A clinical trial with ivabradine in patients with stable coronary artery disease

• Register: CTRI
• Last refreshed on: 24 November 2021
• Main ID: CTRI/2010/091/000132
• Date of registration: 09-03-2010
• Prospective Registration: Yes
• Primary sponsor: Institut de Recherches Internationales Servier IRIS
• Public title: A clinical trial with ivabradine in patients with stable coronary artery disease
• Scientific title: Effects of ivabradine in patients with stable coronary artery disease without clinical heart failure. A randomised double-blind placebo-controlled international multicentre study. Study assessInG the morbi-mortality beNefits of the If inhibitor ivabradine in patients with coronary arterY disease ( SIGNIFY)
• Date of first enrolment: 14-06-2010
• Target sample size: 16850
• Recruitment status: Completed
• URL: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=1347
• Study type: Interventional
• Study design: Randomized, Parallel Group, Placebo Controlled Trial; Method of generating randomization sequence:Other Method of allocation concealment:Centralized Blinding and masking:Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
• Phase: Phase 3

Countries of recruitment

Argentina, Armenia, Australia, Austria, Belarus, Belgium, Brazil, Bulgaria, Canada, China, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Georgia, Germany, Greece, Hungary, India, Ireland, Italy, Kazakhstan, Latvia, Lithuania, Malaysia, Mexico, Norway, Philippines, Poland, Portugal, Republic of Korea, Romania, Russian Federation, Serbia , Singapore, Slovakia, Slovenia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, The former Yugoslav Republic of Macedonia, Turkey, Ukraine, United Kingdom, Uruguay, Viet Nam

Contacts

• Name: Dr Ajaykumar Yadav
• Affiliation: Serdia Pharmaceuticals (India) Pvt Ltd

• Name: Dr Ajaykumar YADAV
• Affiliation: Serdia Pharmaceuticals (India) Pvt Ltd

Key inclusion & exclusion criteria

Inclusion criteria: The main inclusion criteria will be:

(1) History of coronary artery disease documented by either (a) a previous myocardial infarction ( > 3 months) or (b) a coronary revascularisation in 2 or more major coronary arteries ( > 3 months) or, in the absence of (a) and (b), (c) the imaging evidence of at least 50% narrowing in one or more major coronary arteries plus either a positive non invasive stress test, or a hospitalisation with a documented clinical diagnosis of unstable angina (within 12 months prior to selection), and

(2) Preserved left ventricular systolic function defined as left ventricular ejection fraction of 41% or higher on a two-dimensional echocardiography or a radionuclide ventriculography or computed tomography angiography or magnetic resonance imaging, and

(3) Sinus rhythm and resting heart rate equal to or higher than 70 bpm on 2 consecutive resting standard 12-lead ECGs performed at least 5 minutes apart, at selection and inclusion visits (if one of the 2 HR measurements is 68 or 69 bpm at the inclusion visit, it will be allowed to include the patient, provided that the mean of both HR measurements at the visit is > 70 bpm), and

(4) Informed consent obtained, and

(5) Presence of the following additional cardiovascular risk factors:

(Note: the risk factor(s) that were used to select the patient must be present also at the inclusion visit)

- At least one of the following:

­ Symptomatic patients in CCS class II or higher at selection and inclusion visits,

­ Objective evidence of myocardial ischemia induced by stress testing (within 12 months prior to selection in patients who did not undergo subsequent coronary revascularisation), either:

 A positive exercise tolerance test with an horizontal or down-sloping ST segment depression of at least 2 mm (0.2 mV) for more than 0.08 sec after the J point on at least 3 consecutive complexes, in patients without abnormal ST segment at rest and without any condition that may interfere with the results,

 Or inducible myocardial ischemia with reversible abnormalities involving at least 2 segments in any imaging technique,

­ Discharged from hospital with a documented diagnosis of major coronary event (acute myocardial infarction or unstable angina) within 12 months prior to selection.

- Or at least two of the following:

­ Documented low HDL cholesterol ( < 1 mmol/L or 40 mg/dL) and / or documented high LDL cholesterol ( > 4 mmol/L or 160 mg/dL despite lipid lowering treatment),

­ Presence of type 1 or 2 diabetes mellitus treated with an oral hypoglycaemic drug or insulin,

­ Presence of peripheral artery disease (symptomatic or not) documented by either: previous limb angioplasty, stenting or bypass surgery; or intermittent claudication; or ankle brachial index < 0.9 in at least one limb; or angiographic evidence of significant ( > 50%) peripheral artery stenosis in at least one limb; or evidence from a non-invasive measurement of significant ( > 50% or reported as hemodynamically significant) peripheral artery stenosis in at least one limb,

­ Current smoker (10 cigarettes or more per day on average),

­ Age > 70 years.


Exclusion criteria: The main non-inclusion criteria will be:

(1) Unstable cardiovascular condition,

(2) Clinical signs and / or symptoms of heart failure in NYHA class II or higher, or hospitalisation for heart failure as a primary diagnosis within the last 12 months,

(3) Contra-indications to the administration of ivabradine or current treatment with marketed ivabradine.



Age minimum:
Age maximum:
Gender:

Health Condition(s) or Problem(s) studied

Health Condition 1: null- Stable coronary artery disease without clinical heart failure

Intervention(s)

Intervention1: Ivabradine plus treatment as usual: 5/7.5/10 mg B.I.D. Following a run-in period of 14 to 30 days during which placebo will be dispensed to patients in a single-blind way; the active double-blind period (ivabradine versus placebo) will last from 18 months to 48 months (expected duration of treatment, could be extended up to 5 years)
Intervention2: appropriate cardiovascular treatment for coronary artery disease: As prescribed by investigator
Control Intervention1: Placebo: 1 tab B.I.D. Following a run-in period of 14 to 30 days during which placebo will be dispensed to patients in a single-blind way; the active double-blind period (ivabradine versus placebo) will last from 18 months to 48 months (expected duration of treatment, could be extended up to 5 years)
Control Intervention2: appropriate cardiovascular treatment for coronary artery disease: as prescribed by investigator

Primary Outcome(s)

The purpose of this study is to demonstrate that ivabradine reduces cardiovascular events in patients with stable coronary artery disease without clinical heart failure.

The primary objective is to demonstrate the superiority of ivabradine over placebo in the reduction of cardiovascular mortality or non-fatal myocardial infarction (composite endpoint).

Timepoint: Planned duration of the study for a patient: 18 to 48 months with the possibility to prolong up to 5 years.

- Expected study completion date: September 2013.

Secondary Outcome(s)

Secondary objectives:1 non-composite endpoints:Time to occurrence of the first event among cardiovascular (CV) death or non-fatal myocardial infarction (MI),coronary revascularisation (elective or otherwise),new onset or worsening heart failure

Composite endpoints:Fatal or non-fatal MI,Fatal or non-fatal MI,coronary revascularisation,

Fatal or non-fatal MI,coronary revascularisation,unstable angina,CV death,non-fatal MI,non-fatal stroke,Non-fatal MI,coronary revascularisation,unstable anginaTimepoint: 18 to 48 months

Secondary ID(s)

EudraCT number 2009-011360-10

NIL

CL3-16257-083

Source(s) of Monetary Support

Institut de recherches internationales Servier I.R.I.S. 6, place de Pleiades, 92415 Courbevoie, Cedex, Paris, France

Secondary Sponsor(s)

Serdia Pharmaceuticals India Pvt Ltd

Ethics review

Status: Approved
Approval date: 05/11/2009
Contact:

The Independent Ethics Committee, Escorts Heart Institute

Status: Approved
Approval date: 27/11/2009
Contact:

Life Care Instiitute of Medical Science and Research, Hospital Ethics Committee

Status: Approved
Approval date: 04/12/2009
Contact:

Spandan Heart Institute and Research Centre Ethical Committee

Status: Approved
Approval date: 12/12/2009
Contact:

Ethics Committee, Holy Family Hospital

Status: Approved
Approval date: 20/12/2009
Contact:

Ethics Committee, Ruby Hall Clinic

Status: Approved
Approval date: 19/01/2010
Contact:

PSG Institute of Medical Sciences & Research, Institutional Human Ethics Committee

Status: Approved
Approval date: 17/02/2010
Contact:

Artemis Health Sciences Institutional Review Board

Status: Approved
Approval date: 20/02/2010
Contact:

Sujlam Independent Ethics Commitee

Status: Approved
Approval date: 13/03/2010
Contact:

Medanta Institutional Review Board

Status: Approved
Approval date: 17/09/2010
Contact:

Insitutional Review Board, Max Healthcare

Status: Approved
Approval date: 11/12/2010
Contact:

B.M. Birla Heart Research Centre Ethics Committee

Status: Approved
Approval date: 09/03/2011
Contact:

Institutional Ethics Committee, Frontier Lifeline Pvt. Ltd.

Status: Approved
Approval date: 24/03/2011
Contact:

Institutional Ethics Committee, KEMHRC, Pune