Cholic Acid for Hepatic Steatosis in Lipodystrophy

Phase II Study of Cholic Acid for Hepatic Steatosis in Lipodystrophy Patients

To evaluate the efficacy and safety of cholic acid therapy in treating lipodystrophy patients with hepatic steatosis. This is a randomized, double-blind, placebo-controlled cross-over study.

Study Overview

• Status: Completed
• Conditions: Hepatic Steatosis
• Intervention / Treatment: Drug: Cholic Acid

Detailed Description

Lipodystrophies are rare disorders characterized by selective loss of adipose tissue and predisposition to develop insulin resistance and its associated metabolic complications such as dyslipidemia, diabetes mellitus and hepatic steatosis. Nonalcoholic hepatic steatosis or steatohepatitis caused by excessive accumulation of triglycerides in hepatocytes, in fact, is a common feature of these disorders. Often a cause for significant morbidity and even mortality in lipodystrophic patients, hepatic steatosis poses a significant therapeutic challenge. Recent insight into the role of primary bile acids, cholic acid and chenodeoxycholic acid, which are endogenous ligands for the farnesoid X receptor (FXR), in regulating hepatic triglyceride homeostasis offers new treatment options for hepatic steatosis. Cholic acid was shown to inhibit hepatic triglyceride accumulation by more than 50% in a mouse model of hepatic steatosis and hypertriglyceridemia. Cholic acid has been previously used to treat inborn errors of bile acid synthesis in children without any side effects. In other studies in adults, cholic acid has been reported to be well tolerated. Therefore, we propose to investigate a potentially safe therapeutic option for its efficacy in reducing hepatic steatosis in patients with lipodystrophies.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390-9052
      • University of Texas Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with lipodystrophies as diagnosed by clinical criteria.
• Hepatic steatosis (>5.6% hepatic triglyceride content) as demonstrated by 1H magnetic resonance spectroscopy.
• Age 6-70 years.
• Alcohol intake of less than 40 g per week.

Exclusion Criteria:

• Laboratory or other histologic findings highly suggestive of liver disease due to causes other than non-alcoholic steatohepatitis, such as chronic viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, biliary obstruction or genetic liver diseases such as Wilson's disease, hemochromatosis or alpha-1-antitrypsin deficiency.
• Treatment with drugs associated with steatohepatitis, e.g., corticosteroids, high dose estrogens, methotrexate, amiodarone, , sulfasalazine, or oxacillin in the 6 months prior to the study.
• Decompensated liver disease as evidenced by clinical features of hepatic failure (variceal bleeding, ascites, hepatic encephalopathy etc.) and laboratory investigations (prolonged prothrombin time, hypoalbuminemia, presence of esophageal varices etc.)
• Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver mass on imaging study suggestive of liver cancer.
• Use of drugs which can potentially decrease hepatic steatosis during previous 3 months; ursodeoxycholic acid, high-dose vitamin E, betaine, acetylcysteine and choline. Thiazolidinediones are allowed if dose has been stable for 3 months prior to screening.
• Significant systemic or major illnesses other than liver disease, such as congestive heart failure, cerebrovascular disease, respiratory failure, renal failure (serum creatinine >2 mg/dL), acute pancreatitis, organ transplantation, serious psychiatric disease, and malignancy, that could interfere with the trial and adequate follow up.
• Acute medical illnesses precluding participation in the studies.
• Known HIV-infected patient.
• Current substance abuse.
• Pregnant or lactating women.
• Hematocrit of less than 30%. - History of weight loss during past 3 months.
• Patients on bile acid binding resins, cholestyramine, colestipol, colesevelam.
• Hypersensitivity or intolerance to CA or any components of its formulation

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cholic Acid active capsules; Cholic Acid weight based dose for 6 months double-blind	Drug: Cholic Acid; Capsules of active Cholic Acid or matching placebo, total dose is 15 mg/kg per day, maximum dose of 1500 mg per day, taken PO, BID.
Placebo Comparator: Placebo for Cholic Acid; Placebo for Cholic Acid for 6 months double-blind	Drug: Cholic Acid; Capsules of active Cholic Acid or matching placebo, total dose is 15 mg/kg per day, maximum dose of 1500 mg per day, taken PO, BID.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic Triglyceride (%)	Measured by proton magnetic resonance spectroscopy (MRS)	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Serum Triglycerides	Months 6

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: FDA Office of Orphan Products Development
• Investigators: Principal Investigator: Abhimanyu Garg, M.D., University of Texas Southwestern Medical Center

Publications and helpful links

General Publications

• Ahmad Z, Subramanyam L, Szczepaniak L, Simha V, Adams-Huet B, Garg A. Cholic acid for hepatic steatosis in patients with lipodystrophy: a randomized, controlled trial. Eur J Endocrinol. 2013 Apr 15;168(5):771-8. doi: 10.1530/EJE-12-0969. Print 2013 May.

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: April 4, 2007
• First Submitted That Met QC Criteria: April 4, 2007
• First Posted (Estimate): April 6, 2007

Study Record Updates

• Last Update Posted (Actual): January 17, 2019
• Last Update Submitted That Met QC Criteria: January 16, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: lipodystrophy
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Skin Diseases; Liver Diseases; Lipid Metabolism Disorders; Skin Diseases, Metabolic; Fatty Liver; Lipodystrophy; Gastrointestinal Agents; Cholic Acids
• Other Study ID Numbers: 3085; FD003085

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No