Clinical trial NCT02305095: Genomic Response Analysis of Heart Failure Therapy in African Americans
Official title: Genomic Analysis of the Enhanced Response to Heart Failure Therapy in African Americans
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Heart Failure
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2014-12-02
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Detailed description: 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. Despite the clear survival benefits of treatment with FDC I/H in the African American Heart Failure Trial (AHeFT), the drug is prescribed in only 25% of black subjects who would potentially benefit.

In terms of the enhanced response evident in the A-HeFT investigation, race is likely a marker of differences in genomic background. Genetic variation of the G protein beta sub unit GNB3 has been studied extensively for its role in hypertension. A polymorphism exists at position 825 (T/C) which is functionally silent but tightly linked to a splicing variant resulting in a truncated protein. The GNB3 T haplotype is far more prevalent in blacks and associated with low renin hypertension. Evaluation of 350 subjects in the genetic sub-study of AHeFT suggests that the GNB3 TT genotype, found in 50% of African Americans but only 10-15% of whites, was linked to an enhanced therapeutic response to FDC I/H. This investigation will evaluate the hypothesis that the GNB3 TT genotype is a marker of enhanced therapeutic response to FDC I/H in African Americans with HFrEF.

The study will enroll a cohort of 500 African Americans with HFrEF, initiate therapy with FDC I/H and follow them for up to two years. Subjects will be genotyped at entry for the GNB3 polymorphism and response to therapy compared by genotype. Therapeutic response will be quantified using the composite score, the primary endpoint of AHeFT, which incorporates mortality, heart failure hospitalizations, and a change in quality of life (QoL) score at six months.

Aim 2 will do a similar analysis of response to therapy by GNB3 genotype using improvement in left ventricular end diastolic diameter (LVEDD) or left ventricular ejection fraction (LVEF) by echocardiogram after six months on therapy as the outcomes measure. Aim 3 will use admixture analysis to determine first how global ancestry (the % African ancestral DNA for an individual) impacts on the outcome measures of drug response, and how the global ancestry acts as a modifier for the effect of GNB3.

Eligibility criteria: Inclusion Criteria:

1. 18 years and older
2. 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\*\*
3. New York Heart Association (NYHA) Class II-IV
4. 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)
5. 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).

Exclusion Criteria:

1. History of intolerance to either nitrates or hydralazine
2. Treatment with the combination of hydralazine and nitrates for the previous 3 months
3. Revascularization or myocardial infarction within last 90 days
4. 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
5. 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)
6. Women who are currently pregnant, planning on becoming pregnant in the next two years, or those who do not agree to prevent pregnancy.
7. Subjects who are on continuous home inotropes, a left ventricular assist device, or who are post cardiac transplant.

Primary outcomes:
measure: 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)
timeFrame: 2 years
Secondary outcomes:
measure: Survival
timeFrame: 2 years
measure: Survival free from heart failure hospitalization
timeFrame: 2 years
measure: Change in Quality of Life Assessment by Minnesota Living with Heart Failure Questionnaire
timeFrame: 6 months
Other outcomes:
Locations:
city: Tuscaloosa
country: United States
facility: University of Alabama Medical Center
state: Alabama
city: Atlanta
country: United States
facility: Morehouse School of Medicine
state: Georgia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois of Chicago
state: Illinois
city: New Orleans
country: United States
facility: Tulane University Heart and Vascular Institute
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachsetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Newark
country: United States
facility: Rutgers University Health Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center Bronx New York
state: New York
city: Cleveland
country: United States
facility: MetroHealth System
state: Ohio
city: Philadelphia
country: United States
facility: Temple University Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: University of South Carolina
state: South Carolina
city: Germantown
country: United States
facility: Stern Cardiovascular Foundation
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: University of Pittsburgh Medical Center
name: Dennis McNamara, MD
role: PRINCIPAL_INVESTIGATOR
References: