Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients

NCT02430077 | Completed Phase 2 Results DMC

• 1 other identifier: STU 062014-033
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

Brief Summary

Lipodystrophies are rare disorders characterized by selective loss of adipose tissue and predisposition to insulin resistance and its metabolic complications. Hepatic steatosis is a common complication in patients with partial and generalized lipodystrophies.Despite aggressive management of diabetes and hyperlipidemia, hepatic steatosis and its complications present a therapeutic challenge in many patients. Due to this large disease burden, it is important to assess the efficacy and safety of novel therapies for hepatic steatosis in patients with lipodystrophies.There are, however, no systematic studies evaluating various therapeutic interventions for reducing hepatic steatosis in patients with lipodystrophies. A variety of drugs have been investigated in nonlipodystrophic patients with non-alcoholic hepatic steatosis and steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). Recent data support the activation of the farnesoid X receptor (FXR, NR1H4), a nuclear hormone receptor regulated by bile acids, for treatment of NASH and NAFLD. FXR activates transcription of several genes particularly the atypical nuclear receptor small heterodimer partner (SHP, NR0B2) and thus can influence triglyceride metabolism within hepatocytes.Both cholic acid (CA) and chenodeoxycholic acid (CDCA) are ligands for FXR, however, UDCA which is the 7 hydroxy β-epimer of CDCA, does not activate FXR. Obeticholic acid (OCA) is a first-in-class selective FXR agonist which has approximately 100 fold greater FXR-agonistic activity in the nanomolar range, as compared to CDCA .It therefore appears that FXR modulation offers interesting therapeutic possibilities in treating hepatic steatosis. This study is primarily designed to study efficacy of OCA, a strong FXR ligand, in reducing hepatic triglyceride levels in patients with hepatic steatosis and Familial Partial Lipodystrophy (FPLD). If proven to be effective, it may reduce morbidity and mortality as a result of sequelae of hepatic steatosis in patients with lipodystrophies.

Conditions

Familial Partial Lipodystrophy

Keywords

Hepatic Steatosis

Outcome Measures

Primary Outcomes (1)

• Change in the Liver Triglycerides (TG).

  The primary end-point variable was the change in the liver TG content assessed using proton-density fat fraction mapping by Magnetic Resonance Imaging (MRI).

  Baseline, 4 months

Secondary Outcomes (6)

• Change in Serum Triglyceride Levels

  Baseline, Month 4

• Change in Serum Levels of Alanine Aminotransferase

  Baseline, Month 4

• Change in Serum Levels of Aspartate Aminotransferases

  Baseline, Month4

• Change in Serum Levels of Gamma-Glutamyl Transpeptidase

  Baseline, Month 4

• Changes in Serum Insulin Levels

  Baseline, Month 4

Study Arms (2)

Active capsule of Obeticholic acid

EXPERIMENTAL

Patient will receive obeticholic acid (OCA) in the dose of 25 mg/day for a period of 4 months.

Drug: Obeticholic Acid

Pacebo for Obeticholic acid

PLACEBO COMPARATOR

Patient will recieve placebo in the dose of 25 mg/day for a period of 4 months.

Drug: Placebo

Interventions

Obeticholic Acid DRUG

Capsules of obeticholic acid (OCA) or an identical placebo in the dose of 25 mg/day for a period of 4 months .

Also known as: NEW DRUG APPLICATION

Active capsule of Obeticholic acid

Placebo DRUG

Identical to Obeticholic Acid - placebo drug

Also known as: Identical to Obeticholic Acid placebo drug

Pacebo for Obeticholic acid

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with familial partial lipodystrophy of the Dunnigan variety with heterozygous disease-causing missense mutation in lamin A/C (LMNA) gene.
• Hepatic steatosis (\>5.6% hepatic triglyceride content) as demonstrated by 1H magnetic resonance spectroscopy.
• Age 18-70 years.
• Alcohol intake of less than 20 g per day in females and 30 g per day in males.
• Participants and their partners with whom they are having sex, must use medically-acceptable birth control (contraceptives) during the study. Medically-acceptable methods of contraception include: (1) surgical sterilization, such as hysterectomy, tubal ligation or vasectomy. (2) approved hormonal contraceptives, such as birth control pills, patch or ring; Depo-Provera, Implanon. (3) barrier methods, such as condom, cervical cap or diaphragm used with a spermicide. (4) an intrauterine device (IUD).

You may not qualify if:

• 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, tamoxifen, valproic acid, sulfasalazine, or oxacillin for more than 2 weeks 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 with INR \> 1.3, hypoalbuminemia with serum albumin less than 3.0 g/dL, direct bilirubin \> 1.3 mg/dL, or 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, thiazolidinediones, high-dose vitamin E, betaine, acetylcysteine and choline.
• 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 woman.
• Hematocrit of less than 30%.
• History of weight loss during past 3 months.
• Patients on bile acid binding resins, cholestyramine, colestipol or colesevelam.
• Hypersensitivity or intolerance to OCA or any components of its formulation.
• Failure to give informed consent 16 .Previous clinical diagnosis of diabetes mellitus or fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%.

Sponsors & Collaborators

• Abhimanyu Garg: lead

Study Sites (2)

UT Southwestern Medical Center 5323 Harry Hines Blvd

Dallas, Texas, 75390-8537, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Lipodystrophy, Familial Partial; Fatty Liver

Interventions

obeticholic acid; Investigational New Drug Application

Condition Hierarchy (Ancestors)

Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipodystrophy; Skin Diseases, Metabolic; Skin Diseases; Skin and Connective Tissue Diseases; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Drug Approval; Drug Development; Investigative Techniques; Evaluation Studies as Topic

Results Point of Contact

• Title: Abhimanyu Garg
• Organization: UT Southwestern Medical Center

Abhimanyu.garg@utsouthwestern.edu

2146482895

Study Officials

• Abhimanyu Garg, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: PROFESSOR, Internal Medicine

Study Record Dates

• First Submitted: April 24, 2015
• First Posted: April 29, 2015
• Study Start: June 1, 2016
• Primary Completion: October 1, 2022
• Study Completion: December 1, 2022
• Last Updated: August 27, 2024
• Results First Posted: December 13, 2023

Record last verified: 2024-08

Locations

US (2)