Genomic Response Analysis of Heart Failure Therapy in African Americans

NCT02305095 | Completed DMC

• 2 other identifiers: 3648634MD009118-01
• Study Type: observational
• Target: 225
• Locations: 1 country
• Sites: 19

Brief Summary

The response to therapy with a fixed dose combination of isosorbide dinitrate and hydralazine (FDC I/H) is enhanced in African Americans with heart failure and reduced ejection fraction (HFrEF) when compared to similar white cohorts. This study will seek to confirm the previous genetic sub-study from AHeFT which suggested a functional polymorphism of guanine nucleotide binding protein beta polypeptide 3 subunit (GNB3), C825T in exon 10, influences the therapeutic efficacy of FDC I/H. This study will initiate treatment with FDC I/H in 500 self designated African American subjects with systolic heart failure. They will be followed for up to two years on therapy. Clinical outcomes (survival, heart failure hospitalizations, and change in quality of life) on FDC I/H will be compared by GNB3 genotype subset. The hypothesis to be confirmed is that subjects homozygous for the T allele (those with the GNB3 TT genotype which is present in approximately 50% of black subjects) demonstrate enhanced therapeutic benefit from FDC I/H.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (1)

• Composite score (CS) no units. (survival, heart failure hospitalization, and change in the raw quality of life score on the Minnesota Living with Heart Failure Questionnaire)

  The CS combines three outcome variables into a single "score". Composite score adds points for survival over 2 years of follow up (death at any time yields -3 points, survival to end of study results in 0), heart failure hospitalization over 2 years of follow up (yes at any time results in -1 point, no results in 0), and the change in the raw quality of life score on the Minnesota Living with Heart Failure Questionnaire from entry to 6 months (change of ten units or greater=increase +2, decrease-2; change 5 to 9= increase+1, decrease -1; change \< 5 units for the raw score yields 0 points). The CS will range from -6 to +2 for each patient.

  2 years

Secondary Outcomes (3)

• Survival

  2 years

• Survival free from heart failure hospitalization

  2 years

• Change in Quality of Life Assessment by Minnesota Living with Heart Failure Questionnaire

  6 months

Study Arms (2)

GNB3 TT

All subjects with the GNB3 TT genotype for the polymorphism at position 825 (T/C). They will be initiated on therapy with FDC I/H, followed for 2 years and response to therapy quantified by a composite score (CS).

Drug: FDC I/H

GNB3 C

All subjects with at least one copy of the GNB3 C allele which includes both subjects homozygous for the 825C allele (GNB3 CC genotype) and subjects who are heterozygous (GNB3 TC genotype).They will be initiated on therapy with FDC I/H, followed for 2 years and response to therapy quantified by a composite score (CS).

Drug: FDC I/H

Interventions

FDC I/H DRUG

All subjects in both groups will be initiated on drug, FDC I/H with dose titrated up to target doses based on clinical guidelines

Also known as: BiDil

GNB3 C; GNB3 TT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Adult subjects with systolic heart failure who are self designation as African Americans are potentially eligible for the study.

You may qualify if:

• years and older
• History of heart failure with an LVEF (less than OR equal to) \< 0.35 for at least 6 months OR an LVEF \< 0.45 with left ventricular internal end diastole (defined by a diameter of more than 2.9 cm per square meter of body surface area OR more than 6.5 cm on the basis of echocardiography). \*\* Echo must be done within 6 months of enrollment\*\*
• New York Heart Association (NYHA) Class II-IV
• Background heart failure therapy that includes angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), and beta blockers (BBs) for at least 3 months (or documentation of intolerance to ACEi/ARBs and BBs)
• Self-designated race as African American or black (would include subjects whose country of origin was outside the USA such as Africa, the Caribbean, or Central America).

You may not qualify if:

• History of intolerance to either nitrates or hydralazine
• Treatment with the combination of hydralazine and nitrates for the previous 3 months
• Revascularization or myocardial infarction within last 90 days
• Received cardiac resynchronization therapy (CRT) AND did not have an assessment of cardiac function documenting an LVEF \< 35% (less than OR equal to 35%) at least 90 days post CRT
• Presence of clinically significant valvular heart disease, hypertrophic or restrictive cardiomyopathy, active myocarditis, or uncontrolled hypertension. (Note that uncontrolled hypertension is defined as blood pressure consistently greater than 160 mmHg systolic and 95 mmHg diastolic)
• Women who are currently pregnant, planning on becoming pregnant in the next two years, or those who do not agree to prevent pregnancy.
• Subjects who are on continuous home inotropes, a left ventricular assist device, or who are post cardiac transplant.

Sponsors & Collaborators

• University of Pittsburgh: lead

Study Sites (19)

University of Alabama Medical Center

Tuscaloosa, Alabama, 35401, United States

Location

Morehouse School of Medicine

Atlanta, Georgia, 30310, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Illinois of Chicago

Chicago, Illinois, 60612, United States

Location

Tulane University Heart and Vascular Institute

New Orleans, Louisiana, 70112, United States

Location

Ochsner

New Orleans, Louisiana, 70121, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Massachsetts General Hospital

Boston, Massachusetts, 02113, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Rutgers University Health Center

Newark, New Jersey, 07102, United States

Location

Montefiore Medical Center Bronx New York

The Bronx, New York, 10461, United States

Location

MetroHealth System

Cleveland, Ohio, 44109, United States

Location

Temple University Medical Center

Philadelphia, Pennsylvania, 19140, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Stern Cardiovascular Foundation

Germantown, Tennessee, 38138, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

University of Virginia

Charlottesville, Virginia, 22903, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

Serum and DNA banked at baseline.

MeSH Terms

Conditions

Heart Failure

Interventions

isosorbide-hydralazine combination

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Officials

• Dennis McNamara, MD

  University of Pittsburgh Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine and Director, Center for Heart Failure Research

Study Record Dates

• First Submitted: September 25, 2014
• First Posted: December 2, 2014
• Study Start: May 1, 2015
• Primary Completion: December 31, 2020
• Study Completion: September 30, 2022
• Last Updated: April 20, 2023

Record last verified: 2023-04

Locations

US (19)