Clinical trial NCT01865812: Phase 2 Study on Effects of Obeticholic Acid (OCA) on Lipoprotein Metabolism in Participants With Primary Biliary Cirrhosis
Official title: A Phase 2 Clinical Trial Investigating the Effects of Obeticholic Acid on Lipoprotein Metabolism in Subjects With Primary Biliary Cirrhosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Biliary Cirrhosis
Lead sponsor: Intercept Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2013-05-31
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Absolute Change From Baseline In High-density Lipoprotein (HDL) Cholesterol Concentration
timeFrame: Baseline, Week 8
measure: Absolute Change From Baseline In HDL Particle Size
timeFrame: Baseline, Week 8
measure: Absolute Change From Baseline In HDL Particle Number
timeFrame: Baseline, Week 8
Secondary outcomes:
measure: Median Change From Baseline In HDL Cholesterol Concentration At Weeks 4, 8, and 12
timeFrame: Baseline, Week 4, Week 8, Week 12
measure: Median Change From Baseline In HDL Particle Size At Weeks 4, 8, and 12
timeFrame: Baseline, Week 4, Week 8, Week 12
measure: Median Change From Baseline In HDL Particle Number At Weeks 4, 8, and 12
timeFrame: Baseline, Week 4, Week 8, Week 12
measure: Median Change From Week 8 In HDL Cholesterol Concentration At Week 12
timeFrame: Week 8, Week 12
measure: Median Change From Week 8 In HDL Particle Size At Week 12
timeFrame: Week 8, Week 12
measure: Median Change From Week 8 In HDL Particle Number At Week 12
timeFrame: Week 8, Week 12
measure: Maximum Plasma Concentration (Cmax) Of OCA And Conjugates
timeFrame: Week 8
measure: Time To Reach Cmax (Tmax) For OCA And Conjugates
timeFrame: Week 8
measure: Area Under The Concentration-time Curve From Hour 0 To Last Sampling Time (Hour 6) (AUC0-6) For OCA And Conjugates
timeFrame: Week 8
measure: Median Change From Baseline In Total Cholesterol
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In Total Triglycerides
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In Low-density Lipoprotein (LDL) Cholesterol (Direct)
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In LDL Particle Size
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In Total LDL Particles
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In Very Low-density Lipoprotein (VLDL) Cholesterol
timeFrame: Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In VLDL Particle Size
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In VLDL Particles
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In Apolipoprotein A1 (ApoA1)
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In Apolipoprotein B (ApoB)
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In ApoA1/ApoB Ratio
timeFrame: Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In Apolipoprotein E
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In Lipoprotein-a
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT, Last Dose
measure: Median Change From Baseline In Lecithin-cholesterol Acyltransferase Activity
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Cholesteryl Ester Transfer Protein
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Prebeta-1 HDL Concentration
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Macrophage Cholesterol Efflux
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In C-reactive Protein
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Glycoprotein A
timeFrame: Baseline, Week 12, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Fibroblast Growth Factor-19
timeFrame: Baseline, Week 4, Week 8/End of Treatment (EOT), Week 12, Month 6, Month 12, Month 18, Month 24/EOT
measure: Participants With Lipoprotein X
timeFrame: Week 12 and Last Dose
measure: Median Change From Baseline In Alkaline Phosphatase
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Gamma-glutamyl Transferase
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Alanine Aminotransferase
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Aspartate Aminotransferase
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Total And Unconjugated (Direct) Bilirubin
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Albumin
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Prothrombin Time
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Prothrombin International Normalized Ratio
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Enhanced Liver Fibrosis (ELF) Score
timeFrame: Baseline, Month 12, Month 24/EOT
measure: Median Change From Baseline In Hyaluronic Acid
timeFrame: Baseline, Month 12, Month 24/EOT
measure: Median Change From Baseline In Amino-terminal Propeptide Of Type III Procollagen
timeFrame: Baseline, Month 12, Month 24/EOT
measure: Median Change From Baseline In Tissue Inhibitor Of Metalloproteinases 1
timeFrame: Baseline, Month 12, Month 24/EOT
measure: Median Change From Baseline In Hepatic Stiffness
timeFrame: Baseline, Month 12, Month 24/EOT
measure: Median Change From Baseline In Total Bile Acids
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Total Endogenous Bile Acid
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Total UDCA
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Total Chenodeoxycholic Acid
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Total Lithocholic Acid
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Total Cholic Acid
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Median Change From Baseline In Total Deoxycholic Acid
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24/EOT
measure: Absolute Change From Baseline In HDL Cholesterol Concentration
timeFrame: Baseline, Month 24/EOT
measure: Absolute Change From Baseline In HDL Particle Size
timeFrame: Baseline, Month 24/EOT
measure: Absolute Change From Baseline In HDL Particle Number
timeFrame: Baseline, Month 24/EOT
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Scripps Clinic
state: California
city: Sacramento
country: United States
facility: University of California, Davis Medical Center
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: Richmond
country: United States
facility: McGuire DVAMC
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
Study officials:
affiliation: Intercept Pharmaceuticals, Inc.
name: George Harb, MD
role: STUDY_DIRECTOR
References: