Nicotinamide Riboside as an Enhancer of Exercise Therapy in Hypertensive Older Adults (The NEET Trial)

NCT ID: NCT04112043

Last Updated: 2024-06-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 147 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-28
• Study Completion Date: 2023-05-26

Brief Summary

More than 80% of older adults have hypertension, with higher prevalence of high systolic blood pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death. Novel compound, nicotinamide riboside may enhance the effects of exercise therapy in hypertensive older adults.

Detailed Description

More than 80% of older adults have hypertension, with a higher prevalence of high systolic blood pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death. Because drug therapy that lowers SBP is associated with side effects such as hypotension, syncope, and kidney dysfunction, there is a great need for effective lifestyle SBP-lowering interventions for the older population that can replace drug therapy. While aerobic exercise is a recommended lifestyle intervention for controlling SBP and preventing CV disease naturally, in older adults it has been shown to be less effective in vascular-tissue remodeling because of arterial stiffness, resulting in less efficient SBP control. Reduced bioavailability of nicotinamide adenine dinucleotide (NAD+), a cofactor for the deacetylase sirtuin1 (SIRT1), may contribute to age-related vascular dysfunction via oxidative stress and reduced nitric oxide (NO). Exercise-induced overexpression of NAD+-dependent SIRT1 improves the bioavailability of NO. Preclinical evidence suggests that poor vascular function improvement in response to exercise in older mice is caused by insufficient NAD+ levels to stimulate SIRT1 activity. Importantly, replenishment of NAD+ levels induced vascular remodeling, improved vascular function, and reduced SBP in mice. An objective of this study, therefore, is to test a combination of aerobic exercise and nicotinamide riboside, a compound that replenishes NAD+ levels, to optimize exercise's SBP-lowering effect in hypertensive older adults. Initial human clinical trials demonstrated that nicotinamide riboside supplementation (1,000 mg/day) was safe and showed a higher potential to reduce SBP and arterial stiffness in participants with elevated SBP. As we have preclinical evidence that combining NAD+ replenishment with exercise is an ideal strategy for improving vascular function, our central hypothesis is that the intervention of aerobic-exercise training combined with nicotinamide riboside supplementation will reduce SBP in hypertensive older adults more effectively than will exercise alone. We will enroll 54 participants ≥ 55 years and older into either: (1) 1,000 mg/day of nicotinamide riboside plus 3 days/week of supervised, center-based walking exercise (n=18), or (2) the same exercise program combined with placebo (n=18), or (3) 1,000 mg/day of nicotinamide riboside alone (n=18). All participants will undergo daytime continuous SBP at baseline, 3 weeks, and 6 weeks, and arterial-stiffness measurements by pulse-wave velocity at baseline and at 6 weeks. Elevated SBP will be determined as daytime average equal to or above 130 mmHg, measured by the 24-hour blood-pressure device. To our knowledge, this study will be the first attempt to enhance exercise therapy with nicotinamide riboside in hypertensive older adults. We believe that nicotinamide riboside is "the missing piece of the puzzle" in improving vascular remodeling and SBP management in older adults. Preliminary evidence from this pilot study may support a full-scale Phase III clinical trial in hypertensive older adults. The ultimate goal of this line of research is to find adjuvant strategies to improve the exercise's SBP-lowering effects in older adults.

Conditions

Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

NR plus Walking Exercise

1,000 mg/day of NR combined with three days/week of supervised, center-based walking exercise (n=18)

Group Type: ACTIVE_COMPARATOR

Walking Exercise

Intervention Type: BEHAVIORAL

Participants randomized to this intervention 3 days/week of supervised, center-based walking exercise.

Nicotinamide Riboside (NR)

Intervention Type: DRUG

Participants randomized to this intervention will receive 1,000 mg/day of NR.

Walking Exercise plus Placebo

1,000 mg/day of Placebo combined with three days/week of supervised, center-based walking exercise (n=18)

Group Type: ACTIVE_COMPARATOR

Walking Exercise

Intervention Type: BEHAVIORAL

Participants randomized to this intervention 3 days/week of supervised, center-based walking exercise.

NR Alone

1,000 mg/day of NR

Group Type: ACTIVE_COMPARATOR

Nicotinamide Riboside (NR)

Intervention Type: DRUG

Participants randomized to this intervention will receive 1,000 mg/day of NR.

Interventions

Walking Exercise

Participants randomized to this intervention 3 days/week of supervised, center-based walking exercise.

Intervention Type: BEHAVIORAL

Nicotinamide Riboside (NR)

Participants randomized to this intervention will receive 1,000 mg/day of NR.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age 55 years and older
• Daytime average of systolic blood pressure of ≥ 130 mmHg and < 160 mmHg.
• Sedentary lifestyle, defined as < 150 min/wk of moderate physical activity as assessed by the CHAMPS questionnaire.
• Willingness to be randomized to either treatment group
• Willingness to participate in all study procedures

Exclusion Criteria

• Failure to provide informed consent.
• Pregnant
• Change in blood pressure therapy (type or dose) within the last 3 months- Temporary Exclusion
• Daytime average of systolic blood pressure ≥160 mmHg.
• Regular consumption of nicotinamide riboside supplement
• Current involvement in supervised rehabilitation program
• Absolute contraindication(s) to exercise training according to American College of Sports Medicine guidelines [11]
• Daytime average of systolic blood pressure below 130mm Hg or Diastolic BP ≥ 100mm Hg.
• Peripheral vascular disease; peripheral neuropathy; retinopathy
• Severe cardiac disease, including NYHA Class III or IV congestive heart failure, clinically significant aortic stenosis, history of cardiac arrest, use of a cardiac defibrillator, or uncontrolled angina;
• Myocardial infarction or stroke within past year
• Significant cognitive impairment, including known dementia diagnosis or a Mini-Mental State Examination exam score < 24
• Progressive, degenerative neurologic disease, e.g., Parkinson's Disease, multiple sclerosis;
• Severe rheumatologic or orthopedic diseases, e.g., awaiting joint replacement, active inflammatory disease;
• Severe pulmonary disease, requiring steroid therapy or the use of supplemental oxygen;
• Hip fracture, hip or knee replacement, or spinal surgery within past 4 months;
• Other significant co-morbid conditions that would impair ability to participate in the exercise-based intervention
• Simultaneous participation in another intervention trial

• Minimum Eligible Age: 55 Years
• Maximum Eligible Age: 105 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robert Mankowski, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

UF Institute on Aging

Gainesville, Florida, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

OCR26682

Identifier Type: OTHER

Identifier Source: secondary_id

5R21AG064282

Identifier Type: NIH

Identifier Source: secondary_id

View Link

AWD06755

Identifier Type: OTHER

Identifier Source: secondary_id

IRB201900746 -N-R

Identifier Type: -

Identifier Source: org_study_id