A Study to Assess ARI-3037MO on Hepatic Fat Metabolism in Patients With Dysglycemia and Evidence of Hepatic Steatosis

Study Overview
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Brief Summary
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Primary objective To investigate the effect of a 24-week, twice daily dosing regimen of ARI-3037MO compared to placebo on plasma triglyceride (TG) levels, liver enzymes and hepatic fat content in patients with dysglycemia and hepatic steatosis due to nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Secondary Objective To investigate the safety and tolerability of a 24-week, twice daily dosing regimen of ARI-3037MO compared to placebo in patients with dysglycemia and evidence of NAFLD or NASH.

Detailed Description
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This randomized,double-blind, placebo-controlled study will enroll 36 men and women with a diagnosis of NAFLD orNASH. The study will be conducted over a period of approximately 28 wks and will include:a Screening Phase (Days -14to -1); a 24-week long Treatment Phase, during which patients will be randomly assigned to receive ARI-3037MO or placebo; an End-of-study Visit (ESV) scheduled 2 wks after the end of the Treatment Phase The Screening Phase will include 2 visits. Visit 1:There will be an initial assessment of a patient's eligibility for participation in the study. A complete medical history will be obtained and prospective study patients will undergo physical examinations and laboratory evaluations. For patients who have had a liver biopsy in the 6months prior to Visit 1, the histology findings, i.e., NAS, steatosis score and fibrosis score will be recorded. Visit 2:Approximately 1 week after Visit 1, and after the results of clinical laboratory screening test results have been reviewed by the Principal Investigator (PI), patients will be contacted to advise them of their eligibility to continue in the study. Eligible patients will undergo liver magnetic resonance imaging (MRI) to assess intrahepatic fat content. Treatment Phase Patients with MRI results showing intrahepatic fat content of ≥10% will be entered into the Treatment Phase of the study. The Treatment Phase will include 4 outpatient visits over a period of 24 weeks. Visit 3:Patients will be randomly assigned to receive ARI-3037MO or placebo on Day 1 of a 24-week long outpatient treatment period. Baseline assessments, including FibroTest®, FibroScan® and clinical laboratory tests, will be performed, and patients will take study drug twice daily. Visits 4, 5 and 6: During the Treatment Phase, patients will visit the study clinic at 4, 12 and 24 weeks (± 4 days) after Day 1 for evaluations and examinations and to collect study drug. Twenty-four weeks after the start of dosing, at the end of the Treatment Phase, patients will undergo a follow-up MRI and FibroScan† to assess change from baseline in intrahepatic fat content and liver fibrosis, respectively. †If FibroScan equipment is available at the study site End-of-Study Visit Visit 7:An ESV will occur 2 weeks (± 4 days) after the end of the Treatment Phase.

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Placebo
* Drug: ARI-3037MO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients ≥ 18 years of age at study entry Female patients must be of nonchildbearing potential Have a stable diet and agree to maintain this diet throughout the study Have not gained or lost ≥ 10 lbs (4.5 kg) of body weight within 6months prior to Screening Visit 1 Have a body mass index (BMI) between 28 and 45 kg.m-2, inclusive Have elevated alanine aminotransferase (ALT) levels. For men: 50 IU/L to 250 IU/L, inclusive. For women: 40 IU/L to 240 IU/L, inclusive. Have HbA1c of < 9.5 Have a intrahepatic fat content of ≥ 10% confirmed by liver MRI If taking antidiabetic therapies (excluding thiazolidines as per exclusion Criterion No. 13), i.e., metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, insulin; must be on a stable dose for at least 3months prior to Screening Visit 1. Similarly, if taking lipid lowering therapies; must be on a stable dose for at least 3 months prior to Screening Visit 1. Understands the study requirements and the treatment procedures, is willing to comply with all protocol-required evaluations and provides written informed consent before any study specific tests or procedures are performed Exclusion Criteria: A history of hepatic disease such as chronic hepatitis C virus or concurrent active hepatitis B virus (i.e., serum positive for hepatitis B surface antigen) Autoimmune hepatitis Primary biliary cirrhosis Sclerosing cholangitis Hereditary hemochromatosis History of chronic / repeat blood transfusion (i.e., ≥ 20 units of blood) Alpha-1 anti-trypsin deficiency Wilson's disease Thyroid disease Bariatric surgery within 5 years prior to Screening Visit 1 Hepatic disease due to substance abuse Have any concurrent disease or condition not listed above that, in the opinion of the PI, would make the patient unsuitable for participation in the study Currently taking thiazolidines (glitazone therapy, i.e., Rosiglitazone, Pioglitazone) Liver biopsy in the past 90 days with negative results for cirrhosis and steatosis No evidence of hepatic decompensation or elevated serum bilirubin > 1.5 times the upper limit of normal Estimated glomerular filtration rate < 60 mL/min according to the Modification of Diet in Renal Disease equation Known substance abuse Current smoker or a history of smoking (> 10 cigarettes, > 3 cigars or > 3 pipes/day) Current consumption of > 3 units of alcohol per day (> 21 units per week) for men and > 2 units of alcohol per day (> 14 units per week) for women Currently participating in another clinical study

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Control<br>|
| Experimental: ARI-3037MO<br>ARI-3037MO | Drug: ARI-3037MO<br>* Treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as measured by change in intra hepatic fat content | Change in intra hepatic fat content by MRI | 24 wks | 
| Efficacy as measured by change in plasma ALT levels | Change in plasma ALT levels from baseline | 24 wks | 
| Efficacy as measured by change in plasma TG levels | Change in plasma TG levels from baseline | 24 wks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as measured by the occurrence of flushing (number of episodes) and itching (number of episodes) | Occurrence of cutaneous symptoms | 24 wks | 
| Safety as measured by effect of ARI-3037MO on on glycemic control | Change in HbA1c levels from baseline | 24 wks | 
| Safety as measured by effect of ARI-3037MO on serum bilirubin, alkaline phosphatase, Prothrombin time and plasma albumin levels | Change of liver function tests from baseline | 24 wks | 
| Safety as measured by effect of ARI-3037MO on gastrointestinal systems; episodes of nausea, vomiting and diarrhea | occurrence of GI symptoms | 24 wks |