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

• Main:Time to first occurrence of major adverse cardiovascular event, which is a composite of CV death, non-fatal MI, and stroke. [ Time Frame: 36 months ]
• Substudy 1; Change from baseline in carotid plaque burden in the bifurcation region of the index carotid artery [ Time Frame: 36 months ]
• Substudy 2; 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 yearly visits. [ Time Frame: 36 months ]

• Main:Time to first occurrence of the composite cardiovascular endpoint consisting of cardiovascular death, non-fatal MI, stroke and hospitalization for unstable angina requiring unplanned revascularization. [ Time Frame: 36 months ]
• Main:Time to new onset type 2 diabetes among patients with pre-diabetes at randomization. [ Time Frame: 36 months ]
• Main:Time to first occurrence of non-fatal MI, stroke and all-cause mortality composite. [ Time Frame: 36 months ]
• Main: Time to all-cause mortality. [ Time Frame: 36 months ]
• Substudy 1; Change from baseline of the total vessel wall area at Month 3 of the index carotid artery. [ Time Frame: 36 months ]
• Substudy 1; Mean total vessel wall area across the left and right carotid artery at Month 3 and Month 24. [ Time Frame: 36 months ]
• Substudy 1; Change from baseline in corresponding total vessel wall area in the left and right carotid arteries. [ Time Frame: 36 months ]
• Substudy 1; The existence of a baseline total vessel wall area by treatment interaction as well as the consistency of the treatment effect across subgroups. [ Time Frame: 36 months ]
• Substudy 2; Change from baseline in insulin sensitivity index. [ Time Frame: 36 months ]
• Substudy 2; 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. [ Time Frame: 36 months ]
• Substudy 2; Change from baseline in fasting pro-insulin concentration /insulin concentration ratio. [ Time Frame: 36 months ]
• Substudy 2; Change from baseline in OGTT stimulated area under the curve (AUC) 0-120 min of C-peptide concentration. [ Time Frame: 36 months ]

• Time to the first occurrence of the composite cardiovascular endpoint consisting of cardiovascular death, non-fatal MI, stroke, and hospitalization for unstable angina requiring unplanned revascularization. [ Time Frame: 36 months ]
• Time to new onset type 2 diabetes among those with pre-diabetes at randomization. [ Time Frame: 36 months ]
• Time to first occurrence of non-fatal MI, stroke, and all-cause mortality composite. [ Time Frame: 36 months ]
• Time to all-cause mortality. [ Time Frame: 36 months ]

Main Study (CACZ885M2301): The purpose of the pivotal phase of this trial is to test the hypothesis that canakinumab treatment of patients with MI at least one month prior to study entry and elevated hsCRP will 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 is 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 is 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 increases insulin secretion and insulin sensitivity.

• Drug: Canakinumab
• Drug: Placebo

• Experimental: Canakinumab Dose 50 mg

  Pivotal Phase:

  Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care therapy.

  Extension Phase:

  Blinded canakinumab 50 mg quarterly subcutaneous + standard of care therapy, switched to open-label canakinumab 150 mg quarterly subcutaneous + standard of care therapy after 9 months.

  Intervention: Drug: Canakinumab
• Experimental: Canakinumab Dose 150 mg

  Pivotal Phase:

  Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care therapy.

  Extension Phase:

  Blinded canakinumab 150 mg quarterly subcutaneous + standard of care therapy, switched to open-label canakinumab 150 mg quarterly subcutaneous + standard of care therapy after 9 months.

  Intervention: Drug: Canakinumab
• Experimental: Canakinumab Dose 300 mg

  Pivotal Phase:

  Blinded Canakinumab 300 mg quarterly subcutaneous (with one additional dose at week 2) + standard of care therapy.

  Extension phase:

  Blinded canakinumab 300 mg quarterly subcutaneous + standard of care therapy, switched to open-label canakinumab 150 mg quarterly subcutaneous + standard of care therapy after 9 months.

  Intervention: Drug: Canakinumab
• Placebo Comparator: Placebo

  Pivotal Phase:

  Blinded matching placebo quarterly subcutaneous + standard of care therapy.

  Extension Phase:

  Blinded matching placebo quarterly subcutaneous + standard of care therapy, switched to open-label canakinumab 150 mg quarterly subcutaneous + standard of care therapy after 9 months.

  Intervention: Drug: Placebo

• Canada JM, Fronk DT, Cei LF, Carbone S, Erdle CO, Abouzaki NA, Melchior RD, Thomas CS, Christopher S, Turlington JS, Trankle CR, Thurber CJ, Evans RK, Dixon DL, Van Tassell BW, Arena R, Abbate A. Usefulness of C-Reactive Protein Plasma Levels to Predict Exercise Intolerance in Patients With Chronic Systolic Heart Failure. Am J Cardiol. 2016 Jan 1;117(1):116-20. doi: 10.1016/j.amjcard.2015.10.020. Epub 2015 Oct 19.
• Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011 Oct;162(4):597-605. doi: 10.1016/j.ahj.2011.06.012. Epub 2011 Sep 14.

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. Other protocol-defined inclusion/exclusion criteria may apply