Hepatic Steatosis
Conditions
Keywords
lipodystrophy
Brief summary
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.
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.
Interventions
DRUGCholic 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.
Sponsors
FDA Office of Orphan Products Development
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic Triglyceride (%) | 6 months | Measured by proton magnetic resonance spectroscopy (MRS) |
Secondary
| Measure | Time frame |
|---|---|
| Serum Triglycerides | Months 6 |
Countries
United States
Participant flow
Recruitment details
Recruitment December 2006 through April 2010. A total of 37 subjects were screened for this trial.
Participants by arm
| Arm | Count |
|---|---|
| Characteristics of All Patients Enrolled Participants who were randomized to receive either Cholic acid or Placebo | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention 1 (6 Months) | Lost to Follow-up | 3 | 0 |
| Intervention 1 (6 Months) | unrelated illness | 0 | 2 |
| Intervention 2 (6 Months) | Unrelated illness ineligible for MRS | 0 | 1 |
Baseline characteristics
| Characteristic | Characteristics of All Patients Enrolled |
|---|---|
| Age, Continuous | 46 years STANDARD_DEVIATION 15.3 |
| Hepatic TG (%) | 23.89 Fat/Fat+Water (%) |
| Serum Triglyceride | 389 mg/dL |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 5 / 14 | 4 / 15 |
| serious Total, serious adverse events | 0 / 14 | 0 / 15 |
Outcome results
Primary
Hepatic Triglyceride (%)
Measured by proton magnetic resonance spectroscopy (MRS)
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cholic Acid | Hepatic Triglyceride (%) | 15.9 Fat/Fat+Water (%) |
| Placebo | Hepatic Triglyceride (%) | 14.8 Fat/Fat+Water (%) |
p-value: 0.4295% CI: [-19.7, 61.1]Mixed Models Analysis
Secondary
Serum Triglycerides
Time frame: Months 6
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cholic Acid | Serum Triglycerides | 390 mg/dL |
| Placebo | Serum Triglycerides | 340 mg/dL |
p-value: 0.4595% CI: [-17.7, 50.8]Mixed Models Analysis