Heart FailureRIDD-HFNCT02353312
Rhode Island Diastolic Dysfunction - Heart Failure
A study testing Kuvan in people with Heart Failure and Cardiovascular Disease, run by Providence VA Medical Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure, Cardiovascular Disease
- What is being tested?
- Kuvan
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2015to Dec 2018
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
Who cannot join
- 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
Show all 13Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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
- Being tested
- Kuvan
- Keywords
- Diastolic, Biopterin, Therapeutic Use, Drug Therapy, Quality of Life
- Medical subject headings
- Heart Failure, Cardiovascular Diseases, Heart Murmurs
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KuvanDrug
Also called sapropterin dihydrochloride
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.
| Study group | Role | What they receive |
|---|---|---|
| Initial Intervention Arm | Experimental | 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 Receives: Drug: Kuvan |
| Delayed Intervention Arm | Active comparator | 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 Receives: Drug: Kuvan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline (period 0), 3 mos (period 1), 6 mos (period 2)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2015 (estimated)
- Study startMar 2015
- Primary completionDec 2018
- Study completionDec 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- Providence VA Medical Center
- Sponsor type
- US federal agency
- Collaborators
- BioMarin Pharmaceutical, Lifespan
- Responsible party
- Principal investigator, Wen-Chih Wu, Providence VA Medical Center
- Investigators
- Wen-Chih Wu, MD, MPH, Principal investigator, Providence VA Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02353312
- Sponsor's protocol ID
- 2014-051
- Acronym
- RIDD-HF
- Status last verified
- Jul 2025
- First submitted
- 29 Dec 2014
- Last updated
- 3 Jul 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Rhode Island Diastolic Dysfunction - Heart Failure
- ClinicalTrials.gov ID
- NCT02353312
- Acronym / sponsor ID
- RIDD-HF / 2014-051
- Conditions
- Heart Failure, Cardiovascular Disease
- Keywords
- Diastolic, Biopterin, Therapeutic Use, Drug Therapy, Quality of Life
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 28 participants (actual)
- Lead sponsor
- Providence VA Medical CenterUS federal agency
- Collaborators
- BioMarin Pharmaceutical, Lifespan
- Study start
- Mar 2015
- Primary completion
- Dec 2018 (actual)
- Study completion
- Dec 2018 (actual)
- First posted
- 2 Feb 2015 (estimated)
- Results
- Posted 3 Jul 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Initial Intervention Arm | Experimental | Drug: KuvanKuvan® 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 |
| Delayed Intervention Arm | Active comparator | Drug: KuvanStandard 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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).
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| KuvanAlso: sapropterin dihydrochlorideKuvan® (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. | Drug | Delayed Intervention Arm, Initial Intervention Arm |
Primary outcome
Change From Baseline in Oxygen Consumption During Maximal Bike Exercise
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jul 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Wen-Chih Wu, MD, MPH principal investigator
Providence VA Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Kuvan in people with Heart Failure and Cardiovascular Disease, run by Providence VA Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Jul 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline in Oxygen Consumption During Maximal Bike Exercise (time frame: Baseline (period 0), 3 mos (period 1), 6 mos (period 2)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jul 2025.