RIDD-HF: Rhode Island Diastolic Dysfunction - Heart Failure

Sponsor

Providence VA Medical Center (U.S. Fed)

Overall Status

Completed

CT.gov ID

NCT02353312

Collaborator

BioMarin Pharmaceutical (Industry), Lifespan (Other)

Enrollment

Location

Arms

Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure Cardiovascular Disease	Drug: Kuvan	N/A

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

28 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Rhode Island Diastolic Dysfunction - Heart Failure

Study Start Date :

Mar 1, 2015

Actual Primary Completion Date :

Dec 1, 2018

Actual Study Completion Date :

Dec 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Initial Intervention Arm Kuvan® supplementation in addition to standard care for heart failure for three months. At the end of three months, stop Kuvan®, patients will only receive Standard care for heart failure for another 3 months	Drug: Kuvan Kuvan® (sapropterin dihydrochloride) will be initiated at 10mg/kg/day with meals for one week. After telephone contact on day 7, assuming no adverse effects are noted, the patient will be instructed to increase their daily dose to 20mg/kg/day with meals for the remainder of the 3 months. Other Names: sapropterin dihydrochloride
Active Comparator: Delayed Intervention Arm Standard care for heart failure for three months. At the end of three months, Starting Kuvan® supplementation in addition to Standard care for heart failure for another 3 months	Drug: Kuvan Kuvan® (sapropterin dihydrochloride) will be initiated at 10mg/kg/day with meals for one week. After telephone contact on day 7, assuming no adverse effects are noted, the patient will be instructed to increase their daily dose to 20mg/kg/day with meals for the remainder of the 3 months. Other Names: sapropterin dihydrochloride

Arm

Intervention/Treatment

Experimental: Initial Intervention Arm

Kuvan® supplementation in addition to standard care for heart failure for three months. At the end of three months, stop Kuvan®, patients will only receive Standard care for heart failure for another 3 months

Drug: Kuvan

Kuvan® (sapropterin dihydrochloride) will be initiated at 10mg/kg/day with meals for one week. After telephone contact on day 7, assuming no adverse effects are noted, the patient will be instructed to increase their daily dose to 20mg/kg/day with meals for the remainder of the 3 months.

Other Names:

sapropterin dihydrochloride

Active Comparator: Delayed Intervention Arm

Standard care for heart failure for three months. At the end of three months, Starting Kuvan® supplementation in addition to Standard care for heart failure for another 3 months

Drug: Kuvan

Other Names:

sapropterin dihydrochloride

Outcome Measures

Primary Outcome Measures

Change from baseline in VO2 consumption [3 mos, 6 mos]
This parameter will be obtained via cardiopulmonary exercise stress testing.

Secondary Outcome Measures

Change from baseline in echocardiographic parameters of diastolic dysfunction [3 mos, 6 mos]
echocardiographic parameters of diastolic dysfunction
Change from baseline in Quality of life measured by Kansas City Cardiomyopathy Questionnaire [3 mos, 6 mos]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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
Diagnosis of hypertension, diabetes, or heart failure in medical records.
Eligible subjects must be ambulatory (not dependent on any ambulatory assist devices including cane or walker).

Exclusion Criteria:

Any history of documented ejection fraction <50%
Significant COPD (defined as oxygen-dependent COPD)
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)
Presence of hypertrophic cardiomyopathy
Presence of infiltrative/restrictive cardiomyopathy
Echocardiographic evidence of moderate or severe aortic or mitral valve stenosis or regurgitation
Previously diagnosed phenylketonuria
End stage renal disease requiring hemodialysis
Pre-existing seizure disorder
Terminal illness (not including heart failure) with expected survival of one year or less
Females who are pregnant or breastfeeding. All females of child bearing age will undergo pregnancy testing prior to randomization.
Recent hospitalization within three months.
Previous Bioprosthetic and/or mechanical aortic or mitral valves