Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients
Condition: Familial Partial Lipodystrophy
MeSH terms: Lipodystrophy, Familial Partial; Lipodystrophy
Intervention: Obeticholic Acid; Placebo
Intervention description: Capsules of obeticholic acid (OCA) or an identical placebo in the dose of 25 mg/day for a period of 4 months .; Identical to Obeticholic Acid - placebo drug
Intervention MeSH terms: Chenodeoxycholic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Hepatic Steatosis

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients with familial partial lipodystrophy of the Dunnigan variety with heterozygous
             disease-causing missense mutation in lamin A/C (LMNA) gene.

          2. Hepatic steatosis (>5.6% hepatic triglyceride content) as demonstrated by 1H magnetic
             resonance spectroscopy.

          3. Age 18-70 years.

          4. Alcohol intake of less than 20 g per day in females and 30 g per day in males.

          5. 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).

        Exclusion Criteria:

          1. 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.

          2. 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.

          3. 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.)

          4. Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml
             and/or liver mass on imaging study suggestive of liver cancer.

          5. Use of drugs which can potentially decrease hepatic steatosis during previous 3
             months; ursodeoxycholic acid, thiazolidinediones, high-dose vitamin E, betaine,
             acetylcysteine and choline.

          6. 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.

          7. Acute medical illnesses precluding participation in the studies.

          8. Known HIV-infected patient.

          9. Current substance abuse.

         10. Pregnant or lactating woman.

         11. Hematocrit of less than 30%.

         12. History of weight loss during past 3 months.

         13. Patients on bile acid binding resins, cholestyramine, colestipol or colesevelam.

         14. Hypersensitivity or intolerance to OCA or any components of its formulation.

         15. Failure to give informed consent 16 .Previous clinical diagnosis of diabetes mellitus
             or fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%.