Rhode Island Diastolic Dysfunction - Heart Failure

NCT ID: NCT02353312

Last Updated: 2025-07-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-31
• Study Completion Date: 2018-12-31

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.

Conditions

Heart Failure; Cardiovascular Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Kuvan

Intervention Type: DRUG

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.

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

Group Type: ACTIVE_COMPARATOR

Kuvan

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

sapropterin dihydrochloride

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

BioMarin Pharmaceutical

INDUSTRY

Sponsor Role: collaborator

Lifespan

OTHER

Sponsor Role: collaborator

Providence VA Medical Center

FED

Sponsor Role: lead

Responsible Party

Wen-Chih Wu

Staff Cardiologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wen-Chih Wu, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Providence VA Medical Center

Locations

Providence VAMC

Providence, Rhode Island, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

2014-051

Identifier Type: -

Identifier Source: org_study_id