Heart FailureGRAHF-2NCT02305095
Genomic Response Analysis of Heart Failure Therapy in African Americans
An observational study of Heart Failure, run by University of Pittsburgh at 19 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure
- What is being tested?
- FDC I/H
- How many people
- 225 participants
- Where
- 19 sitesUnited States
- Study dates
- 1 May 2015to 30 Sep 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Adult subjects with systolic heart failure who are self designation as African Americans are potentially eligible for the study.
Who may be able to join
- 18 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).
Who cannot join
- 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.
Trial locations and contacts
19 sites in 1 country.
19 sites in 1 country
United States19 sites
Morehouse School of Medicine
Atlanta, Georgia, 30310
Emory University
Atlanta, Georgia, 30322
University of Maryland Medical Center
Baltimore, Maryland, 21201
Massachsetts General Hospital
Boston, Massachusetts, 02113
University of South Carolina
Charleston, South Carolina, 29425
University of Virginia
Charlottesville, Virginia, 22903
Northwestern University
Chicago, Illinois, 60611
University of Illinois of Chicago
Chicago, Illinois, 60612
MetroHealth System
Cleveland, Ohio, 44109
Henry Ford Health System
Detroit, Michigan, 48202
Stern Cardiovascular Foundation
Germantown, Tennessee, 38138
Baylor College of Medicine
Houston, Texas, 77030
Tulane University Heart and Vascular Institute
New Orleans, Louisiana, 70112
Ochsner
New Orleans, Louisiana, 70121
Rutgers University Health Center
Newark, New Jersey, 07102
Temple University Medical Center
Philadelphia, Pennsylvania, 19140
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15213
Montefiore Medical Center Bronx New York
The Bronx, New York, 10461
University of Alabama Medical Center
Tuscaloosa, Alabama, 35401
About this study
Official title: Genomic Analysis of the Enhanced Response to Heart Failure Therapy in African Americans
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.
Read the 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.
- Conditions
- Heart Failure
- Being tested
- FDC I/H
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FDC I/HDrug
Also called BiDil
All subjects in both groups will be initiated on drug, FDC I/H with dose titrated up to target doses based on clinical guidelines
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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). Receives: Drug: FDC I/H |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 2 years
Secondary outcomes (3)
Survival
Comparison of survival on therapy by GNB3 genotype
Measured: 2 years
Survival free from heart failure hospitalization
Comparison of event free survival by GNB3 genotype.
Measured: 2 years
Change in Quality of Life Assessment by Minnesota Living with Heart Failure Questionnaire
Evaluate the change in the raw score of the Quality of Life questionnaire by GNB3 genotype.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Dec 2014 (estimated)
- Study start1 May 2015
- Primary completion31 Dec 2020
- Study completion30 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by University of PittsburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 225 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pittsburgh
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dennis M. McNamara, MD, MS, University of Pittsburgh
- Investigators
- Dennis McNamara, MD, Principal investigator, University of Pittsburgh Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02305095
- Sponsor's protocol ID
- 3648634
- Other IDs
- MD009118-01
- Acronym
- GRAHF-2
- Status last verified
- Apr 2023
- First submitted
- 25 Sep 2014
- Last updated
- 20 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 20 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genomic Analysis of the Enhanced Response to Heart Failure Therapy in African Americans
- ClinicalTrials.gov ID
- NCT02305095
- Acronym / sponsor ID
- GRAHF-2 / 3648634
- Conditions
- Heart Failure
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 225 participants (actual)
- Lead sponsor
- University of PittsburghUniversity, hospital or other
- Study start
- 1 May 2015 (actual)
- Primary completion
- 31 Dec 2020 (actual)
- Study completion
- 30 Sep 2022 (actual)
- First posted
- 2 Dec 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| GNB3 TT | – | Drug: FDC I/HAll 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). |
| GNB3 C | – | Drug: FDC I/HAll 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Adult subjects with systolic heart failure who are self designation as African Americans are potentially eligible for the study.
Key inclusion criteria (5 listed)
- 18 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).
Key exclusion criteria (7 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FDC I/HAlso: BiDilAll subjects in both groups will be initiated on drug, FDC I/H with dose titrated up to target doses based on clinical guidelines | Drug | GNB3 C, GNB3 TT |
Primary outcome
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)
Time frame: 2 years
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.
3 secondary outcomes
Survival
Time frame: 2 years
Survival free from heart failure hospitalization
Time frame: 2 years
Change in Quality of Life Assessment by Minnesota Living with Heart Failure Questionnaire
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Apr 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dennis McNamara, MD principal investigator
University of Pittsburgh Medical Center
19 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Heart Failure, run by University of Pittsburgh at 19 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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) (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Apr 2023.