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

Phase 3

Completed

• Conditions: Atherosclerosis
• Interventions: Drug: Placebo; Drug: Canakinumab; Drug: Standard of care

• Registration Number: NCT01327846
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2011-03-29
• Study First Submitted QC: 2011-03-31
• Study First Posted: 2011-04-04
• Study Start: 2011-04-11
• Primary Completion: 2017-03-28
• Disposition First Submitted: 2018-02-23
• Disposition First Submitted QC: 2018-02-23
• Disposition First Posted: 2018-02-26
• Study Completion: 2019-04-14
• Results First Submitted: 2019-11-25
• Status Verified: 2020-01
• Results First Submitted QC: 2020-01-10
• Last Update Submitted: 2020-01-10
• Results First Posted: 2020-01-22
• Last Update Posted: 2020-01-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10066

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Canakinumab Dose 50 mg	Standard of care	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
Canakinumab Dose 150 mg	Standard of care	Pivotal Phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy
Canakinumab Dose 300 mg	Standard of care	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
Placebo	Placebo	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
Placebo	Standard of care	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
Canakinumab Dose 150 mg	Canakinumab	Pivotal Phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy
Canakinumab Dose 50 mg	Canakinumab	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
Canakinumab Dose 300 mg	Canakinumab	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

Primary Outcome Measures

Name	Time	Method
Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components	From randomization, to end of treatment plus 30 days, up to approximately 6 years	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.
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

Name	Time	Method
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 Fasting Pro-Insulin Concentration/Insulin Concentration Ratio	From randomization up to approximately 6 years
Core Phase All-cause Mortality, Non-fatal MI, or Non-fatal Stroke	From randomization, to end of treatment plus 30 days, up to approximately 6 years	Occurrence of the composite endpoint consisting of all-cause mortality, non-fatal IM, or non-fatal stroke
Summary of Adverse Events (Extension Phase)	From start of Extension phase, to end of treatment plus 30 days, up to approximately 2 years	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.
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
Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization	From randomization, to end of treatment pus 30 days, up to approximately 6 years	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
Core Phase All-cause Mortality	From randomization, to end of treatment plus 30 days, up to approximately 6 years	Number of participant deaths
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
Summary of Adverse Events (Core Phase)	From randomization, to end of treatment plus 30 days, up to approximately 6 years	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.
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
Patients With Core Phase New Onset Type 2 Diabetes Among Patients With Pre-diabetes at Randomization	From randomization up to approximately 6 years	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)
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): 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 1 (Core Phase): Change From Baseline in Corresponding Total Vessel Wall Area in the Left and Right Carotid Arteries	24 months

Trial Locations

Locations (1)

Novartis Investigative Site; 🇬🇧 York, United Kingdom