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

Tracking Information
First Submitted Date ICMJE	March 29, 2011
First Posted Date ICMJE	April 4, 2011
Last Update Posted Date	March 20, 2018
Actual Study Start Date ICMJE	April 11, 2011
Actual Primary Completion Date	March 28, 2017 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: August 14, 2012)	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 ]
Original Primary Outcome Measures ICMJE; (submitted: March 31, 2011)	Time to first occurrence of a major adverse cardiovascular event, which is a composite endpoint consisting of cardiovascular death, non-fatal MI, and stroke. [ Time Frame: 36 months ]
Change History	Complete list of historical versions of study NCT01327846 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: August 14, 2012)	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 ]
Original Secondary Outcome Measures ICMJE; (submitted: March 31, 2011)	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 ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Cardiovascular Risk Reduction Study (Reduction in Recurrent Major CV Disease Events)
Official Title ICMJE	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
Brief Summary	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.
Detailed Description	There will be a seamless transition from the pivotal phase to the extension phase of the main study. LPLV of the pivotal phase will be in 02/2017.
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Atherosclerosis
Intervention ICMJE	Drug: Canakinumab Other Name: ACZ885; Drug: Placebo; Drug: Standard of care 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
Study Arms	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. Interventions: Drug: Canakinumab Drug: Standard of care; 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. Interventions: Drug: Canakinumab Drug: Standard of care; 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. Interventions: Drug: Canakinumab Drug: Standard of care; 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. Interventions: Drug: Canakinumab Drug: Placebo Drug: Standard of care
Publications *	Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ; CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018 Jan 27;391(10118):319-328. doi: 10.1016/S0140-6736(17)32814-3. Epub 2017 Nov 13.; Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ; CANTOS Trial Group. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Oct 21;390(10105):1833-1842. doi: 10.1016/S0140-6736(17)32247-X. Epub 2017 Aug 27.; Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017 Sep 21;377(12):1119-1131. doi: 10.1056/NEJMoa1707914. Epub 2017 Aug 27.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Actual Enrollment ICMJE; (submitted: March 19, 2018)	10061
Original Estimated Enrollment ICMJE; (submitted: March 31, 2011)	7302
Estimated Study Completion Date	March 2, 2020
Actual Primary Completion Date	March 28, 2017 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Czechia, Estonia, Germany, Greece, Guatemala, Hungary, Iceland, India, Italy, Japan, Korea, Republic of, Latvia, Lithuania, Mexico, Netherlands, Norway, Peru, Poland, Puerto Rico, Romania, Russian Federation, Serbia, Slovakia, Slovenia, South Africa, Sweden, Taiwan, Turkey, United Kingdom, United States
Removed Location Countries	Czech Republic, Ecuador, Former Serbia and Montenegro, Israel
Administrative Information
NCT Number ICMJE	NCT01327846
Other Study ID Numbers ICMJE	CACZ885M2301; 2010-022970-14 ( EudraCT Number )
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement	Not Provided
Responsible Party	Novartis ( Novartis Pharmaceuticals )
Study Sponsor ICMJE	Novartis Pharmaceuticals
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account	Novartis
Verification Date	March 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP