Study to Assess the Relationship Between Daily Dosing of NRPT and Changes in Liver Fat in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine if there is a relationship between daily consumption of NRPT, over a six-month (26-week) period, and changes in liver fat accumulation, compared to placebo and change from Baseline in healthy volunteers. In addition, an exploratory assessment of markers of inflammation and liver fat metabolism will be examined.

Official Title
-----------------
A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Study to Assess the Relationship Between Daily Dosing of NRPT and Changes in Liver Fat in Healthy Volunteers

Conditions
-----------------
Fatty Liver

Intervention / Treatment
-----------------
* Dietary Supplement: Group 1 NRPT
* Dietary Supplement: Group 2 NRPT
* Other: Group 3 Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: MRI-PDFF of at least 15%, as measured at Visit 2 (Baseline). Men or women between the ages of 18 and 70 years. BMI between 25.0 and 39.9 kg/m2. Non-smokers (>3 months of non-smoking). If on a statin regimen, history (> 1 month) of stable dose. Able to understand and cooperate with study procedures, and have signed a written informed consent prior to any study procedures. Exclusion Criteria: Diagnosis of NASH (Non-Alcoholic Steatohepatitis). Bilirubin >2x ULN Other causes of liver inflammation including Hepatitis A, B or C, HIV, confirmed or suspected cirrhosis, Wilson's disease, autoimmune hepatitis, hemochromatosis, alcoholic steatohepatitis, pancreatitis, or prescription medications known to cause liver damage, or known to be hepatotoxic. (Evidence of hepatocellular injury or hepatocyte ballooning.) Subjects with a history of bariatric surgery. Significant weight loss (> 5% body weight) or rapid weight loss (> 1.6kg/week), within six (6) months of the Screening Visit. Current or recent (within six (6) months of the Screening Visit) history of significant gastrointestinal, renal, pulmonary, hepatic or biliary disease, endocrine diseases (Type II Diabetes permitted) or other invasive weight loss treatments. Individual taking prescription or over-the-counter medications, including dietary supplements, known to alter lipid metabolism or liver function, within four (4) weeks of randomization. Use of supplements containing pterostilbene, resveratrol, nicotinamide, or niacin, or consumption of red wine (more than 8 oz. per week) or blueberries (more than one serving per week). Pregnant or lactating women or women of childbearing potential who are not using an approved method of contraception. A woman is considered to be of childbearing potential unless she is post-hysterectomy, one or more years postmenopausal, or one or more years following tubal ligation. History of significant cardiovascular or coronary heart disease (CVD or CHD, respectively) as defined as having had a coronary artery bypass procedure, coronary stent or angioplasty, or myocardial infarction in the previous six (6) months. History of cancer, other than non-melanoma skin cancer and basal cell carcinoma, within the previous five years. Poorly controlled or uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥95 mmHg). Recent history of prolonged alcohol (>3 months) use (within past six (6) months) or excessive alcohol use, defined as >14 drinks per week (one drink = 12 oz. beer, 4 oz. wine, 1.5 oz. hard liquor). Exposure to any investigational agent within four (4) weeks or five (5) half-lives, prior to the Screening Visit. Subjects planning to undergo surgery during the study period or up to 1 month after the study Any serious psychiatric disease or disorder, which, in the opinion of the investigator, would preclude the subject from participating in the study. Any known intolerance to the investigational ingredients of this investigational product. Has a condition the Investigator believes would interfere with the evaluation of the subject, or may put the subject at undue risk during the course of the study, including potentially abnormal lab results, due to a traumatic event.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 1X dose of NRPT<br>250 mg of NR and 50 mg of PT | Dietary Supplement: Group 1 NRPT<br>* Two capsules of NRPT and two placebo will be taken once daily in the morning for 26 weeks. Each NRPT capsule will contain 125 mg NR and 25 mg PT.<br>|
| Experimental: Group 2: 2X dose of NRPT<br>500 mg of NR and 100 mg of PT | Dietary Supplement: Group 2 NRPT<br>* Four capsules of NRPT will be taken once daily in the morning for 26 weeks. Each NRPT capsule will contain 125 mg NR and 25 mg PT.<br>|
| Placebo Comparator: Group 3: Placebo<br>Placebo capsules contain microcrystalline cellulose, silicon dioxide and magnesium stearate | Other: Group 3 Placebo<br>* Four placebo capsules will be taken once daily in the morning for 26 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fatty Liver Index | Change from Baseline in Fatty Liver Index (FLI) will be evaluated within each subject and compared between treatment groups. FLI: = (e^0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (GGT) + 0.053*waist circumference - 15.745) / (1 + e^0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (GGT) + 0.053*waist circumference - 15.745) * 100. | 6 months | 
| Change in Hepatic Fat Fraction | Change from Baseline in mean percent HFF across all nine Couinaud segments will be evaluated within each subject and compared between treatment groups. | 6 months | 
| Change in Insulin Resistance (HOMA-IR) | Change from Baseline in HOMA-IR will be evaluated within each subject and compared between treatment groups. HOMA-IR: = ([glucose x insulin]/450) For this measure, the comparison is between the placebo and the two IP groups at end-of-study | 6 months | 
| Change in liver fat content | To determine if there is a dose effect of NRPT on changes from baseline in liver fat content compared to placebo, as determined by MRI-PDFF. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Adverse Events | To determine the safety of NRPT as measured by number of adverse events and serious adverse events. | 6 months | 
| Safety: LFT's | To determine the safety of NRPT as measured by change in liver function tests (AST U/L, ALT U/L, GGT U/L, Alk Phos U/L) from baseline. | 6 months |