The Effect Of NS-0200 Versus Placebo On Hepatic Fat Content In Patients With Non Alcoholic Fatty Liver Disease

Study Overview
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Brief Summary
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The goal of this study is to determine if NS-0200 can reduce the amount of liver fat in patients diagnosed with non-alcoholic fatty liver disease (NAFLD). This study will compare two doses of NS-0200 to placebo in NAFLD patients.

Detailed Description
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This is a randomized, 16-week, placebo-controlled, double-blind study to evaluate the effect of two fixed-dose combinations of leucine, metformin and sildenafil, NS-0200 compared to placebo, on the reduction of liver fat in patients diagnosed with non-alcoholic fatty liver disease (NAFLD). Subjects meeting all the inclusion criteria and no exclusion criteria will be randomized to one of three study arms. The primary objective of this study is to evaluate the change in hepatic fat content assessed by proton-density-fat-fraction (PDFF) employing magnetic resonance imaging (MRI) in subjects from : Screening/Visit 2 (Day-7/Week-1) to Study Termination/Visit 8 (Day 112/Week 16) receiving two fixed-dose combinations of leucine, metformin and sildenafil compared to placebo. Secondary objectives will also assess changes in serum alanine aminotransferase (ALT) activity, change in circulating cytokeratin 18, a surrogate marker of necro-inflammation, change in HbA1c, change in fasting glucose, insulin and insulin sensitivity, change in blood lipids such as cholesterol, LDL, HDL, triglycerides, and changes in in C-reactive protein. In addition this study will evaluate the safety and tolerability of NS-0200. Patients will have two screening visits, the first to determine their eligibility based on lab tests and the second based on the percentage of hepatic fat assessed by MRI imaging. Once qualified, patients will be randomly assigned to either one of the treatment groups or the placebo control group and monitored for a total of 16 weeks. Patients will return to the clinic each month for lab tests, and routine examinations. At the conclusion of the treatment period patients will again undergo an MRI scan to examine the percentage of hepatic fat.

Official Title
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A Randomized, Blinded, Placebo-Controlled Study To Evaluate The Effect Fixed-Dose Leucine, Metformin, Sildenafil Combinations(NS-0200) Versus Placebo On Hepatic Fat Assessed By MRI In Non Alcoholic Fatty Liver Disease Patients

Conditions
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NAFLD

Intervention / Treatment
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* Drug: Leu-Met-Sil 0.5
* Drug: Leu-Met-Sil 1.0
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 at study entry. Is male, or female and, if female, meets all of the following criteria: Not breastfeeding Post-menopausal or negative serum pregnancy test result (human chorionic gonadotropin, beta subunit [β-hCG]) at Screening /Visit 1 (Day-14/Week-2) (not required for hysterectomized females) If of childbearing potential (including peri-menopausal women who have had a menstrual period within one year) must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as double barrier methods [male condom with spermicide, with or without cervical cap or diaphragm], implants, injectables, oral contraceptives [must have been using for at least the last 3 months], some intrauterine contraceptive devices, tubal ligation, or in an established relationship with a vasectomized partner) during the entire duration of the study. Has been diagnosed with NAFLD via CT (positive for excess liver fat), ultrasound (positive for excess liver fat), MRI (PDFF showing > 15% liver fat) or via biopsy (showing >33% fat) within the past six months. If diagnosis was between 3 and 6 months prior to Screening, an ultrasound (positive for excess liver fat) is required prior to the Screening /Visit 1 (Day-14/Week-2) MRI. Has liver fat (as measured by PDFF via MRI) greater than 15% at Screening/Visit 2 (Day-7/Week-1) Has had ALT levels >30 U/L for men, >19 U/L for women measured within 8 weeks of enrollment Has an HbA1c equal to or less than 9% at Screening /Visit 1 (Day-14/Week-2) Has a BMI between 25kg/m2 and 40 kg/m2 Otherwise stable health for preceding twelve weeks Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) either normal or with abnormalities consistent with NAFLD. Is able to read, understand, and sign the informed consent forms (ICF) and, when applicable, an authorization to use and disclose protected health information form (consistent with Health Insurance Portability and Accountability Act of 1996 [HIPAA] legislation), communicate with the investigator, and understand and comply with protocol requirements. - Exclusion Criteria: Clinically significant renal dysfunction defined as a serum creatinine concentration >1.4 mg/dL (females) or >1.6 mg/dL (males) or a blood urea nitrogen concentration >45 mg/dL at screening. Use of any of the following medications: Metformin Combination drugs that include Metformin Sildenafil Tadalafil Vardenafil Pioglitazone Rosiglitazone Short acting insulins An alpha blocker Oral nitrates Medications associated with increased hepatic steatosis Insulins OCT2/MATE inhibitors (e.g. cimetidine, quinidine, and pyrimethamine) Methotrexate Tamoxifen Corticosteroids (Nasal steroids are allowed if the subject has been on a stable dose for the past 12 weeks and the dose employed does not exceed the maximal recommended dose.) Estrogens Amiodarone Valproic acid Coumadin Isoniazide Nucleoside analogues used for the treatment of HIV infections Any dietary supplement other than multi-vitamins Evidence of significant alcohol consumption (defined as >7 drinks/week for females and >14 drinks/week for males) within 6 months prior to randomization or presence or suspicion of other forms of chronic liver disease (e.g., cirrhosis, autoimmune hepatitis (>1:160 ANA), Wilson's disease, Hemochromatosis (Ferritin >1000 ug/L and percent iron saturation >45%), hepatitis A, B or C) Has a clinically significant medical condition that could potentially affect study participation and/or personal well-being, as judged by the investigator, including but not limited to the following conditions: Unable to undergo MRI or contraindications for MRI procedure History of cardio- or cerebro-vascular disease event within the previous 6 months Requires anti-coagulation therapy Gastrointestinal disorders including, but not limited to, the following: pancreatitis, inflammatory bowel disease, or other diseases associated with malabsorption or persistent abdominal discomfort Endocrine disorders other than type 2 diabetes and hypothyroidism on stable replacement therapy Chronic infection (e.g., tuberculosis, human immunodeficiency virus infection, hepatitis A virus, hepatitis B virus, or hepatitis C virus) Neurological or psychiatric diseases that preclude valid execution of informed consent or may interfere with the subject's compliance with study procedures (e.g., major depressive disorder within the last 2 years, a history of suicidal behavior in the last 3 months) History of other psychiatric disorders including schizophrenia and bipolar disorder) Participation in a weight loss program within the past 3 months. Weight change ≥5% during the past month. History of substance abuse (including alcohol abuse as defined above) in the past 3 months or a positive screen for drugs of abuse or alcohol at screening. Has received any investigational drug within 3 months of Screening. Has donated blood within 3 months before Screening or is planning to donate blood during the study. Has had a serious infection, such as pneumonia in the previous 12 weeks Has known allergies or hypersensitivity to metformin, sildenafil or leucine Is an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at the clinical study site, or NuSirt Biopharma. Is employed by NuSirt Biopharma (defined as an employee, temporary contract worker, or designee responsible for the conduct of the study). -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Leu Met Sil 0.5mg<br>Leu-Met-Sil 0.5: 3 capsules BID consisting of 2 capsules containing 550 mg L-leucine each and 1 capsule containing 500 mg metformin and 0.5 mg of sildenafil. | Drug: Leu-Met-Sil 1.0<br>* NS-200 high dose<br>* Other names: NS-0200-1.0;|
| Experimental: Leu Met Sil 1.0mg<br>Leu-Met-Sil 1.0: 3 capsules BID consisting of 2 capsules containing 550 mg L-leucine each and 1 capsule containing 500 mg metformin and 1.0 mg of sildenafil. | Drug: Leu-Met-Sil 0.5<br>* NS-0200 low dose<br>* Other names: NS-0200-0.5;Drug: Leu-Met-Sil 1.0<br>* NS-200 high dose<br>* Other names: NS-0200-1.0;|
| Placebo Comparator: Placebo<br>Placebo: 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) | Drug: Placebo<br>* Placebo<br>* Other names: Control arm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hepatic Fat | To evaluate the change in hepatic fat content assessed by proton-density-fat-fraction (PDFF) employing magnetic resonance imaging (MRI). | Baseline, Day 112 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum AlanineAaminotransferase (ALT) Levels | Serum AlanineAminotransferase (ALT) will be examined through standard blood chemistry | Baseline, Day 112 | 
| Change in Circulating Cytokeratin 18 Fragments (M30) | Change in Circulating Cytokeratin 18 Fragments (M30) from Baseline to Week 16 will be examined through standard blood chemistry | Baseline, Day 112 | 
| Change in Heamoglobin A1c (HbA1c) | HbA1c will be examined through standard blood chemistry | Baseline, Day 112 | 
| Change in Fasting Glucose | Fasting glucose will be examined through standard fasting blood chemistry | Baseline, Day 112 | 
| Change in Insulin | Insulin levels will be examined through standard blood chemistry | Baseline, Day 112 | 
| Change in Blood Lipids (Cholesterol) | Lipid levels such as cholesterol will be examined by standard blood chemistry | Baseline, Day 112 | 
| Change in Blood Lipids (High Density Lipoprotein:HDL) | Lipid levels such as HDL will be examined by standard blood chemistry | Baseline, Day 112 | 
| Change in Low Density Lipoproteins (LDL) | Lipid levels such as LDL will be examined by standard blood chemistry | Baseline, Day 112 | 
| Change in Triglycerides | Lipid levels such as triglycerides will be examined by standard blood chemistry | Baseline, Day 112 | 
| Change in C-reactive Protein | CRP levels will be examined by standard blood chemistry | Baseline, Day 112 | 
| Change in Insulin Sensitivity (HOMA-IR) | HOMA-IR levels will be examined by standard blood chemistry | Baseline, Day 112 |