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

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.

Timeline

Start

2011-04-11

Primary completion

2017-03-28

Completion

2019-04-14

Outcome

Met primary endpoint

paper The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point reads as unknown PMID 28845751 ↗

release “Phase III CANTOS study met the primary endpoint, a composite of heart attack, stroke and cardiovascular death” reads as met primary endpoint novartis.com ↗

release “ACZ885 (canakinumab) CANTOS phase III study met its primary endpoint with a statistically significant 15% reduction of MACE” reads as met primary endpoint novartis.com ↗

Publications

• Scheidegger C, Wandel S, Mutze T. Covariate Adjustment for the Win Odds: Application to Cardiovascular Outcomes Trials. Stat Med. 2026 May;45(10-12):e70602. doi: 10.1002/sim.70602.
• Woo J, Zhai T, Yang F, Xu H, Healey ML, Yates DP, Beste MT, Steensma DP. Effect of Clonal Hematopoiesis Mutations and Canakinumab Treatment on Incidence of Solid Tumors in the CANTOS Randomized Clinical Trial. Cancer Prev Res (Phila). 2024 Sep 4;17(9):429-436. doi: 10.1158/1940-6207.CAPR-23-0342.
• Woo J, Lu D, Lewandowski A, Xu H, Serrano P, Healey M, Yates DP, Beste MT, Libby P, Ridker PM, Steensma DP. Effects of IL-1beta inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial. Blood Adv. 2023 Dec 26;7(24):7471-7484. doi: 10.1182/bloodadvances.2023011578.
• Ridker PM, Tuttle KR, Perkovic V, Libby P, MacFadyen JG. Inflammation drives residual risk in chronic kidney disease: a CANTOS substudy. Eur Heart J. 2022 Dec 7;43(46):4832-4844. doi: 10.1093/eurheartj/ehac444.
• Svensson EC, Madar A, Campbell CD, He Y, Sultan M, Healey ML, Xu H, D'Aco K, Fernandez A, Wache-Mainier C, Libby P, Ridker PM, Beste MT, Basson CT. TET2-Driven Clonal Hematopoiesis and Response to Canakinumab: An Exploratory Analysis of the CANTOS Randomized Clinical Trial. JAMA Cardiol. 2022 May 1;7(5):521-528. doi: 10.1001/jamacardio.2022.0386.
• Everett BM, MacFadyen JG, Thuren T, Libby P, Glynn RJ, Ridker PM. Inhibition of Interleukin-1beta and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial. J Am Coll Cardiol. 2020 Oct 6;76(14):1660-1670. doi: 10.1016/j.jacc.2020.08.011.
• Schieker M, Conaghan PG, Mindeholm L, Praestgaard J, Solomon DH, Scotti C, Gram H, Thuren T, Roubenoff R, Ridker PM. Effects of Interleukin-1beta Inhibition on Incident Hip and Knee Replacement : Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial. Ann Intern Med. 2020 Oct 6;173(7):509-515. doi: 10.7326/M20-0527. Epub 2020 Aug 4.
• Vallurupalli M, MacFadyen JG, Glynn RJ, Thuren T, Libby P, Berliner N, Ridker PM. Effects of Interleukin-1beta Inhibition on Incident Anemia: Exploratory Analyses From a Randomized Trial. Ann Intern Med. 2020 Apr 21;172(8):523-532. doi: 10.7326/M19-2945. Epub 2020 Mar 24.
• Rothman AM, MacFadyen J, Thuren T, Webb A, Harrison DG, Guzik TJ, Libby P, Glynn RJ, Ridker PM. Effects of Interleukin-1beta Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk: A Secondary Analysis of CANTOS. Hypertension. 2020 Feb;75(2):477-482. doi: 10.1161/HYPERTENSIONAHA.119.13642. Epub 2019 Dec 30.
• Ridker PM, MacFadyen JG, Thuren T, Libby P. Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1beta inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis. Eur Heart J. 2020 Jun 14;41(23):2153-2163. doi: 10.1093/eurheartj/ehz542.
• Everett BM, Cornel JH, Lainscak M, Anker SD, Abbate A, Thuren T, Libby P, Glynn RJ, Ridker PM. Anti-Inflammatory Therapy With Canakinumab for the Prevention of Hospitalization for Heart Failure. Circulation. 2019 Mar 5;139(10):1289-1299. doi: 10.1161/CIRCULATIONAHA.118.038010.
• Solomon DH, Glynn RJ, MacFadyen JG, Libby P, Thuren T, Everett BM, Ridker PM. Relationship of Interleukin-1beta Blockade With Incident Gout and Serum Uric Acid Levels: Exploratory Analysis of a Randomized Controlled Trial. Ann Intern Med. 2018 Oct 16;169(8):535-542. doi: 10.7326/M18-1167. Epub 2018 Sep 18.
• Ridker PM, Libby P, MacFadyen JG, Thuren T, Ballantyne C, Fonseca F, Koenig W, Shimokawa H, Everett BM, Glynn RJ. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J. 2018 Oct 7;39(38):3499-3507. doi: 10.1093/eurheartj/ehy310.
• Ridker PM, MacFadyen JG, Glynn RJ, Koenig W, Libby P, Everett BM, Lefkowitz M, Thuren T, Cornel JH. Inhibition of Interleukin-1beta by Canakinumab and Cardiovascular Outcomes in Patients With Chronic Kidney Disease. J Am Coll Cardiol. 2018 May 29;71(21):2405-2414. doi: 10.1016/j.jacc.2018.03.490.
• Everett BM, Donath MY, Pradhan AD, Thuren T, Pais P, Nicolau JC, Glynn RJ, Libby P, Ridker PM. Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes. J Am Coll Cardiol. 2018 May 29;71(21):2392-2401. doi: 10.1016/j.jacc.2018.03.002. Epub 2018 Mar 12.
• 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-1beta 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-1beta 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.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Canakinumab	Monoclonal antibody	50 mg	—
Subject	Canakinumab	Monoclonal antibody	150 mg	—
Subject	Canakinumab	Monoclonal antibody	300 mg	—

Indications