Mechanistic Study of Nicotinamide Riboside on NAD+ Biology in Individuals With Combined Pulmonary Hypertension

Pulmonary hypertension (PH) is a serious condition that puts strain on the heart and lungs and often leads to frequent hospital stays and shortened life expectancy. The most common cause is heart disease affecting the left side of the heart. A particularly high-risk form, called combined pre- and post-capillary pulmonary hypertension (CPH), occurs in about one in four people with heart failure. There are currently no approved treatments for CPH, and many patients develop right-sided heart failure and die earlier than expected.

This study is based on a new approach that uses advanced computer methods to analyze a patient's unique biology and identify potential drug targets. Using this method, we identified nicotinamide riboside (NR) as a promising option for people with CPH. NR is a form of vitamin B3 that helps the body make NAD⁺, a substance essential for how cells produce energy and stay healthy. NAD⁺ plays an important role in how heart and blood vessel cells function.

Previous research in animals suggests NR may help improve blood vessel changes in the lungs and support heart function. NR has also shown potential benefits in human studies related to cell energy, mitochondrial health, and reducing oxidative stress. In this study, NR is used only as a dietary supplement that supports normal body processes, not as a proven treatment.

The investigators will conduct a small, carefully controlled study in which participants receive NR and a placebo at different times. The goal is to understand how NR affects biological and biochemical markers in the body, not to test whether it improves symptoms or outcomes. Any clinical measurements are included only to help interpret the biological effects.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: Placebo; Dietary supplement: Nicotinamide Riboside (NR)

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thomas E Strayer, PhD; Phone Number: 615-936-0156; Email: thomas.e.strayer@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Vanderbilt University Medical Center
      • Principal Investigator: Evan L Brittain, MD
      • Contact: Thomas E Strayer, PhD; Phone Number: 615-936-0156; Email: thomas.e.strayer@vumc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged >/= 18 to 85 years of age
• Diagnosis of Combined pre-/post-capillary PH (CPH) defined as mean pulmonary artery pressure >20mmHg, pulmonary capillary wedge pressure >15mmHg, and pulmonary vascular resistance ³3 Wood units
• NYHA Class I - III
• A qualifying Baseline RHC performed within 2 years of consent Clinical echocardiogram within the prior year with LVEF>/= 45%
• Stable PH-specific and/or HF medication regimen and ≤1 diuretic adjustment within the three months prior to enrollment.
• Ambulatory - able to perform the walk test

Exclusion Criteria:

• Pulmonary hypertension due to congenital heart disease, connective tissue disease, or heritable pulmonary arterial hypertension
• Prohibited from regular activity due to wheelchair bound status, bed-bound status, reliance on a cane/walker, activity-limiting angina, activity-limiting osteoarthritis, or other conditions that limit activity
• Pregnancy
• Drug and toxin-associated PAH patients with active drug use
• Prior or active diagnosis of cirrhosis
• Active Malignancy
• Patients with evidence of moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, or with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 3 times the upper limit of normal (ULN), should be excluded
• eGFR by MDRD <30mL/mi
• FEV1< 60% predicted with more than mild abnormalities on lung imaging Current enrollment in or completion of any other investigational product study within 30 days of Screening.
• Hospitalization for any indication within 30 days of Day 1.
• History of severe allergic or anaphylactic reaction or hypersensitivity to NR
• No known mutation in NDUFB7

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo portion of the trial	Drug: Placebo; Participants will be randomized to receive either NR or a placebo for 6 weeks, followed by a 3-week washout period. After this, they will receive the alternate treatment for an additional 6 weeks.
Active Comparator: Nicotinamide riboside (NR); NR Portion of the trial	Dietary supplement: Nicotinamide Riboside (NR); Participants will be randomized to receive either 1000mg NR Daily or a placebo for 6 weeks, followed by a 3-week washout period. After this, they will receive the alternate treatment for an additional 6 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biochemical: Change in NADH:Ubiquinone Oxidoreductase Subunit B7		Baseline, Week 6, Week 9, Week 15
Exploratory physiological measure: Change in 6-minute walk distance	The 6MWT measures the distance (in meters), a participant can walk at a comfortable speed on a flat, hard surface in 6 minutes. The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out daily physical activities.	Baseline, Week 6, Week 9, Week 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in N-terminal pro-B-type natriuretic peptide Values		Baseline, Week 6, Week 9, Week 15
Change in New York Heart Association Functional classification (NYHA)	The New York Heart Association (NYHA) functional classification is a widely used system for assessing the severity of heart failure based on symptoms and their impact on physical activity. It is divided into four classes: Class I includes individuals with no limitations on physical activity and no symptoms during ordinary activities; Class II includes individuals with mild limitations on physical activity, where ordinary physical activity causes fatigue, shortness of breath, or other symptoms; Class III includes individuals with marked limitations on physical activity, where less-than-ordinary activity results in symptoms; and Class IV includes individuals who are unable to engage in any physical activity without discomfort and may experience symptoms even at rest. The NYHA functional class will be evaluated at Baseline and Visit 2. The NYHA functional classification is an ordinal scale ranging from Class I to Class IV, with lower class numbers indicating better functional status. Imp	Baseline, Week 6, Week 9, Week 15
Change in Empahsis-10 score	The emPHasis-10 is a short and easy questionnaire that consists of 10 items that address breathlessness, fatigue, control, and confidence. Each item is scored on a semantic differential six-point scale (0-5), with contrasting adjectives at each end. A total emPHasis-10 score is derived using simple aggregation of the 10 items. emPHasis-10 scores range from 0 to 50, higher scores indicate worse quality of life	Baseline, Week 6, Week 9, Week 15
Change in SF-36 Score	The SF36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical and emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. Remote subjects will complete the SF-36 at baseline and each subsequent visit during the study. Each SF-36 domain is scored using a standardized transformation to a 0-100 scale, with higher scores indicating better health status (i.e., fewer limitations, less pain, greater well-being, and higher vitality). Improvements over time are reflected by increases in domain scores relative to baseline.	Baseline, Week 6, Week 9, Week 15
Change in Minnesota Living with Heart Failure Questionnaire	The MLHF (Minnesota Living with Heart Failure Questionnaire) is a widely used disease-specific instrument designed to assess the impact of heart failure on an individual's quality of life. The MLHF includes 21 items that evaluate various aspects of physical, emotional, and social functioning as affected by heart failure. It focuses on areas such as 1) physical limitations due to heart failure symptoms; 2) the emotional impact of living with heart failure; 3) interference with social activities; 4) effects on usual daily activities; and 5) overall quality of life as perceived by the patient. Participants will complete the MLHF at baseline and during each subsequent visit to monitor changes in their quality of life throughout the study. Each MLHF item is scored on a 6-point Likert scale ranging from 0 ("no impact") to 5 ("very much"), reflecting how much heart failure has affected the patient during the past month. Item scores are summed to produce a total score ranging from 0 to 105, w	Baseline, Week 6, Week 9, Week 12
Change in Tricuspid annular plane systolic excursion		Baseline, Week 6, Week 9, Week 15
Change in RV Fractional Area	Right ventricular fractional area change (RV FAC) is a non-invasive measure of right ventricular systolic function assessed using transthoracic echocardiography. RV FAC is calculated from standard echocardiographic images by comparing right ventricular area during diastole and systole. Higher RV FAC values indicate better right ventricular function. Change in RV FAC from baseline will be used to assess changes in right ventricular systolic performance during the study.	Baseline, Week 6, Week 9, Week 15
Change in RV Longitudinal Strain	Right ventricular longitudinal strain is a non-invasive measure of right ventricular myocardial function assessed using transthoracic echocardiography with strain analysis. RV longitudinal strain quantifies myocardial deformation of the right ventricle during systole. More negative strain values indicate better right ventricular systolic function. Change in RV longitudinal strain from baseline will be used to assess changes in right ventricular myocardial performance during the study.	Baseline, Week 6, Week 9, Week 15
Incidence of Treatment-Emergent Adverse Event	This will be a measure of adverse events in the study	Baseline, Week 6, Week 9, Week 15
Number of patients with an incidence of death		Week 16
Change in NAD+		Baseline, 6-weeks, 9-weeks, 12-weeks
,Change in NADH.		Baseline, 6-week, 9-week, 12-week
Change in Nicotinamide Mononucleotide		Baseline, 6-week, 9 week, 15 week

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Evan L Brittain, MD, VUmc

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2026
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): July 30, 2027

Study Registration Dates

• First Submitted: April 22, 2026
• First Submitted That Met QC Criteria: April 28, 2026
• First Posted (Actual): May 4, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; nicotinamide-beta-riboside
• Other Study ID Numbers: 260020; R01HL163960 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will provide a data dictionary/dataset available upon reasonable request as needed.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No