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

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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:
Information provided by (Responsible Party):
NuSirt Biopharma

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.


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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


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




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



Information from the National Library of Medicine

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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.

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).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02546609


Locations
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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
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Study Director: Orville Kolterman, MD NuSirt Biopharma

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Responsible Party: NuSirt Biopharma
ClinicalTrials.gov Identifier: NCT02546609     History of Changes
Other Study ID Numbers: NS-0200-01
First Posted: September 11, 2015    Key Record Dates
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:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
Metformin
Sildenafil Citrate
Hypoglycemic Agents
Physiological Effects of Drugs
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents