Use of a Novel Drug in People With Non-alcoholic Steatohepatitis (NASH) or Non-alcoholic Fatty Liver Disease (NAFLD)

Study Overview
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Brief Summary
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Does the novel drug decrease liver fat in subjects with NASH or NAFLD as compared to placebo

Detailed Description
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We propose to evaluate hepatic fat and hepatic fibrosis using magnetic resonance elastography (MRE) liver (pre vs. post). We will also establish glucose tolerance status by our established labeled oral glucose tolerance test (OGTT) (6,6 ²H2 glucose). Following baseline evaluation subjects with biopsy/MRE proven NASH will be randomized to one of two groups and treated either with active drug (AZ compound) or placebo for 12 weeks (plus or minus 1 week). Subjects with history suggestive of non-alcoholic fatty liver disease (NAFLD) or NASH will be invited to participate. If they meet criteria following initial screening they will be included in the study. OGTT, liver MRE will be repeated. Liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT),alkaline phosphatase (ALP)] as well as other safety tests [creatine phosphokinase (CPK), thyroid stimulating hormone (TSH), international normalized ratio (INR),total bilirubin] will be measured before, monthly during therapy and at one month following therapy. Furthermore, we will also do the subgroup analysis in NASH/NAFLD subjects with and without diabetes to see the effect of the drug.

Official Title
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A Randomized, Double-Blinded, Placebo-controlled Phase IIa Study to Assess the Efficacy and Safety of a Novel AstraZeneca Compound in Subjects With Non-alcoholic Steatohepatitis (NASH) or Non-alcoholic Fatty Liver Disease (NAFLD)

Conditions
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Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: AZ compound
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 21-75 Body Mass Index (BMI) >19 kg/m^2 Subjects with biopsy/MRE proven NASH [MRE liver fat ≥ 5%, with elevated liver enzymes ALT <5x upper limit normal (ULN)]. Subjects with NAFLD and MRE shows F0 or greater fibrosis Subjects with history suggestive of NAFLD/NASH Total bilirubin must be < 1.5 x ULN and INR must be < 1.3 at baseline screening. TSH and CPK will be within normal limits (WNL) at screening. Subjects with type 2 diabetes who are on stable doses of medications (except pioglitazone) to control hyperglycemia and have baseline HbA1c of 10% or lower. Hemoglobin must be greater than or equal to 12.0 in males and 11.0 in females. Exclusion Criteria: Medications that may affect glucose metabolism such as corticosteroids, opiates, barbiturates, and anticoagulants. Subjects with anemia, and symptoms suggestive of undiagnosed illness, overt hepatic disease, stroke, Alzheimer's disease, autoimmune hepatitis, alcoholism or increased alcohol consumption over the American Diabetes Association (ADA) guidelines. Any disorder that may potentially impact the outcome measures. Pregnant women and children. Subjects planning weight loss or in any weight loss program. Subjects taking TZD's, Atazanavir, Indinavir, Ketoconazole, Valproic acid, Silybum marianum and Valeriana officinalis.

Ages Eligible for Study
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Minimum Age: 21 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active drug AZ compound<br>AZ compound 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg). | Drug: AZ compound<br>* AZ compound 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg).<br>|
| Placebo Comparator: Placebo<br>Placebo 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg). | Other: Placebo<br>* Placebo 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Hepatic Fat | Percentage Hepatic fat measured using Magnetic Resonance Imaging (Proton Density Fat Fraction). A cut-off of <5% is used to distinguish between normal and fatty liver. | baseline, approximately 12 weeks | 
| Number of Participants With no Conversion of [13C] Cortisone to [13C] Cortisol | Hepatic conversion of [13C] cortisone to [13C] cortisol was assessed before and after the treatment in both groups using the triple tracer cortisol test. | baseline, approximately 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver Fibrosis Measured With MRE in kPa | Liver fibrosis will be measured with Magnetic Resonance Enterography (MRE) at baseline and then compared after  12 weeks of treatment. A clinical cut-off of 2.93 kPa was used to classify the results as either normal or elevated liver stiffness. Change in Liver fibrosis (kPa) is compared in between the groups. | baseline, approximately 12 weeks | 
| Total Insulin Sensitivity (Si) and Hepatic Insulin Sensitivity (Si Liver) | Total insulin sensitivity (Si) and hepatic insulin sensitivity (Si liver) will be measured with an Oral glucose Tolerance test at baseline and after  12 weeks of treatment. | baseline, approximately 12 weeks |