Research on Nicorandil Treatment of Patients Diagnosed as CHD (Coronary Heart Disease) With Stable Angina (SIGMART)

A Prospective, Multi-center, Random, Open-label Research on Nicorandil Treatment of Patients Diagnosed as CHD (Coronary Heart Disease) With Stable Angina

This study of 402 cases of stable angina subjects who were diagnosed as Coronary Heart Disease (CHD) is a randomized, blank controlled, multi-center clinical study. Subjects who are taking standard treatment with stable symptoms will receive a 24-hour ambulatory electrocardiogram (ECG) (Holter) examination. They will be randomly divided into two groups. The nicorandil group will receive nicorandil 5 milligram (mg) (3 times a day = tid) on top of the standard treatment for 12 weeks, while the control group will stay on standard treatment. Nitrates and beta blockers need to be maintained on a stable dose. Other drugs that do not affect the primary endpoint may be adjusted per investigators decision.

Study Overview

• Status: Completed
• Conditions: Coronary Disease; Stable Angina
• Intervention / Treatment: Drug: Nicorandil; Drug: Standard Treatment

• Study Type: Interventional
• Enrollment (Actual): 402
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • For Locations in

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject must be diagnosed as stable CHD, and must have at least one of these histories:

  1. A history of coronary revascularization Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass Surgery at least 3 months ago
  2. Myocardial infarction
  3. More than 50 percent (%) stenosis detected by angiography
  4. Exercise Tolerance Testing (ETT) or Computed Tomography Angiography (CTA) showed more than 50% stenosis with typical angina symptoms
• Subjects must have at least 2 times of typical symptoms of myocardial ischemia occurred within a week Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Coronary syndrome or considering acute coronary syndrome (ACS)
• Left main coronary artery disease without revascularization
• Aortic stenosis
• Obstructive hypertrophic cardiomyopathy
• Subjects with hypertension systolic blood pressure (SBP) greater than (>) 170 millimeters of mercury (mmHg) or diastolic blood pressure (DBP) >100 mmHg) or hypotension (SBP less than [<] 90 mmHg or DBP<60 mmHg)
• Diagnosis as postural hypotension before
• Congestive heart failure (New York Heart Association [NYHA] class III - IV
• Ejection fraction (EF)<40% by Echocardiography
• Arrhythmias requiring active treatment
• Gastro-intestinal ulcer
• Concomitant medication such as Sulphonyl urea, PDE-5 inhibitor such as sildenafil, Trimetazidine for treatment of angina pectoris Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard treatment plus nicorandil; The subjects will receive nicorandil 5 milligram (mg ) tablet orally three times daily for a period of 12 weeks along with one of the standard antianginal therapies (such as aspirin, beta-blockers, lipid lowering statins and angiotensin-converting enzyme inhibitors [(ACEIs] as permitted by disease condition /as per standard local practices/prescribed per discretion of investigators).	Drug: Nicorandil; The subjects will receive Nicorandil 5 mg tablet orally three times daily for a period of 12 weeks along with the standard treatment.; Drug: Standard Treatment; The subjects will receive one of the standard anti-anginal therapies which included but not limited to aspirin, ACEI, lipid lowering statins and beta blockers according to the recommendation of guidelines. If the subject's condition permitted, they should take all these medicines. However, the dose, route, frequency and duration were determined by investigators according to subject's specific condition.
Other: Standard treatment	Drug: Standard Treatment; The subjects will receive one of the standard anti-anginal therapies which included but not limited to aspirin, ACEI, lipid lowering statins and beta blockers according to the recommendation of guidelines. If the subject's condition permitted, they should take all these medicines. However, the dose, route, frequency and duration were determined by investigators according to subject's specific condition.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Myocardial Ischemia Attacks in 24 Hours	Myocardial ischemia attack was evaluated by 24-hour Holter monitoring based on the following criteria: 0.08 seconds after the J point in electrocardiogram (ECG) or compared with baseline levels, ST-segment with horizontal or downward sloping down greater than or equal to (>=) 0.1 millivolts (mV), and lasted for >= 1 minute, and at least 1 minute of interval with another ischemic attack, as one array myocardial ischemia.	At Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Myocardial Ischemic Burden at Week 12	The total myocardial ischemic burden was defined as the product of the decrease, total array and total time of ST-segment in symptomatic and asymptomatic myocardial ischemia subjects within 24 hours.	Baseline, Week 12
Change From Baseline in Maximum ST-depression at Week 12	The maximum ST- depression was evaluated from sum of all leads for all the subjects with myocardial ischemia attack. Absolute value of maximum ST-depression was used for calculation.	Baseline, Week 12
Change From Baseline in Longest Duration of ST Segment Depression at Week 12	The maximum ST- depression was evaluated from sum of all leads for all the subjects with myocardial ischemia attack. The longest duration of ST segment depression of all leads for all the subjects with myocardial ischemia attack.	Baseline, Week 12
Percentage of Subjects Experienced Ischemic Heart Attack During the Six-minute Walk Test	The percentage of subjects who experienced ischemic heart attack during the Six-minute walk test (6-MWT) were evaluated.The 6-MWT was the distance that a subject could walk in 6 minutes. Subjects were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. The 6-MWT was completed within 1-hour after wearing Holter.	At Week 12
Heart Rate Variability (HRV) Rate: Time Domain	HRV is the degree of fluctuation in the length of the intervals between heart beats. All HRV parameters are calculated on 'normal-to-normal' (NN) inter-beat intervals (or NN intervals) caused by normal heart contractions. Standard deviation of all NN intervals (SDNN) and Standard deviation of the averages of NN intervals (SDANN) are the two time domain methods used to determine heart rate variability. Two variants of the SDNN, created by dividing the 24-hour monitoring period into 5-minute segments, are the SDNN index and the SDANN index. The SDNN index is the mean of all the 5-minute standard deviations of NN (normal RR) intervals during the 24-hour period, while the SDANN index is the standard deviation of all the 5-minute NN interval means.	At Week 12
Heart Rate Variability (HRV) Rate: Frequency Domain Power-24 Hour	HRV is the degree of fluctuation in the length of the intervals between heart beats. All HRV parameters are calculated on 'normal-to-normal' (NN) inter-beat intervals (or NN intervals) caused by normal heart contractions. The HRV was evaluated based on frequency domain power-24 hours.	At Week 12
Number of Arrhythmia Occurred Within 24 Hours	The number of ventricular tachycardia and premature ventricular beats that occurred within 24 hours.	At Week 12
ECG QT Dispersion	The ECG QT dispersion was defined as the difference between the longest (QTmax) and the shortest (QTmin) QT intervals within a 12-lead ECG.	At Week 12
Number of Subjects Experienced Angina Attack		Baseline up to 12 Weeks
Frequency of Angina Attack	The total number of times angina attacks occurred within a week (number of times/week)	At Week 12
Number of Subjects Relieved From Angina Attack After the Consumption of Nitroglycerin		At Week 12
Number of Nitroglycerin Tablets Consumed in a Week		At Week 12
Walk Distance in Six Minute Walk (6-MWT) Test at Week 12	The 6-MWT distance was the distance that a subject could walk in 6 minutes. Subjects were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. The 6-MWT was completed within 1-hour after wearing Holter.	At Week 12
Number of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Death, and AEs Leading to Discontinuation	An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as the AEs that occurred between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.	From the first dose of study drug administration up to 30 days after the last dose of study drug administration (up to 16 weeks )
Number of Subjects Who Showed Compliance to Nicorandil	Compliance percent (%) was calculated by using the formula: (actual total dose divided by planned total dose) multiplied by 100. If subject compliance was less than 80% or greater than 120%, then that subject was considered as non compliant. The compliance of subjects taking nicorandil was evaluated.	Baseline up to 12 Weeks

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Merck Serono Co., Ltd., China

Publications and helpful links

General Publications

• Jiang J, Li Y, Zhou Y, Li X, Li H, Tang B, Dai X, Ma T, Li L, Huo Y. Oral nicorandil reduces ischemic attacks in patients with stable angina: A prospective, multicenter, open-label, randomized, controlled study. Int J Cardiol. 2016 Dec 1;224:183-187. doi: 10.1016/j.ijcard.2016.08.305. Epub 2016 Aug 21.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: July 15, 2011
• First Submitted That Met QC Criteria: July 15, 2011
• First Posted (Estimate): July 18, 2011

Study Record Updates

• Last Update Posted (Estimate): April 14, 2016
• Last Update Submitted That Met QC Criteria: March 15, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Stable angina; Nicorandil
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Chest Pain; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Angina Pectoris; Angina, Stable; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Micronutrients; Vitamins; Vitamin B Complex; Nicorandil
• Other Study ID Numbers: EMR200101-501