental oxygen | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Hospitalized requiring invasive mechanical ventilation | 5 Participants | 2 Participants | 3 Participants | 10 Participants |
| Hospitalized requiring nasal high-flow oxygen or non-invasive ventilation, or both | 3 Participants | 3 Participants | 5 Participants | 11 Participants |
| Hospitalized requiring supplemental oxygen | 5 Participants | 9 Participants | 6 Participants | 20 Participants |
| Hyperlipidemia | 12 Participants | 8 Participants | 9 Participants | 29 Participants |
| Hypertension | 11 Participants | 9 Participants | 12 Participants | 32 Participants |
| Lymphocyte count (reference range 1.0-4.0 k/uL) | 0.8 k/uL | 0.7 k/uL | 0.5 k/uL | 0.7 k/uL |
| N-terminal pro B-type natriuretic peptide (pg/mL) (reference range <125 pg/mL) | 371 pg/mL | 372 pg/mL | 810 pg/mL | 479 pg/mL |
| Race/Ethnicity, Customized African-American | 8 Participants | 4 Participants | 5 Participants | 17 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 6 Participants | 9 Participants | 10 Participants | 25 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 15 participants | 14 participants | 16 participants | 45 participants |
| Remdesivir | 10 Participants | 5 Participants | 6 Participants | 21 Participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Male | 11 Participants | 9 Participants | 13 Participants | 33 Participants |
| Stroke | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Temperature | 36.8 degrees Celsius | 37.4 degrees Celsius | 36.8 degrees Celsius | 36.9 degrees Celsius |
| Time from symptoms onset to randomization | 6 days | 9 days | 6 days | 7 days |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 15 | 3 / 14 | 4 / 16 |
| other Total, other adverse events | 11 / 15 | 11 / 14 | 11 / 16 |
| serious Total, serious adverse events | 5 / 15 | 6 / 14 | 7 / 16 |
Outcome results
Primary
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
Time frame: Up to day 14
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose Intervention | Number of Participants With Clinical Improvement at Day 14 | 9 Participants |
| Low Dose Intervention | Number of Participants With Clinical Improvement at Day 14 | 7 Participants |
| Control | Number of Participants With Clinical Improvement at Day 14 | 9 Participants |
Secondary
All-cause Mortality
Number of patients who expired after treatment
Time frame: Up to day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose Intervention | All-cause Mortality | 1 Participants |
| Low Dose Intervention | All-cause Mortality | 3 Participants |
| Control | All-cause Mortality | 3 Participants |