Pulmonary Hypertension
Conditions
Brief summary
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.
Interventions
DIETARY_SUPPLEMENTNicotinamide 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.
DRUGPlacebo
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.
Sponsors
Vanderbilt University Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical: Change in NADH:Ubiquinone Oxidoreductase Subunit B7 | Baseline, Week 6, Week 9, Week 15 | — |
| Exploratory physiological measure: Change in 6-minute walk distance | Baseline, Week 6, Week 9, Week 15 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Baseline, Week 6, Week 9, Week 15 | 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 |
| Change in Empahsis-10 score | Baseline, Week 6, Week 9, Week 15 | 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 |
| Change in SF-36 Score | Baseline, Week 6, Week 9, Week 15 | 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. |
| Change in Minnesota Living with Heart Failure Questionnaire | Baseline, Week 6, Week 9, Week 12 | 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 |
| Change in Tricuspid annular plane systolic excursion | Baseline, Week 6, Week 9, Week 15 | — |
| Change in RV Fractional Area | Baseline, Week 6, Week 9, Week 15 | 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. |
| Change in RV Longitudinal Strain | Baseline, Week 6, Week 9, Week 15 | 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. |
| Incidence of Treatment-Emergent Adverse Event | Baseline, Week 6, Week 9, Week 15 | This will be a measure of adverse events in the study |
| 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 | — |
Countries
United States
Contacts
CONTACTThomas E Strayer, PhD
PRINCIPAL_INVESTIGATOREvan L Brittain, MD
VUMC
Outcome results
None listed