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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2 Clinical Trial Investigating the Effects of Obeticholic Acid on Lipoprotein Metabolism in Subjects With Primary Biliary Cirrhosis

Conditions
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Primary Biliary Cirrhosis

Intervention / Treatment
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* Drug: Obeticholic Acid


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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 Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OCA: 10 mg<br>Obeticholic acid, oral administration, 10 milligrams (mg), 8 weeks | Drug: Obeticholic Acid<br>* 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.<br>* Other names: INT-747;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline In High-density Lipoprotein (HDL) Cholesterol Concentration |  | Baseline, Week 8 | 
| Absolute Change From Baseline In HDL Particle Size |  | Baseline, Week 8 | 
| Absolute Change From Baseline In HDL Particle Number |  | Baseline, Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Change From Baseline In HDL Cholesterol Concentration At Weeks 4, 8, and 12 |  | Baseline, Week 4, Week 8, Week 12 | 
| 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 HDL Particle Number At Weeks 4, 8, and 12 |  | Baseline, Week 4, Week 8, Week 12 | 
| 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 Week 8 In HDL Particle Number At Week 12 |  | Week 8, Week 12 | 
| Maximum Plasma Concentration (Cmax) Of OCA And Conjugates | Results are reported in nanograms per milliliter (ng/mL). | Week 8 | 
| Time To Reach Cmax (Tmax) For OCA And Conjugates | Results are reported in hours (h). | Week 8 | 
| 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). | Week 8 | 
| 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 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 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 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 | 
| Median Change From Baseline In Total LDL Particles | Results are reported in nanomoles per liter (nmol/L). | 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). | Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose | 
| 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 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 Apolipoprotein A1 (ApoA1) | Results are reported in grams per liter (g/L). | 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) |  | 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 |  | 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 | 
| 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 Lecithin-cholesterol Acyltransferase Activity | Results are reported in nanomoles/milliliter/hour (nmol/mL/h). | 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). | 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). | 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. | 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 |  | 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). | Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT | 
| 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 | 
| 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. | Week 12 and Last Dose | 
| Median Change From Baseline In Alkaline Phosphatase | Results are reported in units/Liter (U/L). | Baseline, Month 6, Month 12, Month 18, Month 24/EOT | 
| Median Change From Baseline In Gamma-glutamyl Transferase |  | Baseline, 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 Total And Unconjugated (Direct) Bilirubin |  | Baseline, Month 6, Month 12, Month 18, Month 24/EOT | 
| Median Change From Baseline In Albumin |  | Baseline, Month 6, Month 12, Month 18, Month 24/EOT | 
| Median Change From Baseline In Prothrombin Time | Results are reported in seconds (sec). | Baseline, Month 6, Month 12, Month 18, Month 24/EOT | 
| Median Change From Baseline In Prothrombin International Normalized Ratio |  | 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). | Baseline, Month 12, Month 24/EOT | 
| Median Change From Baseline In Hyaluronic Acid |  | 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). | Baseline, Month 12, Month 24/EOT | 
| Median Change From Baseline In Tissue Inhibitor Of Metalloproteinases 1 |  | Baseline, Month 12, Month 24/EOT | 
| Median Change From Baseline In Hepatic Stiffness | Results are reported in kilopascal (kPa). | Baseline, Month 12, Month 24/EOT | 
| 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 UDCA |  | Baseline, Month 6, Month 12, Month 18, Month 24/EOT | 
| Median Change From Baseline In Total Chenodeoxycholic Acid |  | Baseline, Month 6, Month 12, Month 18, Month 24/EOT | 
| Median Change From Baseline In Total Lithocholic 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 Total Deoxycholic Acid |  | Baseline, Month 6, Month 12, Month 18, Month 24/EOT | 
| Absolute Change From Baseline In HDL Cholesterol Concentration |  | Baseline, Month 24/EOT | 
| Absolute Change From Baseline In HDL Particle Size |  | Baseline, Month 24/EOT | 
| Absolute Change From Baseline In HDL Particle Number |  | Baseline, Month 24/EOT |