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

• ClinicalTrials.gov Identifier: NCT02546609
• Recruitment Status: Completed
• First Posted: September 11, 2015
• Results First Posted: May 2, 2018
• Last Update Posted: May 2, 2018
• Sponsor: NuSirt Biopharma
• Information provided by (Responsible Party): NuSirt Biopharma

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
NAFLD	Drug: Leu-Met-Sil 0.5; Drug: Leu-Met-Sil 1.0; Drug: Placebo	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 91 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: November 19, 2015
• Actual Primary Completion Date: November 30, 2016
• Actual Study Completion Date: January 31, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Leu Met Sil 0.5mg; 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; NS-200 high dose; Other Name: NS-0200-1.0
Experimental: Leu Met Sil 1.0mg; 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; NS-0200 low dose; Other Name: NS-0200-0.5; Drug: Leu-Met-Sil 1.0; NS-200 high dose; Other Name: NS-0200-1.0
Placebo Comparator: Placebo; Placebo: 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w)	Drug: Placebo; Placebo; Other Name: Control arm

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Change in Serum AlanineAaminotransferase (ALT) Levels [ Time Frame: Baseline, Day 112 ]
   Serum AlanineAminotransferase (ALT) will be examined through standard blood chemistry
2. Change in Circulating Cytokeratin 18 Fragments (M30) [ Time Frame: Baseline, Day 112 ]
   Change in Circulating Cytokeratin 18 Fragments (M30) from Baseline to Week 16 will be examined through standard blood chemistry
3. Change in Heamoglobin A1c (HbA1c) [ Time Frame: Baseline, Day 112 ]
   HbA1c will be examined through standard blood chemistry
4. Change in Fasting Glucose [ Time Frame: Baseline, Day 112 ]
   Fasting glucose will be examined through standard fasting blood chemistry
5. Change in Insulin [ Time Frame: Baseline, Day 112 ]
   Insulin levels will be examined through standard blood chemistry
6. Change in Blood Lipids (Cholesterol) [ Time Frame: Baseline, Day 112 ]
   Lipid levels such as cholesterol will be examined by standard blood chemistry
7. Change in Blood Lipids (High Density Lipoprotein:HDL) [ Time Frame: Baseline, Day 112 ]
   Lipid levels such as HDL will be examined by standard blood chemistry
8. Change in Low Density Lipoproteins (LDL) [ Time Frame: Baseline, Day 112 ]
   Lipid levels such as LDL will be examined by standard blood chemistry
9. Change in Triglycerides [ Time Frame: Baseline, Day 112 ]
   Lipid levels such as triglycerides will be examined by standard blood chemistry
10. Change in C-reactive Protein [ Time Frame: Baseline, Day 112 ]
    CRP levels will be examined by standard blood chemistry
11. Change in Insulin Sensitivity (HOMA-IR) [ Time Frame: Baseline, Day 112 ]
    HOMA-IR levels will be examined by standard blood chemistry

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 18-75 at study entry.

2. Is male, or female and, if female, meets all of the following criteria:

   1. Not breastfeeding
   2. 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)
   3. 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.
3. 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.
4. Has liver fat (as measured by PDFF via MRI) greater than 15% at Screening/Visit 2 (Day-7/Week-1)
5. Has had ALT levels >30 U/L for men, >19 U/L for women measured within 8 weeks of enrollment
6. Has an HbA1c equal to or less than 9% at Screening /Visit 1 (Day-14/Week-2)
7. Has a BMI between 25kg/m2 and 40 kg/m2
8. Otherwise stable health for preceding twelve weeks
9. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) either normal or with abnormalities consistent with NAFLD.

10. 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.

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Exclusion Criteria:

1. 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.

2. Use of any of the following medications:

   1. Metformin
   2. Combination drugs that include Metformin
   3. Sildenafil
   4. Tadalafil
   5. Vardenafil
   6. Pioglitazone
   7. Rosiglitazone
   8. Short acting insulins
   9. An alpha blocker
   10. Oral nitrates
   11. Medications associated with increased hepatic steatosis
   12. Insulins

   13. 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
   14. Any dietary supplement other than multi-vitamins
3. 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)

4. 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:

   1. Unable to undergo MRI or contraindications for MRI procedure
   2. History of cardio- or cerebro-vascular disease event within the previous 6 months
   3. Requires anti-coagulation therapy
   4. Gastrointestinal disorders including, but not limited to, the following: pancreatitis, inflammatory bowel disease, or other diseases associated with malabsorption or persistent abdominal discomfort
   5. Endocrine disorders other than type 2 diabetes and hypothyroidism on stable replacement therapy
   6. Chronic infection (e.g., tuberculosis, human immunodeficiency virus infection, hepatitis A virus, hepatitis B virus, or hepatitis C virus)
   7. 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)
   8. History of other psychiatric disorders including schizophrenia and bipolar disorder)
5. Participation in a weight loss program within the past 3 months.
6. Weight change ≥5% during the past month.
7. 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.
8. Has received any investigational drug within 3 months of Screening.
9. Has donated blood within 3 months before Screening or is planning to donate blood during the study.
10. Has had a serious infection, such as pneumonia in the previous 12 weeks
11. Has known allergies or hypersensitivity to metformin, sildenafil or leucine
12. 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.

13. Is employed by NuSirt Biopharma (defined as an employee, temporary contract worker, or designee responsible for the conduct of the study).

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Contacts and Locations

Locations

United States, California

Catalina Research Institute

Chino, California, United States, 91710

University of California San Diego

San Diego, California, United States, 92103

United States, Colorado

Rocky Mountain Research

Wheat Ridge, Colorado, United States, 80033

United States, Georgia

Atlanta Gastroenterology Associates

Atlanta, Georgia, United States, 30312

GI Specialists of Georgia

Marietta, Georgia, United States, 30060

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46202

United States, North Carolina

University of North Carolina Chapel Hill

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Sterling Research

Cincinnati, Ohio, United States, 45246

United States, Tennessee

Premier Clinical Research

Clarksville, Tennessee, United States, 37043

Gastro One

Germantown, Tennessee, United States, 38138

Quality Medical Research

Nashville, Tennessee, United States, 37211

United States, Virginia

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

Sponsors and Collaborators

NuSirt Biopharma

Investigators

• Study Director: Orville Kolterman, MD; NuSirt Biopharma

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zemel MB, Kolterman O, Rinella M, Vuppalanchi R, Flores O, Barritt AS 4th, Siddiqui M, Chalasani N. Randomized Controlled Trial of a Leucine-Metformin-Sildenafil Combination (NS-0200) on Weight and Metabolic Parameters. Obesity (Silver Spring). 2019 Jan;27(1):59-67. doi: 10.1002/oby.22346.

• Responsible Party: NuSirt Biopharma
• ClinicalTrials.gov Identifier: NCT02546609
• Other Study ID Numbers: NS-0200-01
• First Posted: September 11, 2015
• Results First Posted: May 2, 2018
• Last Update Posted: May 2, 2018
• Last Verified: April 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Digestive System Diseases