Exercise and NO in HFrEF

NCT03136029 | Completed Early Phase 1 DMC

• 1 other identifier: F1311-R
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Heart Failure With Reduced Ejection Fraction

Keywords

HFrEF; Exercise Intolerance; Nitric Oxide

Outcome Measures

Primary Outcomes (1)

• Blood Flow

  ultrasound Doppler

  four years

Study Arms (6)

Oral AOx

EXPERIMENTAL

8 week oral antioxidant treatment

Dietary Supplement: Antioxidant

Oral AOx (placebo)

PLACEBO COMPARATOR

Placebo for arm 1

Dietary Supplement: Antioxidant

Oral BH4

EXPERIMENTAL

8 week oral tetrahydrobiopterin treatment

Dietary Supplement: Tetrahydrobiopterin (BH4)

Oral BH4 (placebo)

PLACEBO COMPARATOR

Placebo for arm 3

Dietary Supplement: Tetrahydrobiopterin (BH4)

Ex training

EXPERIMENTAL

8-week knee-extensor exercise training program

Other: Exercise training

Ex training (attn con)

SHAM COMPARATOR

Attention control for arm 5

Other: Exercise training

Interventions

Antioxidant DIETARY_SUPPLEMENT

Daily consumption of over-the-counter vitamins (600mg alpha lipoic acid, 1000mg vitamin c, 600IU vitamin E)

Oral AOx; Oral AOx (placebo)

Tetrahydrobiopterin (BH4) DIETARY_SUPPLEMENT

Daily consumption of BH4 (10mg/kg)

Also known as: Kuvan

Oral BH4; Oral BH4 (placebo)

Exercise training OTHER

Aerobic exercise training program (3x/week for 8 weeks, 1 hour per session)

Ex training; Ex training (attn con)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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.
• 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.
• 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)

Sponsors & Collaborators

• VA Office of Research and Development: lead
• University of Utah: collaborator

Study Sites (1)

VA Salt Lake City Health Care System, Salt Lake City, UT

Salt Lake City, Utah, 84148-0001, United States

Location

MeSH Terms

Interventions

Antioxidants; sapropterin; Exercise

Intervention Hierarchy (Ancestors)

Biological Factors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Protective Agents; Physiological Effects of Drugs; Specialty Uses of Chemicals; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• David W. Wray, PhD

  VA Salt Lake City Health Care System, Salt Lake City, UT

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2017
• First Posted: May 2, 2017
• Study Start: June 1, 2018
• Primary Completion: May 31, 2025
• Study Completion: July 31, 2025
• Last Updated: August 6, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)