Clinical trial NCT02353312: Rhode Island Diastolic Dysfunction - Heart Failure
Official title: Rhode Island Diastolic Dysfunction - Heart Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heart Failure
Cardiovascular Disease
Keywords: Diastolic
Biopterin
Therapeutic Use
Drug Therapy
Quality of Life
Lead sponsor: Providence VA Medical Center
Sponsor class: FED
Collaborators: name: BioMarin Pharmaceutical
name: Lifespan
First posted: 2015-02-02
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: To study the hypothesis that treating patients with underlying diastolic dysfunction with oral Kuvan® (BH4, also known as tetrahydrobiopterin) in addition to current best practices will improve metabolic and echocardiographic diastolic function parameters.

Detailed description: Congestive heart failure carries a significant epidemiologic and economic burden in today's healthcare system and is associated with increased morbidity and mortality in those affected.

There are approximately 5 million people in the United States with heart failure, and of those, nearly half have heart failure with preserved ejection fraction (HFpEF). HFpEF, also referred to as diastolic heart failure, is a clinical syndrome characterized by prolonged relaxation of the myocardium resulting in symptoms including dyspnea, edema, fatigue, and decreased exercise tolerance, which are clinically indistinguishable from the presentation of heart failure with reduced ejection fraction (HFrEF). The underlying mechanisms in diastolic dysfunction are not clearly elucidated, making targeted therapy a challenge. There are currently no FDA approved treatments for this syndrome, and multiple clinical trials have demonstrated that standard treatments for systolic heart failure are ineffective in treating diastolic dysfunction. One of the proposed underlying mechanisms of diastolic dysfunction is via the reduction of nitric oxide (NO), an endothelium-derived vasodilator that regulates blood pressure and regional blood flow. In 2010, Silberman et al. examined the effect of cardiac oxidation on nitric oxide and found that depletion of tetrahydrobiopterin (BH4), an essential cofactor in the production of nitric oxide, causes uncoupling of nitric oxide synthase, impaired relaxation of cardiac myocytes, and leads to subsequent diastolic dysfunction. The authors further went on to demonstrate that treatment with BH4 can improve diastolic dysfunction in a hypertensive mouse model as well as in isolated cardiac myocytes and may play a role in the treatment of HFpEF.

To the investigators' knowledge, the role of BH4 in treating diastolic dysfunction in human subjects has not been studied.

Eligibility criteria: Inclusion Criteria:

1. Male and female U.S. Veteran patients over the age of eighteen, with echocardiographic findings of \>= Grade 2 diastolic dysfunction \[as per American Society of Echocardiography guidelines\] and
2. Diagnosis of hypertension, diabetes, or heart failure in medical records.
3. Eligible subjects must be ambulatory (not dependent on any ambulatory assist devices including cane or walker).

Exclusion Criteria:

1. Any history of documented ejection fraction \<50%
2. Significant COPD (defined as oxygen-dependent COPD)
3. Acute coronary syndrome within the past three months defined by EKG changes and biomarkers of myocardial necrosis (ie. elevated troponin) in the setting of chest pain or an anginal equivalent)
4. Presence of hypertrophic cardiomyopathy
5. Presence of infiltrative/restrictive cardiomyopathy
6. Echocardiographic evidence of moderate or severe aortic or mitral valve stenosis or regurgitation
7. Previously diagnosed phenylketonuria
8. End stage renal disease requiring hemodialysis
9. Pre-existing seizure disorder
10. Terminal illness (not including heart failure) with expected survival of one year or less
11. Females who are pregnant or breastfeeding. All females of child bearing age will undergo pregnancy testing prior to randomization.
12. Recent hospitalization within three months.
13. Previous Bioprosthetic and/or mechanical aortic or mitral valves

Primary outcomes:
measure: Change from baseline in VO2 consumption
timeFrame: 3 mos, 6 mos
Secondary outcomes:
measure: Change from baseline in echocardiographic parameters of diastolic dysfunction
timeFrame: 3 mos, 6 mos
measure: Change from baseline in Quality of life measured by Kansas City Cardiomyopathy Questionnaire
timeFrame: 3 mos, 6 mos
Other outcomes:
Locations:
city: Providence
country: United States
facility: Providence VAMC
state: Rhode Island
Study officials:
affiliation: Providence VA Medical Center
name: Wen-Chih Wu, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: