A Study of Ivabradine in African-American/ Black Subjects With Heart Failure and Left Ventricular Systolic Dysfunction.

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03456856
• Collaborator: (none)
• Enrollment: 30
• Locations: 3
• Arm: 1
• Actual Duration (Months): 19.7
• Patients Per Site: 10
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study is a prospective, open-label, single-arm intervention study in African-American/Black subjects with heart failure and reduced ejection fraction (HFrEF).

There will be a 7-day screening period, a 57-day open-label treatment period, and a safety follow-up at day 87 or 30 days after the last administration of the investigational product.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure (HF)	Drug: Ivabradine	Phase 4

Detailed Description

The goal of this study is to determine the impact of adding ivabradine therapy to the standard of care (SOC) in African-American/Black subjects with Heart Failure (HF) and reduced ejection fraction (HFrEF) on changes in heart rate (HR) from baseline (SOC alone). Changes in HR from baseline will be correlated with the changes from baseline in activity level of the subjects, as measured by both a standard 6-minute walk distance and an accelerometer device.

The primary hypothesis is that ivabradine effectively reduces HR between baseline and day 57 in African-American/Black subjects. Because mean reductions of approximately 5 beat per minute (bpm) have been observed in the overall placebo-treated subjects in the SHIFT study as well as in the placebo-treated subjects of the subgroup analysis of non-African-American/Black subjects enrolled in the SHIFT study, we will test whether the mean reduction with ivabradine exceeds 5 bpm, and estimate the degree to which the mean reduction with ivabradine exceeds 5 bpm.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Single-arm, Study Assessing the Efficacy and Safety of Ivabradine (Corlanor) in African-American/Black Subjects With Heart Failure and Left Ventricular Systolic Dysfunction
• Actual Study Start Date: Sep 28, 2017
• Actual Primary Completion Date: Apr 19, 2019
• Actual Study Completion Date: May 20, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Ivabradine The starting dose of ivabradine was 5 mg twice daily (BID), although investigators had the discretion to start participants at 2.5 mg BID if participant had a history of conduction defects, or bradycardia that could lead to hemodynamic compromise. Dose was adjusted at Day 15 (and at any other clinical visit) between 2.5 - 7.5 mg BID based on heart rate and signs/symptoms of bradycardia.

Drug: Ivabradine; Film-coated tablets taken orally with food twice a day. Tablets supplied in strengths of 5.0 mg and 7.5 mg. 5.0 tablets were split into equal halves for dosages of 2.5 mg.; Other Names: Corlanor®

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Heart Rate (HR) at Day 57 [Day1 (baseline), Day 57]

   Summary is based on observed data, and no imputation is used for missing values. Least-square mean is from the repeated measures model which includes scheduled visits and baseline HR measurement as covariates. The mean change from baseline in heart rate is compared to -5 beats/min which is observed in the placebo group in the Systolic Heart Failure Treatment with the IF Inhibitor Ivabradine Trial (SHIFT) study ( NCT02441218, PMID 20801500).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject has provided informed consent/assent prior to initiation of any study specific activities/ procedures

• Male or female subject ≥ 18 years of age, describing self as African American/Black

• Must have a diagnosis of heart failure (HF) confirmed by medical records, be in stable condition, and treated with stable optimal pharmacological therapy as per their personal physician's care.

• Left ventricular ejection fraction (LVEF) ≤ 35% confirmed by investigator

• New York Heart Association (NYHA) class II to IV assessed at the time of screening

• Electrocardiogram (ECG) documentation at the time of screening of sinus rhythm with resting heart rate (HR) ≥ 70 bpm by local ECG reading

• Must be able to complete a 6-minute walk test (6MWT) and wear an accelerometer

Exclusion Criteria:

• Recent myocardial infarction (≤ 2 months) or stroke (≤ 1 month) prior to enrollment

• If the subject received within 3 months before or is scheduled to receive within 42 days after enrollment any of the following: revascularization, ventricular assist device, continuous or intermittent inotropic therapy, hospice care, major organ transplant, or is receiving renal replacement therapy by dialysis

• If the subject received implantation of a cardioverter defibrillator or cardiac resynchronization therapy within 42 days before or is scheduled to receive implantation of a cardioverter defibrillator or cardiac resynchronization therapy within 42 days after enrollment

• Severe primary valve disease or scheduled for surgery for valvular heart disease

• Pacemaker with atrial or ventricular pacing (except bi-ventricular pacing) >40% of the time, or with a stimulation threshold at the atrial or ventricular level ≥ 60 bpm

• Permanent atrial fibrillation or flutter

• Sick sinus syndrome, sinoatrial block, or second and third degree atrio-ventricular block

• History of symptomatic or sustained (≥ 30 sec) ventricular arrhythmia unless a cardioverter defibrillator was implanted

• History of congenital QT syndrome

• Any cardioverter defibrillator shock experienced within 1 month of enrollment

• Hypertrophic obstructive cardiomyopathy, active myocarditis or constrictive pericarditis, or clinically significant congenital heart disease

• Chronic antiarrhythmic therapy (except digitalis)

• Scheduled outpatient intravenous (IV) infusions for HF (eg, inotropes,vasodilators [eg, nesiritide], diuretics) or routinely scheduled ultrafiltration

• Evidence of digitalis intoxication within 7 days prior to screening

• Systolic blood pressure > 180 mm Hg or < 90 mm Hg, or diastolic blood pressure > 110 mm Hg or < 50 mm Hg at any time during the screening phase

• Known untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, active vasculitis due to collagen vascular disease

• Have known acute or serious co-morbid condition (e.g, major infection or hematologic, renal, hepatic, metabolic, gastrointestinal or endocrine dysfunction) that may interfere with the study, or severe concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 1 year or malignancy within 5 years prior to enrollment with the following exceptions: localized basal or squamous cell carcinoma of the skin or cervical intraepithelial neoplasia

• Subjects taking QT prolonging medicinal products for cardiovascular (e.g, but not limited to, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone) or non-cardiovascular disease (e.g, but not limited to, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, IV erythromycin).

• Subjects exposed to a strong CYP3A4 inhibitor (examples of strong CYP3A4 inhibitors include; azole antifungals [eg, itraconazole], macrolide antibiotics [e.g, clarithromycin, telithromycin], human immunodeficiency virus (HIV) protease inhibitors, [eg, nelfinavir], and nefazodone]) within 14 days prior to enrollment, or to a strong CYP3A4 inducer (examples of CYP3A4 inducers include; St. John's wort, rifampicin, barbiturates, and phenytoin) within 28 days prior to enrollment

• Subjects who received diltiazem or verapamil within 48 hours prior to enrollment.

• Previously received ivabradine prior to participation in this study

• Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.

• Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 14 days after the last dose of investigational product. Females of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive urine pregnancy test.

• Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 14 days after the last dose of investigational product.

• Subject has known sensitivity to any of the products or components to be administered during dosing.

• Subject likely not to be available to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge.

• History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Wilmington	Delaware	United States	19803
2	Research Site	Detroit	Michigan	United States	48202
3	Research Site	Buffalo	New York	United States	14215

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Feb 14, 2019
• Statistical Analysis Plan - Apr 19, 2019

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Lanfear DE, Neaton KR, Lu C, Liu Y, Dent-Acosta RE. A Phase 4, Open-Label, Single-Arm Study Assessing the Efficacy and Safety of Ivabradine in African American Patients with Heart Failure and Reduced Ejection Fraction. Cardiol Ther. 2020 Dec;9(2):561-568. doi: 10.1007/s40119-020-00196-1. Epub 2020 Aug 17.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03456856
• Other Study ID Numbers: 20160231
• First Posted: Mar 7, 2018
• Last Update Posted: Oct 28, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Amgen: Cardiac; Congestive; Decompensation; Heart Failure; Left-Sided; Myocardial; Corlanor; Ivabradine; African American; Black; Michigan
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Recruitment Details	A total of 30 participants were enrolled at 2 centers in the United States.

Arm/Group Title	Ivabradine
Arm/Group Description	The starting dose of ivabradine was 5 mg twice daily (BID), although investigators had the discretion to start participants at 2.5 mg BID if participant had a history of conduction defects, or bradycardia that could lead to hemodynamic compromise. Dose was adjusted at Day 15 (and at any other clinical visit) between 2.5 - 7.5 mg BID based on heart rate and signs/symptoms of bradycardia.
Period Title: Overall Study
STARTED	30
COMPLETED	27
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Ivabradine
Arm/Group Description	The starting dose of ivabradine was 5 mg twice daily (BID), although investigators had the discretion to start participants at 2.5 mg BID if participant had a history of conduction defects, or bradycardia that could lead to hemodynamic compromise. Dose was adjusted at Day 15 (and at any other clinical visit) between 2.5 - 7.5 mg BID based on heart rate and signs/symptoms of bradycardia.
Overall Participants	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.7 (12.6)
Age, Customized (Count of Participants)
18-64 years	24 80%
65-74 years	5 16.7%
75-84 years	0 0%
>=85 years	1 3.3%
Unknown	0 0%
Sex: Female, Male (Count of Participants)
Female	9 30%
Male	21 70%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	30 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	30 100%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
New York Heart Association (NYHA) Class (Count of Participants)
NYHA Class I	0 0%
NYHA Class II	22 73.3%
NYHA Class III	8 26.7%
NYHA Class IV	0 0%
Primary Cause of Heart Failure (Count of Participants)
Ischemic heart disease	5 16.7%
Non-ischemic heart disease	25 83.3%
Left Ventricular Ejection Fraction (percentage total blood in left ventricle) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage total blood in left ventricle]	25.6 (6.8)
Baseline Heart Rate (beats per minute) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [beats per minute]	83.6 (8.9)
Baseline Systolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	126.8 (17.1)
Baseline Diastolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	73.0 (5.7)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Heart Rate (HR) at Day 57
Description	Summary is based on observed data, and no imputation is used for missing values. Least-square mean is from the repeated measures model which includes scheduled visits and baseline HR measurement as covariates. The mean change from baseline in heart rate is compared to -5 beats/min which is observed in the placebo group in the Systolic Heart Failure Treatment with the IF Inhibitor Ivabradine Trial (SHIFT) study ( NCT02441218, PMID 20801500).
Time Frame	Day1 (baseline), Day 57

Outcome Measure Data

Analysis Population Description

Full analysis set which included all enrolled participants.

Arm/Group Title	Ivabradine
Arm/Group Description	The starting dose of ivabradine was 5 mg twice daily (BID), although investigators had the discretion to start participants at 2.5 mg BID if participant had a history of conduction defects, or bradycardia that could lead to hemodynamic compromise. Dose was adjusted at Day 15 (and at any other clinical visit) between 2.5 - 7.5 mg BID based on heart rate and signs/symptoms of bradycardia.
Measure Participants	30
Least Squares Mean (Standard Error) [beats per minute]	-9.5 (1.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine
	Comments	The estimated mean treatment difference (95% CI) takes into account a presumed -5 bpm change from baseline heart rate in the absence of ivabradine (as seen in the placebo group in the SHIFT study, (NCT02441218, PMID 20801500).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	repeated measures linear model
	Comments
Method of Estimation	Estimation Parameter	least square mean difference
	Estimated Value	-4.5
	Confidence Interval	(2-Sided) 95%; -8.0 to -1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.7
	Estimation Comments

Adverse Events

Time Frame	Day 1 up to Day 87 (30 days after the last dose of IP)
Adverse Event Reporting Description	All-cause mortality is reported for all participants enrolled/randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
Arm/Group Title	Ivabradine
Arm/Group Description	The starting dose of ivabradine was 5 mg twice daily (BID), although investigators had the discretion to start participants at 2.5 mg BID if participant had a history of conduction defects, or bradycardia that could lead to hemodynamic compromise. Dose was adjusted at Day 15 (and at any other clinical visit) between 2.5 - 7.5 mg BID based on heart rate and signs/symptoms of bradycardia.
All Cause Mortality
	Ivabradine
	Affected / at Risk (%)	# Events
Total	0/30 (0%)
Serious Adverse Events
	Ivabradine
	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)
Metabolism and nutrition disorders
Dehydration	1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	Ivabradine
	Affected / at Risk (%)	# Events
Total	7/30 (23.3%)
Nervous system disorders
Dizziness	4/30 (13.3%)
Headache	2/30 (6.7%)
Respiratory, thoracic and mediastinal disorders
Cough	2/30 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.