Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients

This study will be a randomized, placebo-controlled cross-over trial. Patients who are considered eligible for the study will undergo screening evaluation to determine their eligibility for the trial. For those who are found to be eligible, during the baseline period, they will continue their usual diet and other lifestyle measures without changing any medications for 1 month in order to establish a baseline state. Three blood samples will be obtained during this period at the Clinical and Translational Research Center. Following the baseline period, the patients will receive obeticholic acid (OCA) or an identical placebo in the dose of 25 mg/day for a period of 4 months and then will receive the other treatment (OCA or placebo) for 4 months. There will be a wash-out period of 4 months in-between the two study periods.

Patients will be educated to maintain their usual physical activities and diet during the study. The subjects will be admitted to the Clinical and Translational Research Center for the baseline evaluations (at the beginning of the two study periods), and at the end of four months during each study period.

• Obeticholic Acid (Drug), also known as NEW DRUG APPLICATION: Capsules of obeticholic acid (OCA) or an identical placebo in the dose of 25 mg/day for a period of 4 months .
• Placebo (Drug), also known as Identical to Obeticholic Acid placebo drug: Identical to Obeticholic Acid - placebo drug

Primary outcomes

• Change in the Liver Triglycerides (TG). [Baseline, 4 months]: 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).

Secondary outcomes

• Change in Serum Triglyceride Levels [Baseline, Month 4]: Change in the serum levels of Triglycerides from baseline to month 4 is being assessed.
• Change in Serum Levels of Alanine Aminotransferase [Baseline, Month 4]: Change in serum levels of Alanine Aminotransferase from baseline to month 4 is assessed
• Change in Serum Levels of Aspartate Aminotransferases [Baseline, Month4]: Change in serum levels of Aspartate Aminotransferases from baseline to month 4 is assessed
• Change in Serum Levels of Gamma-Glutamyl Transpeptidase [Baseline, Month 4]: Change in serum levels of Gamma-Glutamyl Transpeptidase from baseline to month 4 is assessed
• Changes in Serum Insulin Levels [Baseline, Month 4]: Changes in serum Insulin levels is assessed
• Change in Hepatic Insulin Sensitivity [Baseline, Month 4]: Change in hepatic insulin sensitivity is assessed by suppression of hepatic glucose output during the low-dose and high-dose insulin infusions during the euglycemic clamp study.

Sex: All, ages: 18 Years to 70 Years

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%.

Participant flow

Outcome results

• Change in the Liver Triglycerides (TG). (Primary), Median, percentage of liver triglycerides: Baseline (Month 0) 13.2 (2.8 to 28.5); Obeticholic Acid (Month 4) 6.4 (2.4 to 18.0); Placebo (Month 0) 12.3 (3.6 to 33.3); Placebo (Month 4) 10.6 (3.4 to 29.3)
• Change in Serum Triglyceride Levels (Secondary), Median, mg/dL: Baseline (Month 0) 199.2 (78 to 392); Obeticholic Acid (Month 4) 182.3 (102 to 309.3); Placebo (Month 0) 169.3 (103.5 to 562.0); Placebo (Month 4) 161.3 (93 to 655)
• Change in Serum Levels of Alanine Aminotransferase (Secondary), Median, U/L: Baseline (Month 0) 16.3 (13.5 to 31); Obeticholic Acid (Month 4) 15.8 (13 to 42.5); Placebo (Month 0) 19.0 (11 to 33.5); Placebo (Month 4) 18.5 (12.6 to 33)
• Change in Serum Levels of Aspartate Aminotransferases (Secondary), Median, U/L: Baseline (Month 0) 15.5 (13.5 to 35.5); Obeticholic Acid (Month 4) 16.8 (13.7 to 27); Placebo (Month 0) 18.7 (13.5 to 28.5); Placebo (Month 4) 16.5 (12.5 to 31)
• Change in Serum Levels of Gamma-Glutamyl Transpeptidase (Secondary), Median, U/L: Baseline (Month 0) 27.5 (16.3 to 64); Obeticholic Acid (Month 4) 17 (10.6 to 45.7); Placebo (Month 0) 21.6 (14.6 to 109); Placebo (Month 4) 21.2 (13.5 to 66)
• Changes in Serum Insulin Levels (Secondary)
• Change in Hepatic Insulin Sensitivity (Secondary)

Adverse events

Time frame: 4 months for each intervention separated by a 4-month washout period, approximately 12 months total

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2019-08-02)
• Informed Consent Form (PDF, 2018-04-16)

• Abhimanyu Garg, MD, Principal investigator, University of Texas Southwestern Medical Center