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

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)

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

Study Overview

• Status: Terminated
• Conditions: Non-alcoholic Fatty Liver Disease (NAFLD); Non-alcoholic Steatohepatitis (NASH)
• Intervention / Treatment: Drug: AZ compound; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Yogesh Yadav

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Rita Basu, MD, University of Virginia

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Actual): September 1, 2019
• Study Completion (Actual): September 1, 2019

Study Registration Dates

• First Submitted: September 18, 2015
• First Submitted That Met QC Criteria: November 11, 2015
• First Posted (Estimated): November 16, 2015

Study Record Updates

• Last Update Posted (Actual): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: 15-000013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No: There is not a plan to make IPD available

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No