Phase 2 Study on Effects of Obeticholic Acid (OCA) on Lipoprotein Metabolism in Participants With Primary Biliary Cirrhosis
- Registration Number
- NCT01865812
- Lead Sponsor
- Intercept Pharmaceuticals
- Brief Summary
The purpose of this study was to determine if OCA had an effect on cholesterol levels in the blood in participants with primary biliary cirrhosis (PBC).
- Detailed Description
This was a phase 2, open-label, multicenter study evaluating the effects of OCA on lipoprotein metabolism in participants with PBC; in particular, OCA's effects on high-density lipoprotein cholesterol. Nuclear magnetic resonance spectroscopy was utilized to quantify the changes in lipoprotein particle sizes and concentrations. Components of reverse cholesterol transport were also assessed.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 27
-
Definite or probable PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors:
- History of elevated alkaline phosphatase levels for at least 6 months
- A positive anti-microbial antibody (AMA) titer or, if AMA negative or in low titer (<1:80), PBC-specific antibodies
- Liver biopsy consistent with PBC
-
Taking UDCA for at least 12 months (stable dose for ≥ 3 months) prior to Day 0 or unable to tolerate UDCA (no UDCA for ≥ 3 months prior to Day 0).
-
Contraception: Female participants must have been postmenopausal, surgically sterile, or if premenopausal, were prepared to use ≥ 1 effective (≤ 1% failure rate) method of contraception during the trial and until at least 30 days after the last dose of Investigational Product.
-
Must have provided written informed consent and agreed to comply with the trial protocol.
Key
-
Participants with decompensated PBC (as determined by the Investigator).
-
Severe pruritus or systemic treatment for pruritus (for example, treatment with bile acid sequestrants or rifampicin) within 2 months of Day 0.
-
History or presence of other significant liver diseases including:
- Active or chronic Hepatitis B or C virus infection
- Primary sclerosing cholangitis
- Alcoholic liver disease
- Definite autoimmune liver disease or overlap hepatitis
- Nonalcoholic steatohepatitis
Note: Participants with Gilbert's disease or those with a history of hepatitis B who were currently antigen negative and seroconverted were not considered exclusionary.
-
Uncontrolled diabetes or other uncontrolled or unstable medical condition that may have interfered with trial results.
-
Administration of any of the following medications as specified below:
- Prohibited 28 days prior to Day 0: bile acid sequestrants including cholestyramine, colesevelam, colestipol or omega-3 fatty acid containing dietary supplements
- Prohibited 3 months prior to Day 0 and throughout trial participation: serum-lipid modifying agents including 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, fenofibrate or other fibrates, nicotinic acid and derivatives, ezetimibe, Vitamin E (other than as standard dietary supplement)
- Prohibited 6 months prior to Day 0 and throughout the trial participation: azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; budesonide and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)
- Prohibited 12 months prior to Day 0 and throughout the trial participation: antibodies or immunotherapy directed against interleukins or other cytokines or chemokines
-
Planned change in diet or exercise habits during participation in the trial.
-
Presence or history of clinically significant cardiac arrhythmias that may have prohibited the participant from participating in the trial.
-
If female: known pregnancy, or had a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating.
-
Recent (3 months prior to day 0) participation in another trial involving OCA or participation in another investigational trial (30 days prior to Day 0) and during the trial.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description OCA: 10 mg Obeticholic Acid Obeticholic acid, oral administration, 10 milligrams (mg), 8 weeks
- Primary Outcome Measures
Name Time Method Absolute Change From Baseline In High-density Lipoprotein (HDL) Cholesterol Concentration Baseline, Week 8 Absolute Change From Baseline In HDL Particle Number Baseline, Week 8 Absolute Change From Baseline In HDL Particle Size Baseline, Week 8
- Secondary Outcome Measures
Name Time Method Absolute Change From Baseline In HDL Particle Size Baseline, Month 24/EOT Median Change From Week 8 In HDL Cholesterol Concentration At Week 12 Week 8, Week 12 Median Change From Week 8 In HDL Particle Size At Week 12 Week 8, Week 12 Median Change From Baseline In Albumin Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In HDL Cholesterol Concentration At Weeks 4, 8, and 12 Baseline, Week 4, Week 8, Week 12 Absolute Change From Baseline In HDL Cholesterol Concentration Baseline, Month 24/EOT Absolute Change From Baseline In HDL Particle Number Baseline, Month 24/EOT Median Change From Baseline In Total LDL Particles Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Results are reported in nanomoles per liter (nmol/L).
Median Change From Baseline In VLDL Particle Size Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Median Change From Baseline In HDL Particle Number At Weeks 4, 8, and 12 Baseline, Week 4, Week 8, Week 12 Median Change From Week 8 In HDL Particle Number At Week 12 Week 8, Week 12 Maximum Plasma Concentration (Cmax) Of OCA And Conjugates Week 8 Results are reported in nanograms per milliliter (ng/mL).
Median Change From Baseline In LDL Particle Size Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Time To Reach Cmax (Tmax) For OCA And Conjugates Week 8 Results are reported in hours (h).
Area Under The Concentration-time Curve From Hour 0 To Last Sampling Time (Hour 6) (AUC0-6) For OCA And Conjugates Week 8 Results are reported in hour\*nanograms per milliliter (h\*ng/mL).
Median Change From Baseline In Total Cholesterol Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Median Change From Baseline In Low-density Lipoprotein (LDL) Cholesterol (Direct) Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Median Change From Baseline In VLDL Particles Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Median Change From Baseline In Lipoprotein-a Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Median Change From Baseline In C-reactive Protein Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Glycoprotein A Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT Results are reported in picograms/milliliter (pg/mL).
Median Change From Baseline In HDL Particle Size At Weeks 4, 8, and 12 Baseline, Week 4, Week 8, Week 12 Median Change From Baseline In Apolipoprotein B (ApoB) Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Median Change From Baseline In Very Low-density Lipoprotein (VLDL) Cholesterol Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Results are reported in milligrams per deciliter (mg/dL).
Median Change From Baseline In Prebeta-1 HDL Concentration Baseline, Week 4, Week 8/End of Treatment (EOT), Month 6, Month 12, Month 18, Month 24/EOT Results are reported in microgram/milliliter (ug/mL).
Median Change From Baseline In Hyaluronic Acid Baseline, Month 12, Month 24/EOT Median Change From Baseline In Total Deoxycholic Acid Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Total Triglycerides Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Median Change From Baseline In Lecithin-cholesterol Acyltransferase Activity Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT Results are reported in nanomoles/milliliter/hour (nmol/mL/h).
Median Change From Baseline In Fibroblast Growth Factor-19 Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Alanine Aminotransferase Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Aspartate Aminotransferase Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Prothrombin Time Baseline, Month 6, Month 12, Month 18, Month 24/EOT Results are reported in seconds (sec).
Median Change From Baseline In Total Lithocholic Acid Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Cholesteryl Ester Transfer Protein Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT Results are reported in picomole/milliliter/minute (pmol/mL/min).
Median Change From Baseline In Macrophage Cholesterol Efflux Baseline, Week 4, Week 8/End of Treatment (EOT), Month 6, Month 12, Month 18, Month 24/EOT Results are reported as a percentage of cholesterol.
Median Change From Baseline In Alkaline Phosphatase Baseline, Month 6, Month 12, Month 18, Month 24/EOT Results are reported in units/Liter (U/L).
Median Change From Baseline In Prothrombin International Normalized Ratio Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Amino-terminal Propeptide Of Type III Procollagen Baseline, Month 12, Month 24/EOT Results are reported in micrograms/Liter (ug/L).
Median Change From Baseline In Total Bile Acids Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Total Endogenous Bile Acid Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Total Cholic Acid Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Apolipoprotein A1 (ApoA1) Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Results are reported in grams per liter (g/L).
Median Change From Baseline In ApoA1/ApoB Ratio Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Median Change From Baseline In Apolipoprotein E Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose Participants With Lipoprotein X Week 12 and Last Dose Lipoprotein samples were assessed using nuclear magnetic resonance spectroscopy for the presence/absence of Lipoprotein X. Lipoprotein X sometimes appears with advanced cholestasis and can confound assessment of other lipoprotein concentrations, particularly LDL.
Median Change From Baseline In Gamma-glutamyl Transferase Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Total And Unconjugated (Direct) Bilirubin Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Hepatic Stiffness Baseline, Month 12, Month 24/EOT Results are reported in kilopascal (kPa).
Median Change From Baseline In Total Chenodeoxycholic Acid Baseline, Month 6, Month 12, Month 18, Month 24/EOT Median Change From Baseline In Enhanced Liver Fibrosis (ELF) Score Baseline, Month 12, Month 24/EOT Change in ELF was calculated as ELF score at the end of the study minus ELF score prior to the intervention (at baseline). A decrease in the ELF score was considered good as it reflected a decrease in liver fibrosis, and an increase in ELF score was considered bad as it reflected an increase in liver fibrosis.
Change in ELF scores ranged from -0.56 (good) to + 0.68 (bad).Median Change From Baseline In Tissue Inhibitor Of Metalloproteinases 1 Baseline, Month 12, Month 24/EOT Median Change From Baseline In Total UDCA Baseline, Month 6, Month 12, Month 18, Month 24/EOT
Trial Locations
- Locations (7)
McGuire DVAMC
🇺🇸Richmond, Virginia, United States
Beth Israel Medical Center
🇺🇸New York, New York, United States
Scripps Clinic
🇺🇸La Jolla, California, United States
University of California, Davis Medical Center
🇺🇸Sacramento, California, United States
University of Miami
🇺🇸Miami, Florida, United States
Indiana University Medical Center
🇺🇸Indianapolis, Indiana, United States
Swedish Medical Center
🇺🇸Seattle, Washington, United States