Study of Aramchol in Patients With Fatty Liver Disease or Nonalcoholic Steatohepatitis (Aramchol003)

A Phase II Placebo Controlled Randomised Study of Aramchol on Liver Triglyceride in Patients With Steatosis Due to NAFLD or NASH

Primary purpose: Compare the changes in liver triglycerides concentration in the Aramchol versus the placebo arm following three month treatment.

Secondary purpose: Comparing liver enzymes, markers of endothelial dysfunction, insulin resistance, SCD1 activity and cholesterol synthesis and lipid levels, between the Aramchol and the placebo arms.

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome; Nonalcoholic Steatohepatitis; Non-Alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Aramchol; Drug: Aramchol; Drug: Placebo

Detailed Description

A Phase II, multicenter, double blind, randomized, placebo controlled study on the effect of Aramchol on liver triglycerides concentration in patients with steatosis due to NAFLD or NASH

The purpose of the study is to test whether Aramchol will reduce safely and effectively liver fat concentration in patients with NAFLD and NASH.

Aramchol inhibits the liver enzyme Stearoyl Coenzyme A Desaturase (SCD). It reduces fatty acid synthesis while increasing fatty acid oxidation. It was shown to reduce liver fat in animal models with diet induced Fatty Liver. It has also marked hypocholesterolemic effects, mainly via upregulation of theABCA1 cholesterol transporter. It thus causes(incomplete) SCD inhibition while being antiatherogenic

Primary purpose: Compare the changes in liver triglycerides concentration in the Aramchol versus the placebo arm following three month treatment.

Secondary purpose: Comparing liver enzymes, markers of endothelial dysfunction, insulin resistance, SCD1 activity and cholesterol synthesis and lipid levels, between the Aramchol and the placebo arms.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Israel
  • Beer Sheva, Israel, 84101
    • Soroka Medical Center
  • Hadera, Israel, 38100
    • Hillel Yaffe Medical Center
  • Haifa, Israel, 34362
    • The Lady Davis Carmel Medical Center
  • Haifa, Israel, 31096
    • Rambam
  • Jerusalem, Israel, 91120
    • Hadassah Ein Kerem M.C
  • Kfar Saba, Israel, 44281
    • Meir Medical Center
  • Nazareth, Israel
    • Holy Family Hospital
  • Petah Tikva, Israel, 49100
    • Belinson,Rabin Medical Center
  • Rehovot, Israel, 76100
    • Kaplan M.C
  • Safed, Israel, 13100
    • Safed Ziv Hospital
  • Tel Aviv, Israel, 64239
    • The Tel Aviv Sourasky Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with histologically proven NAFLD or NASH based on a biopsy performed during the preceding 18 months fulfilling the following criteria:

  • At least 15% of hepatocytes showing steatosis,with Fibrosis of not more than stage 3, with at most bridging fibrosis.

Patients with a NAFLD activity score 0-2 will be considered to have NAFLD. Biopsies with an activity score of 3 or more will be considered NASH.

• Triglycerides concentration in the liver of 6% or more as measured by NMRS.
• At least two elevated serum ALT levels in the previous six months, with latest test within 2 months of trial.
• Normal or only slightly impaired synthetic liver function (serum albumin >3.5gm%, INR 0.8-1.3)
• Male or female aged 18-75 years.
• Negative pregnancy test at study entry for females of child bearing potential.
• Females of child bearing potential practicing reliable contraception throughout the study period.
• Signature of the written informed consent

Exclusion Criteria:

• Evidence of cirrhosis on liver biopsy.
• Evidence of fibrosis of more than stage 3 on liver biopsy.
• Patient with liver disease due to acute or chronic hepatitis A, B,C, HIV, and all other liver diseases affecting liver function. Patients with cysts, hemangiomas, or similar abnormalities, are accepted.
• BMI > 35 or >130 kg body weight
• Any other concomitant, significant: metabolic, infectious, inflammatory, neoplastic, or other non-liver disease.
• Various concomitant diseases requiring chronic steroid administration.
• Use of warfarin, metformin, thiaglitazones, insulin or current steroid therapy of more than 3 days.
• Use of other investigational agents < 30 days prior to the study.
• Pregnancy
• Daily alcohol intake > 10gm/day.
• Patients with symptoms of significant mental illness. Inability to cooperate or communicate with the investigator, who are unlikely to comply with the study requirements, or who are unable to give informed consent.
• Performance status: WHO performance status ≥4.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: high dose; Aramchol 300 mg daily (high dose)	Drug: Aramchol; 100mg/d tablets packaged in bottles given orally once a day in the morning within 10 minutes after breakfast for a total period time of 3 months; Other Names: Arachidyl amido cholanoic acid; Drug: Aramchol; 300 mg/d tablets packaged in bottles given orally once a day in the morning within 10 minutes after breakfast for a total period time of 3 months; Other Names: Arachidyl amido cholanoic acid
Experimental: low dose; 100 mg daily (low dose)	Drug: Aramchol; 100mg/d tablets packaged in bottles given orally once a day in the morning within 10 minutes after breakfast for a total period time of 3 months; Other Names: Arachidyl amido cholanoic acid; Drug: Aramchol; 300 mg/d tablets packaged in bottles given orally once a day in the morning within 10 minutes after breakfast for a total period time of 3 months; Other Names: Arachidyl amido cholanoic acid
Placebo Comparator: Placebo; Placebo and two doses will be compared. The Aramchol: placebo ratio is of 2:1.	Drug: Placebo; tablets packaged in bottles given orally once a day in the morning within approximately 10 minutes after breakfast

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The difference between initial and final liver triglyceride concentration (measured by NMRS) comparing the Aramchol and placebo treated patients.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparing secondary variables of liver, metabolic and endothelial functions between the Aramchol and the placebo arms.	Comparing liver enzymes, markers of endothelial dysfunction, insulin resistance, SCD1 activity and cholesterol synthesis and lipid levels, between the Aramchol and the placebo arms	3 months

Collaborators and Investigators

• Sponsor: Galmed Medical Reserch
• Collaborators: Hillel Yaffe Medical Center; Hadassah Medical Organization; Tel-Aviv Sourasky Medical Center; Meir Medical Center; Ziv Hospital; Beilinson Hospital, Petach Tikva,Israel; Kaplan Hospital ,Rehovot,Israel; Soroka Hospital,Beer Sheva,Israel; Rambam Hospital, Haifa, Israel; The Lady Davis Carmel Medical Center; Holy Family Hospital, Nazareth, Israel
• Investigators: Principal Investigator: Ran Oren, Doctor, Liver & Gastroenterology Department,The Tel Aviv Sourasky Medical Center

Publications and helpful links

General Publications

• Leikin-Frenkel A, Goldiner I, Leikin-Gobbi D, Rosenberg R, Bonen H, Litvak A, Bernheim J, Konikoff FM, Gilat T. Treatment of preestablished diet-induced fatty liver by oral fatty acid-bile acid conjugates in rodents. Eur J Gastroenterol Hepatol. 2008 Dec;20(12):1205-13. doi: 10.1097/MEG.0b013e3282fc9743.
• Gilat T, Leikin-Frenkel A, Goldiner I, Juhel C, Lafont H, Gobbi D, Konikoff FM. Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC). Hepatology. 2003 Aug;38(2):436-42. doi: 10.1053/jhep.2003.50348.
• Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, Oren R; FLORA Group. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014 Dec;12(12):2085-91.e1. doi: 10.1016/j.cgh.2014.04.038. Epub 2014 May 9.

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: February 17, 2010
• First Submitted That Met QC Criteria: March 25, 2010
• First Posted (Estimate): March 26, 2010

Study Record Updates

• Last Update Posted (Estimate): January 31, 2012
• Last Update Submitted That Met QC Criteria: January 30, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Insulin Resistance; Metabolic Syndrome; NAFLD; NASH; Fatty Liver; Endothelial Dysfunction; Liver Fat
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Insulin Resistance; Hyperinsulinism; Liver Diseases; Fatty Liver; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Gastrointestinal Agents; Cholic Acids
• Other Study ID Numbers: Aramchol NAFLD Phase-II