Rhode Island Diastolic Dysfunction - Heart Failure (RIDD-HF)

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Cardiovascular Disease
• Intervention / Treatment: Drug: Kuvan

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 Type: Interventional
• Enrollment (Actual): 28
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Rhode Island
    • Providence, Rhode Island, United States, 02908
      • Providence VAMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in VO2 consumption	This parameter will be obtained via cardiopulmonary exercise stress testing.	3 mos, 6 mos

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in echocardiographic parameters of diastolic dysfunction	echocardiographic parameters of diastolic dysfunction	3 mos, 6 mos
Change from baseline in Quality of life measured by Kansas City Cardiomyopathy Questionnaire		3 mos, 6 mos

Collaborators and Investigators

• Sponsor: Providence VA Medical Center
• Collaborators: BioMarin Pharmaceutical; Lifespan
• Investigators: Principal Investigator: Wen-Chih Wu, MD, MPH, Providence VA Medical Center

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: December 29, 2014
• First Submitted That Met QC Criteria: January 28, 2015
• First Posted (Estimate): February 2, 2015

Study Record Updates

• Last Update Posted (Actual): January 30, 2019
• Last Update Submitted That Met QC Criteria: January 28, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Drug Therapy; Quality of Life; Diastolic; Therapeutic Use; Biopterin
• Additional Relevant MeSH Terms: Heart Diseases; Heart Failure; Cardiovascular Diseases
• Other Study ID Numbers: 2014-051