Heart Failure With Reduced Ejection FractionEarly Phase 1NCT03136029
Exercise and NO in HFrEF
A Early Phase 1 study testing Antioxidant, Tetrahydrobiopterin (BH4) and Exercise training in people with Heart Failure With Reduced Ejection Fraction, run by VA Office of Research and Development at 1 site in United States.
Trial summary
Heart disease is the leading cause of death in the United States, accounting for one in every four deaths in 2010 and costing over $300 billion annually in health care, medication, and lost productivity. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure With Reduced Ejection Fraction
- What is being tested?
- Antioxidant, Tetrahydrobiopterin (BH4) and Exercise training
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 68 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jun 2018to 31 Jul 2025
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
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
- General Inclusion/Exclusion Criteria:
- The study group will include subjects with a history of stable cardiomyopathy (ischemic and non-ischemic, >3 months duration, ages 45-75 yrs) despite a minimum of 6 weeks of optimal treatment.
- Optimal therapy will be according to American Heart Association (AHA) /American College of Cardiology (ACC) and Heart Failure Society of America (HFSA) HF guidelines, including treatment with angiotensin-converting enzyme (ACE) and -blocker therapy (for at least 6 weeks), or have documented reason for variation, including medication intolerance, contraindication, patient preference, or personal physician's judgment.
- Patient enrollment will be limited to those individuals with New York Heart Association (NYHA) class II and III symptoms, left ventricular ejection fraction <35% (LVEF), with no or minimal smoking history (<15 pk yrs), and without pacemakers.
Who cannot join
- Patients with atrial fibrillation or HF believed to be secondary to atrial fibrillation will be excluded.
- Patients with HF secondary to significant uncorrected primary valvular disease (except mitral regurgitation secondary to left ventricular dysfunction) will also be excluded.
- Patients will be sedentary, defined here as no regular physical activity for at least the prior 6 months and current activity level will be documented by an activity questionnaire.
- Patients must have no orthopedic limitations that would prohibit them from performing knee-extensor exercise.
- Due to the typical age of patients with HF, all women will be postmenopausal (either natural or surgical) defined as a cessation of menses for at least 2 years, and in women without a uterus, follicle stimulating hormone (FSH) >40 IU/L.
- Women currently taking hormone replacement therapy (HRT) will be excluded from the proposed studies due to the direct vascular effects of HRT Comorbidity Exclusion Criteria: Patients with significant non-cardiac comorbidities, which if present could alter the study results, will be excluded.
Show all 15Show fewer
- These include a diagnosis of Dementia
- Severe chronic obstructive pulmonary disease (COPD)
- Peripheral Vascular Disease
- Anemia
- Sleep-related Breathing Disorder
- Severe Valvular Heart Disease
- Diabetes (if on insulin therapy)
- or End-stage Malignancy
- The investigators will also exclude morbidly obese patients (BMI >40), patients with uncontrolled Hypertension (>160/100), Anemia (Hgb<9) and Severe Renal Insufficiency (individuals with creatinine clearance <30 by the Cockcroft-Gault formula).
Trial locations and contacts
1 site in 1 country.
United States1 site
VA Salt Lake City Health Care System, Salt Lake City, UT
Salt Lake City, Utah, 84148-0001
About this study
Official title: Overcoming Exercise Intolerance in Veterans With Heart Failure: The Role of NO
Heart disease is the leading cause of death in the United States, accounting for one in every four deaths in 2010 and costing over $300 billion annually in health care, medication, and lost productivity. Heart failure with a reduced ejection fraction (HFrEF), a clinical syndrome that develops as a consequence of heart disease, now affects almost 6 million Americans. Within the VA Health Care System, HFrEF hospital admission rates continue to rise, and remain the number one reason for discharge from VA hospitals nationwide. Unfortunately, over one-third of all Veterans suffering from HFrEF die within two years of discharge despite optimized drug therapy, an unacceptably high number. This proposal is focused on how impaired muscle blood flow contributes to exercise intolerance in HFrEF, and on subsequently developing strategies for restoring exercise tolerance and slowing disease progression in this patient group. It is anticipated that knowledge gained from these studies will contribute to improved standard of care, quality of life, and prognosis in this VA patient group.
Read the detailed description
Heart failure with reduced ejection fraction (HFrEF), a clinical syndrome that develops as a consequence of heart disease from multiple etiologies, now affects almost six million Americans, presenting an imminent need for further research addressing the pathophysiology of this pervasive disease. One of the most damaging consequences of the disease is an elevation in sympathetic nervous system (SNS) activity, which manifests peripherally as chronic vasoconstriction. In HFrEF patients, peripheral vasoconstriction acts to limit blood flow in the exercising muscle, promoting exercise intolerance, premature skeletal muscle fatigue, inactivity, and a subsequent acceleration in disease progression. Fortunately, disease-related sympathoexcitation may be remediable. Among the most influential modulators of peripheral SNS expression is the nitric oxide (NO) pathway. Thus, interventions focused on improving NO bioavailability may offer a new, unexplored strategy for inhibiting SNS overactivity in HFrEF, and thus represent a novel approach for improving and exercise tolerance.
Specific Aim 1 will utilize an oral antioxidant (AOx) cocktail to study whether disruptions in oxidative stress can favorably influence exercise tolerance in HFrEF patients.
Specific Aim 2 will examine the efficacy of oral tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS), to improve exercise intolerance in HFrEF patients.
Specific Aim 3 will examine the therapeutic potential of aerobic, knee-extensor (KE) exercise training to improve skeletal muscle blood flow and thus exercise tolerance in HF patients. Importantly, this exercise modality produces a potent training stimulus without the significant cardiopulmonary stress that accompanies more traditional, whole-body exercise. It is proposed that 12 weeks of supervised KE training will increase NO bioavailability and inhibit SNS activity, which will in turn improve vascular function and exercising limb blood flow.
Specific Aim 4 will examine whether the interventional strategies in Aims 1-3 can improve adherence to an 8-week clinical cardiac rehabilitation program. It is hypothesized that chronic AOx consumption (Aim 1), BH4 consumption (Aim 2), and aerobic exercise training (Aim 3) interventions will reduce the rate of attrition from Phase II outpatient Cardiac Rehabilitation in HFrEF patients compared to patients that did not participate in an interventional phase of the study.
The investigators anticipate that disrupting this "vicious cycle" of vasoconstriction in HFrEF may improve overall vascular health to such a degree that significant improvements in exercise-related symptoms are realized, which could therefore improve enrollment in a cardiac rehabilitation program. In this context, findings from the proposed work may provide an important link between vascular and rehabilitative medicine, thus serving to refine current strategies for the treatment of Veterans with HFrEF, ultimately leading to enhanced quality of life in this cohort.
- Being tested
- Antioxidant, Tetrahydrobiopterin (BH4), Exercise training
- Keywords
- HFrEF, Exercise Intolerance, Nitric Oxide
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AntioxidantDietary supplement
Daily consumption of over-the-counter vitamins (600mg alpha lipoic acid, 1000mg vitamin c, 600IU vitamin E)
Tetrahydrobiopterin (BH4)Dietary supplement
Also called Kuvan
Daily consumption of BH4 (10mg/kg)
Exercise trainingOther
Aerobic exercise training program (3x/week for 8 weeks, 1 hour per session)
| Study group | Role | What they receive |
|---|---|---|
| Oral AOx | Experimental | 8 week oral antioxidant treatment Receives: Dietary Supplement: Antioxidant |
| Oral AOx (placebo) | Placebo comparator | Placebo for arm 1 Receives: Dietary Supplement: Antioxidant |
| Oral BH4 | Experimental | 8 week oral tetrahydrobiopterin treatment Receives: Dietary Supplement: Tetrahydrobiopterin (BH4) |
| Oral BH4 (placebo) | Placebo comparator | Placebo for arm 3 Receives: Dietary Supplement: Tetrahydrobiopterin (BH4) |
| Ex training | Experimental | 8-week knee-extensor exercise training program Receives: Other: Exercise training |
| Ex training (attn con) | Sham comparator | Attention control for arm 5 Receives: Other: Exercise training |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood Flow
ultrasound Doppler
Measured: four years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2017
- Study start1 Jun 2018
- Primary completion31 May 2025
- Study completion31 Jul 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Heart Failure With Reduced Ejection FractionStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- 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
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 68 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Collaborators
- University of Utah
- Responsible party
- Sponsor
- Investigators
- David W. Wray, PhD, Principal investigator, VA Salt Lake City Health Care System, Salt Lake City, UT
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03136029
- Sponsor's protocol ID
- F1311-R
- Status last verified
- Aug 2025
- First submitted
- 27 Apr 2017
- Last updated
- 6 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Overcoming Exercise Intolerance in Veterans With Heart Failure: The Role of NO
- ClinicalTrials.gov ID
- NCT03136029
- Acronym / sponsor ID
- F1311-R
- Keywords
- HFrEF, Exercise Intolerance, Nitric Oxide
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 68 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Collaborators
- University of Utah
- Study start
- 1 Jun 2018 (actual)
- Primary completion
- 31 May 2025 (actual)
- Study completion
- 31 Jul 2025 (actual)
- First posted
- 2 May 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Heart disease is the leading cause of death in the United States, accounting for one in every four deaths in 2010 and costing over $300 billion annually in health care, medication, and lost productivity. Heart failure with a reduced ejection fraction (HFrEF), a clinical syndrome that develops as a consequence of heart disease, now affects almost 6 million Americans. Within the VA Health Care System, HFrEF hospital admission rates continue to rise, and remain the number one reason for discharge from VA hospitals nationwide. Unfortunately, over one-third of all Veterans suffering from HFrEF die within two years of discharge despite optimized drug therapy, an unacceptably high number. This proposal is focused on how impaired muscle blood flow contributes to exercise intolerance in HFrEF, and on subsequently developing strategies for restoring exercise tolerance and slowing disease progression in this patient group. It is anticipated that knowledge gained from these studies will contribute to improved standard of care, quality of life, and prognosis in this VA patient group.
Detailed description
Heart failure with reduced ejection fraction (HFrEF), a clinical syndrome that develops as a consequence of heart disease from multiple etiologies, now affects almost six million Americans, presenting an imminent need for further research addressing the pathophysiology of this pervasive disease. One of the most damaging consequences of the disease is an elevation in sympathetic nervous system (SNS) activity, which manifests peripherally as chronic vasoconstriction. In HFrEF patients, peripheral vasoconstriction acts to limit blood flow in the exercising muscle, promoting exercise intolerance, premature skeletal muscle fatigue, inactivity, and a subsequent acceleration in disease progression. Fortunately, disease-related sympathoexcitation may be remediable. Among the most influential modulators of peripheral SNS expression is the nitric oxide (NO) pathway. Thus, interventions focused on improving NO bioavailability may offer a new, unexplored strategy for inhibiting SNS overactivity in HFrEF, and thus represent a novel approach for improving and exercise tolerance.
Specific Aim 1 will utilize an oral antioxidant (AOx) cocktail to study whether disruptions in oxidative stress can favorably influence exercise tolerance in HFrEF patients.
Specific Aim 2 will examine the efficacy of oral tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS), to improve exercise intolerance in HFrEF patients.
Specific Aim 3 will examine the therapeutic potential of aerobic, knee-extensor (KE) exercise training to improve skeletal muscle blood flow and thus exercise tolerance in HF patients. Importantly, this exercise modality produces a potent training stimulus without the significant cardiopulmonary stress that accompanies more traditional, whole-body exercise. It is proposed that 12 weeks of supervised KE training will increase NO bioavailability and inhibit SNS activity, which will in turn improve vascular function and exercising limb blood flow.
Specific Aim 4 will examine whether the interventional strategies in Aims 1-3 can improve adherence to an 8-week clinical cardiac rehabilitation program. It is hypothesized that chronic AOx consumption (Aim 1), BH4 consumption (Aim 2), and aerobic exercise training (Aim 3) interventions will reduce the rate of attrition from Phase II outpatient Cardiac Rehabilitation in HFrEF patients compared to patients that did not participate in an interventional phase of the study.
The investigators anticipate that disrupting this "vicious cycle" of vasoconstriction in HFrEF may improve overall vascular health to such a degree that significant improvements in exercise-related symptoms are realized, which could therefore improve enrollment in a cardiac rehabilitation program. In this context, findings from the proposed work may provide an important link between vascular and rehabilitative medicine, thus serving to refine current strategies for the treatment of Veterans with HFrEF, ultimately leading to enhanced quality of life in this cohort.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Oral AOx | Experimental | Dietary Supplement: Antioxidant8 week oral antioxidant treatment |
| Oral AOx (placebo) | Placebo comparator | Dietary Supplement: AntioxidantPlacebo for arm 1 |
| Oral BH4 | Experimental | Dietary Supplement: Tetrahydrobiopterin (BH4)8 week oral tetrahydrobiopterin treatment |
| Oral BH4 (placebo) | Placebo comparator | Dietary Supplement: Tetrahydrobiopterin (BH4)Placebo for arm 3 |
| Ex training | Experimental | Other: Exercise training8-week knee-extensor exercise training program |
| Ex training (attn con) | Sham comparator | Other: Exercise trainingAttention control for arm 5 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- The study group will include subjects with a history of stable cardiomyopathy (ischemic and non-ischemic, >3 months duration, ages 45-75 yrs) despite a minimum of 6 weeks of optimal treatment.
- Optimal therapy will be according to American Heart Association (AHA) /American College of Cardiology (ACC) and Heart Failure Society of America (HFSA) HF guidelines, including treatment with angiotensin-converting enzyme (ACE) and -blocker therapy (for at least 6 weeks), or have documented reason for variation, including medication intolerance, contraindication, patient preference, or personal physician's judgment.
- Patient enrollment will be limited to those individuals with New York Heart Association (NYHA) class II and III symptoms, left ventricular ejection fraction <35% (LVEF), with no or minimal smoking history (<15 pk yrs), and without pacemakers.
Key exclusion criteria (15 listed)
- Patients with atrial fibrillation or HF believed to be secondary to atrial fibrillation will be excluded.
- Patients with HF secondary to significant uncorrected primary valvular disease (except mitral regurgitation secondary to left ventricular dysfunction) will also be excluded.
- Patients will be sedentary, defined here as no regular physical activity for at least the prior 6 months and current activity level will be documented by an activity questionnaire.
- Patients must have no orthopedic limitations that would prohibit them from performing knee-extensor exercise.
- Due to the typical age of patients with HF, all women will be postmenopausal (either natural or surgical) defined as a cessation of menses for at least 2 years, and in women without a uterus, follicle stimulating hormone (FSH) >40 IU/L.
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 |
|---|---|---|
| AntioxidantDaily consumption of over-the-counter vitamins (600mg alpha lipoic acid, 1000mg vitamin c, 600IU vitamin E) | Dietary supplement | Oral AOx, Oral AOx (placebo) |
| Tetrahydrobiopterin (BH4)Also: KuvanDaily consumption of BH4 (10mg/kg) | Dietary supplement | Oral BH4, Oral BH4 (placebo) |
| Exercise trainingAerobic exercise training program (3x/week for 8 weeks, 1 hour per session) | Other | Ex training, Ex training (attn con) |
Primary outcome
Blood Flow
Time frame: four years
ultrasound Doppler
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2025.
- Individual participant dataSharing planned: No
Related trials for Heart Failure With Reduced Ejection Fraction
Recruiting
Vsling™ III: Clinical Evaluation of the Vsling™ Device for Ventricular Repair in Patients With Heart Failure
HFrEF - Heart Failure With Reduced Ejection Fraction
RecruitingPhase 2
Vsling™ I: Clinical Evaluation of the Vsling™ Device for Ventricular Repair in Patients With Heart Failure
Heart Failure With Reduced Ejection Fraction
RecruitingPhase 4
Empagliflozin in Heart Failure With Reduced Ejection Fraction and End Stage Renal Disease
Heart Failure With Reduced Ejection Fraction, End Stage Renal Disease on Dialysis
Not yet recruitingObservational study
Metabolic Changes in Heart Failure Patients Treated With Vericiguat
Heart Failure, Worsening Heart Failure
RecruitingPhase 3
A Study to Test Whether Vicadrostat (BI 690517) in Combination With Empagliflozin Helps People With Heart Failure and a Weak Pumping Function of the Left Side of the Heart
Heart Failure
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.
David W. Wray, PhD principal investigator
VA Salt Lake City Health Care System, Salt Lake City, UT
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Antioxidant, Tetrahydrobiopterin (BH4) and Exercise training in people with Heart Failure With Reduced Ejection Fraction, run by VA Office of Research and Development 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 4 inclusion and 15 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 6 Aug 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Blood Flow (time frame: four years). 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 6 Aug 2025.