Heart Failure, Cardiovascular Disease
Conditions
Keywords
Diastolic, Biopterin, Therapeutic Use, Drug Therapy, Quality of Life
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.
Interventions
DRUGKuvan
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.
Sponsors
BioMarin Pharmaceutical
Lifespan
Providence VA Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Oxygen Consumption During Maximal Bike Exercise | Baseline (period 0), 3 mos (period 1), 6 mos (period 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Kuvan First, Then no Kuvan 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
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. | 16 |
| No Kuvan First, Then 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
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. | 12 |
| Total | 28 |
Baseline characteristics
| Characteristic | No Kuvan First, Then Kuvan | Total | Kuvan First, Then no Kuvan |
|---|---|---|---|
| Age, Continuous | 72.1 years STANDARD_DEVIATION 5.85 | 71.4 years STANDARD_DEVIATION 8.23 | 70.4 years STANDARD_DEVIATION 9.78 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 26 Participants | 14 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 12 Participants | 26 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 28 / 28 | 28 / 28 |
| serious Total, serious adverse events | 4 / 28 | 6 / 28 |
Outcome results
Primary
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)
Population: All patients who had both baseline and final test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On Kuvan | Change From Baseline in Oxygen Consumption During Maximal Bike Exercise | 14.45 mL/kg/min | Standard Deviation 5 |
| Not on Kuvan | Change From Baseline in Oxygen Consumption During Maximal Bike Exercise | 14.18 mL/kg/min | Standard Deviation 3.69 |
p-value: 0.823t-test, 2 sided