Phase 2 Study on Effects of Obeticholic Acid (OCA) on Lipoprotein Metabolism in Participants With Primary Biliary Cirrhosis

Intercept Pharmaceuticals27 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Primary Biliary Cirrhosis

Interventions

Obeticholic AcidDRUG

All participants were treated with OCA (oral administration, 10 mg, once daily \[QD\]) for 8 weeks and continued their prestudy dose of ursodeoxycholic acid (UDCA). After completion of the 8-week Primary Treatment Phase of the study and the 4-week follow-up period, during which time participants did not take OCA, all eligible participants were offered the opportunity to enter an open-label, long-term safety extension phase, during which they could receive 10 mg OCA QD for up to 2 years.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. 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 2. 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). 3. 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. 4. Must have provided written informed consent and agreed to comply with the trial protocol. Key Exclusion Criteria: 1. Participants with decompensated PBC (as determined by the Investigator). 2. Severe pruritus or systemic treatment for pruritus (for example, treatment with bile acid sequestrants or rifampicin) within 2 months of Day 0. 3. 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. 4. Uncontrolled diabetes or other uncontrolled or unstable medical condition that may have interfered with trial results. 5. 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 6. Planned change in diet or exercise habits during participation in the trial. 7. Presence or history of clinically significant cardiac arrhythmias that may have prohibited the participant from participating in the trial. 8. If female: known pregnancy, or had a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating. 9. 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.

Locations (7)

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

Outcomes

Primary Outcomes

Absolute Change From Baseline In High-density Lipoprotein (HDL) Cholesterol Concentration

Time frame: Baseline, Week 8

Absolute Change From Baseline In HDL Particle Size

Time frame: Baseline, Week 8

Absolute Change From Baseline In HDL Particle Number

Time frame: Baseline, Week 8

Secondary Outcomes

Median Change From Baseline In HDL Cholesterol Concentration At Weeks 4, 8, and 12

Time frame: Baseline, Week 4, Week 8, Week 12

Median Change From Baseline In HDL Particle Size At Weeks 4, 8, and 12

Time frame: Baseline, Week 4, Week 8, Week 12

Median Change From Baseline In HDL Particle Number At Weeks 4, 8, and 12

Time frame: Baseline, Week 4, Week 8, Week 12

Median Change From Week 8 In HDL Cholesterol Concentration At Week 12

Time frame: Week 8, Week 12

Median Change From Week 8 In HDL Particle Size At Week 12

Time frame: Week 8, Week 12

Median Change From Week 8 In HDL Particle Number At Week 12

Time frame: Week 8, Week 12

Maximum Plasma Concentration (Cmax) Of OCA And Conjugates

Results are reported in nanograms per milliliter (ng/mL).

Time frame: Week 8

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Beth Israel Medical Center

New York, New York, United States

McGuire DVAMC

Richmond, Virginia, United States

Swedish Medical Center

Seattle, Washington, United States

Time To Reach Cmax (Tmax) For OCA And Conjugates

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

Results are reported in hour\*nanograms per milliliter (h\*ng/mL).

Time frame: Week 8

Median Change From Baseline In Total Cholesterol

Time frame: 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 Total Triglycerides

Time frame: 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)

Time frame: 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 LDL Particle Size

Time frame: 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 Total LDL Particles

Results are reported in nanomoles per liter (nmol/L).

Time frame: 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

Results are reported in milligrams per deciliter (mg/dL).

Time frame: Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose

Median Change From Baseline In VLDL Particle Size

Time frame: 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

Time frame: 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 Apolipoprotein A1 (ApoA1)

Results are reported in grams per liter (g/L).

Time frame: 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 Apolipoprotein B (ApoB)

Time frame: 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 ApoA1/ApoB Ratio

Time frame: Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose

Median Change From Baseline In Apolipoprotein E

Time frame: 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

Time frame: 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

Results are reported in nanomoles/milliliter/hour (nmol/mL/h).

Time frame: 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 Cholesteryl Ester Transfer Protein

Results are reported in picomole/milliliter/minute (pmol/mL/min).

Time frame: 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 Prebeta-1 HDL Concentration

Results are reported in microgram/milliliter (ug/mL).

Time frame: Baseline, Week 4, Week 8/End of Treatment (EOT), Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Macrophage Cholesterol Efflux

Results are reported as a percentage of cholesterol.

Time frame: Baseline, Week 4, Week 8/End of Treatment (EOT), Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In C-reactive Protein

Time frame: 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

Results are reported in picograms/milliliter (pg/mL).

Time frame: Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Fibroblast Growth Factor-19

Time frame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT

Participants With Lipoprotein X

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.

Time frame: Week 12 and Last Dose

Median Change From Baseline In Alkaline Phosphatase

Results are reported in units/Liter (U/L).

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Gamma-glutamyl Transferase

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Alanine Aminotransferase

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Aspartate Aminotransferase

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Total And Unconjugated (Direct) Bilirubin

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Albumin

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Prothrombin Time

Results are reported in seconds (sec).

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Prothrombin International Normalized Ratio

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Enhanced Liver Fibrosis (ELF) Score

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).

Time frame: Baseline, Month 12, Month 24/EOT

Median Change From Baseline In Hyaluronic Acid

Time frame: Baseline, Month 12, Month 24/EOT

Median Change From Baseline In Amino-terminal Propeptide Of Type III Procollagen

Results are reported in micrograms/Liter (ug/L).

Time frame: Baseline, Month 12, Month 24/EOT

Median Change From Baseline In Tissue Inhibitor Of Metalloproteinases 1

Time frame: Baseline, Month 12, Month 24/EOT

Median Change From Baseline In Hepatic Stiffness

Results are reported in kilopascal (kPa).

Time frame: Baseline, Month 12, Month 24/EOT

Median Change From Baseline In Total Bile Acids

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Total Endogenous Bile Acid

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Total UDCA

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Total Chenodeoxycholic Acid

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Total Lithocholic Acid

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Total Cholic Acid

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Median Change From Baseline In Total Deoxycholic Acid

Time frame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT

Absolute Change From Baseline In HDL Cholesterol Concentration

Time frame: Baseline, Month 24/EOT

Absolute Change From Baseline In HDL Particle Size

Time frame: Baseline, Month 24/EOT

Absolute Change From Baseline In HDL Particle Number

Time frame: Baseline, Month 24/EOT