An interventional study of Kuvan in Heart Failure and Cardiovascular Disease, sponsored by Providence VA Medical Center. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-07-03.
Sponsored by Providence VA Medical Center · Not applicable, Interventional, and Treatment
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.
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.
Exclusion Criteria:
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
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.
Also known as: sapropterin dihydrochloride
Change From Baseline in Oxygen Consumption During Maximal Bike Exercise
The change from baseline in oxygen consumption during maximal bike exercise. This was measured using cardiopulmonary exercise tress test (CPET), recorded in milliliters per kilogram per minute (mL/kg/min). Higher oxygen consumption scores indicate better aerobic capacity and cardiovascular function. An increase in oxygen consumption from baseline to post-intervention signifies an improvement in these areas. Conversely, a decrease would indicate a decline in aerobic capacity and cardiovascular health.
Time frame: Baseline (period 0), 3 mos (period 1), 6 mos (period 2)
| Milestone | Kuvan First, Then no Kuvan | No Kuvan First, Then Kuvan |
|---|---|---|
| Started | 16 | 12 |
| Completed | 13 | 10 |
| Not completed | 3 | 2 |
The change from baseline in oxygen consumption during maximal bike exercise. This was measured using cardiopulmonary exercise tress test (CPET), recorded in milliliters per kilogram per minute (mL/kg/min). Higher oxygen consumption scores indicate better aerobic capacity and cardiovascular function. An increase in oxygen consumption from baseline to post-intervention signifies an improvement in these areas. Conversely, a decrease would indicate a decline in aerobic capacity and cardiovascular health.
| mL/kg/min | On Kuvan | Not on Kuvan |
|---|---|---|
| Change From Baseline in Oxygen Consumption During Maximal Bike Exercise | 14.45 ± 5.00 | 14.18 ± 3.69 |
Collected over 6 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| On Kuvan | 0/28 (0%) | 4/28 (14.3%) | 28/28 (100%) |
| Off Kuvan | 0/28 (0%) | 6/28 (21.4%) | 28/28 (100%) |
| Event | On Kuvan | Off Kuvan |
|---|---|---|
| HospitalizationsInvestigations | 2/28 | 3/28 |
| ER visitInvestigations | 2/28 | 3/28 |
| Event | On Kuvan | Off Kuvan |
|---|---|---|
| Peripheral abdominal edemaVascular disorders | 21/28 | 16/28 |
| OtherVascular disorders | 15/28 | 17/28 |
| RhinorrheaBlood and lymphatic system disorders | 14/28 | 7/28 |
| DiarrheaGastrointestinal disorders | 12/28 | 8/28 |
| weight gainGeneral disorders | 12/28 | 12/28 |
| JVDVascular disorders | 4/28 | 6/28 |
| NauseaGastrointestinal disorders | 4/28 | 2/28 |
| FeverInfections and infestations | 1/28 | 3/28 |
| Pulmonary cracklesRespiratory, thoracic and mediastinal disorders | 1/28 | 1/28 |
| EmesisGastrointestinal disorders | 0/28 | 0/28 |
| Age, Continuous(years) | Kuvan First, Then no Kuvan | No Kuvan First, Then Kuvan | Total |
|---|---|---|---|
| Mean | 70.4 ± 9.78 | 72.1 ± 5.85 | 71.4 ± 8.23 |
| Sex: Female, Male(Participants) | Kuvan First, Then no Kuvan | No Kuvan First, Then Kuvan | Total |
|---|---|---|---|
| Female | 2 | 0 | 2 |
| Male | 14 | 12 | 26 |
| Race (NIH/OMB)(Participants) | Kuvan First, Then no Kuvan | No Kuvan First, Then Kuvan | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 2 | 0 | 2 |
| White | 14 | 12 | 26 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
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Providence VA Medical Center