Clinical trial NCT01094158: Study of Aramchol in Patients With Fatty Liver Disease or Nonalcoholic Steatohepatitis
Official title: A Phase II Placebo Controlled Randomised Study of Aramchol on Liver Triglyceride in Patients With Steatosis Due to NAFLD or NASH
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-Alcoholic Fatty Liver Disease
Nonalcoholic Steatohepatitis
Metabolic Syndrome
Keywords: NAFLD
NASH
Fatty Liver
Metabolic Syndrome
Endothelial Dysfunction
Insulin Resistance
Liver Fat
Lead sponsor: Galmed Medical Reserch
Sponsor class: INDUSTRY
Collaborators: name: Tel-Aviv Sourasky Medical Center
name: Beilinson Hospital, Petach Tikva,Israel
name: Meir Medical Center
name: Kaplan Hospital ,Rehovot,Israel
name: Soroka Hospital,Beer Sheva,Israel
name: Hadassah Medical Organization
name: Hillel Yaffe Medical Center
name: Rambam Hospital, Haifa, Israel
name: The Lady Davis Carmel Medical Center
name: Holy Family Hospital, Nazareth, Israel
name: Ziv Hospital
First posted: 2010-03-26
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The difference between initial and final liver triglyceride concentration (measured by NMRS) comparing the Aramchol and placebo treated patients.
timeFrame: 3 months
Secondary outcomes:
measure: Comparing secondary variables of liver, metabolic and endothelial functions between the Aramchol and the placebo arms.
timeFrame: 3 months
Other outcomes:
Locations:
city: Beer Sheva
country: Israel
facility: Soroka Medical Center
city: Hadera
country: Israel
facility: Hillel Yaffe Medical Center
city: Haifa
country: Israel
facility: Rambam
city: Haifa
country: Israel
facility: The Lady Davis Carmel Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Ein Kerem M.C
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Nazareth
country: Israel
facility: Holy Family HOSPITAL
city: Petah Tikva
country: Israel
facility: Belinson,Rabin Medical Center
city: Rehovot
country: Israel
facility: Kaplan M.C
city: Safed
country: Israel
facility: Safed Ziv Hospital
city: Tel Aviv
country: Israel
facility: The Tel Aviv Sourasky Medical Center
Study officials:
affiliation: Liver & Gastroenterology Department,The Tel Aviv Sourasky Medical Center
name: Ran Oren, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.