Cardiovascular Risk Reduction Study (Reduction in Recurrent Major CV Disease Events)

Study Overview
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Brief Summary
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Main Study (CACZ885M2301): The purpose of the pivotal phase of this trial was to test the hypothesis that canakinumab treatment of patients with myocardial infarction (MI) at least one month prior to study entry and elevated hsCRP could prevent recurrent cardiovascular events. The purpose of the extension phase of the main study is to collect additional long-term safety data on continued exposure to canakinumab in patients who participated in the pivotal phase. Sub-study 1 (CACZ885M2301S1): The purpose of this sub-study was to evaluate the effect of quarterly subcutaneous canakinumab treatment for 24 months comparted with placebo on the carotid plaque burden measured by integrated vascular MRI in patients enrolled in the CACZ885M2301 study (CANTOS). Sub-study 2 (CACZ885M2301S2): The purpose of this CANTOS sub-study was to determine whether, in patients with type 2 diabetes participating in the CANTOS main study, canakinumab compared to placebo, on top of standard of care could increase insulin secretion and insulin sensitivity.

Detailed Description
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Sub-study 1 and 2 were terminated prior to data collection from subjects. However, there is an ongoing extension trial where patients are receiving open-drug label.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Event-driven Trial of Quarterly Subcutaneous Canakinumab in the Prevention of Recurrent Cardiovascular Events Among Stable Post-myocardial Infarction Patients With Elevated hsCRP

Conditions
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Atherosclerosis

Intervention / Treatment
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* Drug: Canakinumab
* Drug: Placebo
* Drug: Standard of care


Participation Criteria
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Eligibility Criteria
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Main Study Inclusion Criteria: Written informed consent Male, or Female of non-child-bearing potential Age ≥ 18 years. Spontaneous MI at least 30 days before randomization. hsCRP ≥ 2 mg/L Substudy 1 Inclusion: All Inclusion from Main Study Acquisition of evaluable baseline MRI images of bilateral carotid arteries by the imaging core laboratory Substudy 2 Inclusion: All inclusion from Main Study T2D at baseline per Main protocol criteria and be on a stable anti-hyperglycemic medication for at least 4 weeks prior to the baseline OGTT test Willing to have the OGTT assessment started before 10 am Main Study Exclusion Criteria: Pregnant or nursing (lactating) women Women of child-bearing potential Any of the following concomitant diseases Planned coronary revascularization (PCI or CABG) Major non-cardiac surgical or endoscopic procedure within past 6 months Multi-vessel CABG surgery within the past 3 years Symptomatic patients with Class IV heart failure (HF) (New York Heart Association [NYHA]. Uncontrolled hypertension Uncontrolled diabetes History or evidence of active tuberculosis (TB) infection Substudy 1 Exclusion All Main exclusion Patients with prior history of carotid angioplasty, stenting, or carotid atherectomy Patients with contraindications to MRI examination (brain aneurysm clip, implanted neural stimulator, implanted cardiac pacemaker, pacemaker wires or defibrillator, prosthetic heart valves, cochlear implant, ocular foreign body or other implanted body, tattoos, implanted insulin pump, metal shrapnel or bullet) Patients prone to claustrophobia or known anxiety disorders BMI > 40 kg/m2 Substudy 2 Exclusion This sub-study does not have any additional exclusion criteria.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Canakinumab Dose 50 mg<br>Pivotal Phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care therapy. Extension Phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy | Drug: Canakinumab<br> <br> * Other names: ACZ885;Drug: Standard of care<br>* Standard of care post-MI background therapy includes, but is not limited to, lipid lowering, anti-hypertensive, beta blockers, and anti-platelet therapy as appropriate<br>|
| Experimental: Canakinumab Dose 150 mg<br>Pivotal Phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy | Drug: Canakinumab<br> <br> * Other names: ACZ885;Drug: Standard of care<br>* Standard of care post-MI background therapy includes, but is not limited to, lipid lowering, anti-hypertensive, beta blockers, and anti-platelet therapy as appropriate<br>|
| Experimental: Canakinumab Dose 300 mg<br>Pivotal Phase: Blinded Canakinumab 300 mg quarterly subcutaneous (with one additional dose at week 2) + standard of care therapy. Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy | Drug: Canakinumab<br> <br> * Other names: ACZ885;Drug: Standard of care<br>* Standard of care post-MI background therapy includes, but is not limited to, lipid lowering, anti-hypertensive, beta blockers, and anti-platelet therapy as appropriate<br>|
| Placebo Comparator: Placebo<br>Pivotal Phase: Blinded matching placebo quarterly subcutaneous + standard of care therapy. Extension Phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy | Drug: Placebo<br> <br> Drug: Standard of care<br>* Standard of care post-MI background therapy includes, but is not limited to, lipid lowering, anti-hypertensive, beta blockers, and anti-platelet therapy as appropriate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | Time to occurrence of CEC (Cardiovascular clinical events adjudication committee) confirmed MACE, which was a composite endpoint consisting of CEC confirmed CV death, CEC confirmed non-fatal MI,or CEC confirmed non-fatal stroke. Patients with the CEC adjudicated reason for death of Unknown were counted as CV (cardiovascular) death. | From randomization, to end of treatment plus 30 days, up to approximately 6 years | 
| Substudy 1 (Core Phase): Change From Baseline in Carotid Plaque Burden in the Bifurcation Region of the Index Carotid Artery |  | 24 months | 
| Substudy 2 (Core Phase): Change From Baseline of the Insulin Secretion Rate (ISR) Relative to Glucose 0-30 Min Defined as Φ30 = AUCISR 0-30 / AUCGluc 0-30 Averaged Across the Year 3, 4, 5 Visits |  | From randomization up to approximately 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | Occurrence of the composite cardiovascular endpoint consisting of cardiovascular death, non-fatal MI, non-fatal stroke or hospitalization for unstable angina requiring unplanned revascularization. MACE includes CV death, non-fatal MI and non-fatal stroke. CEC = Clinical Endpoints Committee | From randomization, to end of treatment pus 30 days, up to approximately 6 years | 
| Patients With Core Phase New Onset Type 2 Diabetes Among Patients With Pre-diabetes at Randomization | Time to CEC confirmed new onset of type 2 diabetes among those with pre-diabetes at randomization (i.e. excluding those that are normoglycemic at baseline) | From randomization up to approximately 6 years | 
| Core Phase All-cause Mortality, Non-fatal MI, or Non-fatal Stroke | Occurrence of the composite endpoint consisting of all-cause mortality, non-fatal IM, or non-fatal stroke | From randomization, to end of treatment plus 30 days, up to approximately 6 years | 
| Core Phase All-cause Mortality | Number of participant deaths | From randomization, to end of treatment plus 30 days, up to approximately 6 years | 
| Summary of Adverse Events (Core Phase) | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) occurring during the double-blind Core phase of the study. AEs/SAEs are any signs or symptoms that occur during the study treatment. | From randomization, to end of treatment plus 30 days, up to approximately 6 years | 
| Summary of Adverse Events (Extension Phase) | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) occurring during the Extension phase of the study. AEs/SAEs are any signs or symptoms that occur during the study treatment. | From start of Extension phase, to end of treatment plus 30 days, up to approximately 2 years | 
| Substudy 1 (Core Phase): Change From Baseline of the Total Vessel Wall Area at Month 3 in the Bifurcation Region of the Index Carotid Artery |  | 3 months | 
| Substudy 1 (Core Phase): Mean Total Vessel Wall Area Across the Left and Right Carotid Artery at Month 3 and Month 24 |  | 24 months | 
| Substudy 1 (Core Phase): Change From Baseline in Corresponding Total Vessel Wall Area in the Left and Right Carotid Arteries |  | 24 months | 
| Substudy 1 (Core Phase): The Existence of a Baseline Total Vessel Wall Area by Treatment Interaction as Well as the Consistency of the Treatment Effect Across Subgroups |  | 24 months | 
| Substudy 2 (Core Phase): Change From Baseline in Insulin Sensitivity Index |  | From randomization up to approximately 6 years | 
| Substudy 2 (Core Phase): Change From Baseline in OGTT Stimulated Area Under Curve (AUC) 0-120 Min of Glucose Concentration, Insulin Concentration, Pro-insulin Concentration, and Insulin Concentration/Glucose Concentration Ratio |  | From randomization up to approximately 6 years | 
| Substudy 2 (Core Phase): Change From Baseline in Fasting Pro-Insulin Concentration/Insulin Concentration Ratio |  | From randomization up to approximately 6 years | 
| Substudy 2 (Core Phase): Change From Baseline in OGTT Stimulated Area Under the Curve (AUC) 0-120 Min of C-peptide Concentration |  | From randomization up to approximately 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular Death, Myocardial Infarction, Stroke, Canakinumab, IL-1B, hsCRP