Effects of Ivabradine in Patients With Stable Coronary Artery Disease Without Clinical Heart Failure (SIGNIFY)

Effects of Ivabradine in Patients With Stable Coronary Artery Disease Without Clinical Heart Failure. A Randomised Double-blind Placebo-controlled International Multicenter Study. Study Assessing the Morbi-mortality Benefits of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease

The purpose of this study is to evaluate the effect of ivabradine on cardiovascular events in patients with coronary artery disease.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Ivabradine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 19102
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Ferrara, Italy, 44100
    • Azienda Ospedaliera Universitaria Di Ferrara
• United Kingdom
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Evidence of coronary artery disease
• Sinus rhythm and resting heart rate equal or higher than 70 bpm

Exclusion Criteria:

• Unstable cardiovascular condition
• Known hypersensitivity to ivabradine or current treatment with marketed ivabradine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Matching placebo tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.
Experimental: Ivabradine	Drug: Ivabradine; 5 mg, 7.5 mg or 10 mg tablets to be taken orally twice daily, at 12-hours intervals, in the morning and in the evening during meals up to 48 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Composite Endpoint	First event among cardiovascular death or non-fatal myocardial infarction	The events are expressed as the time to occurrence of the first event, defined as the duration between the date of randomisation and the date of first occurrence of event, assessed up to 48 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality		From the date of randomisation to death, up to 48 months
Cardiovascular Mortality	Component of the primary composite endpoint	From the date of randomisation to death, up to 48 months
Coronary Mortality	Coronary mortality including sudden death of unknown cause, death from myocardial infarction, death from heart failure, death from coronary artery procedure, presumed arrhythmic death	From the date of randomisation to death, up to 48 months
Fatal Myocardial Infarction	Non-composite secondary endpoint	From the date of randomisation to death, up to 48 months
Non-fatal Myocardial Infarction	Component of the primary composite endpoint	From the date of randomisation to the date of first occurrence of the event, up to 48 months
Elective Coronary Revascularisation	Non-composite secondary endpoint	From the date of randomisation to the date of first occurrence of the event, up to 48 months
Coronary Revascularisation (Elective or Not)	Non-composite secondary endpoint	From the date of randomisation to the date of first occurrence of the event, up to 48 months
Secondary Composite Endpoint	Fatal or non-fatal myocardial infarction	From the date of randomisation to the date of first occurrence of the event, up to 48 months
Secondary Composite Endpoint	Fatal or non-fatal myocardial infarction, coronary revascularisation	From the date of randomisation to the date of first occurrence of the event, up to 48 months
Secondary Composite Endpoint	Fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina	From the date of randomisation to the date of first occurrence of the event, up to 48 months
Secondary Composite Endpoint	Cardiovascular death, non-fatal myocardial infarction, non-fatal stroke	From the date of randomisation to the date of first occurrence of the event, up to 48 months
Secondary Composite Endpoint	Coronary death, non-fatal myocardial infarction	From the date of randomisation to the date of first occurrence of the event, up to 48 months
Secondary Composite Endpoint	Non-fatal myocardial infarction, coronary revascularisation, unstable angina	From the date of randomisation to the date of first occurrence of the event, up to 48 months

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier

Publications and helpful links

General Publications

• Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014 Sep 18;371(12):1091-9. doi: 10.1056/NEJMoa1406430. Epub 2014 Aug 31.
• Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY trial): a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart failure. Am Heart J. 2013 Oct;166(4):654-661.e6. doi: 10.1016/j.ahj.2013.06.024. Epub 2013 Sep 17.

Helpful Links

• Results summary

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: May 5, 2015
• First Submitted That Met QC Criteria: May 13, 2015
• First Posted (Estimated): May 18, 2015

Study Record Updates

• Last Update Posted (Actual): July 26, 2024
• Last Update Submitted That Met QC Criteria: July 24, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Heart Failure; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
• Other Study ID Numbers: CL3-16257-083; 2009-011360-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Researchers can ask for a study protocol, patient-level and/or study-level clinical trial data including clinical study reports (CSRs).

They can ask all interventional clinical studies:

• submitted for new medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• Where Servier or an affiliate are the Marketing Authorization Holders (MAH). The date of the first Marketing Authorization of the new medicine (or the new indication) in one of the EEA Member States will be considered within this scope.

• IPD Sharing Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• IPD Sharing Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR