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Hepatic Impairment Trial of Obeticholic Acid

Primary Purpose

Hepatic Impairment

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
obeticholic acid 10 mg
Sponsored by
Intercept Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Hepatic Impairment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Subject Inclusion Criteria All Subjects

  • Female and male subjects ≥ 18 years of age
  • Subjects will have a minimum body weight of 45 kg or body mass index (BMI)> 18 kg/m2.
  • Contraception: Female subjects must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use ≥ 1 effective method of contraception during the trial and until at least 30 days after administration of OCA.
  • Subjects must provide written informed consent and agree to comply with the trial protocol.

Subjects with Hepatic Impairment:

  • Evidence of hepatic disease

    1. Score ≥ 2 on one of the Child-Pugh parameters, or
    2. Histological diagnosis of cirrhosis or presence of esophageal varices, or
    3. Abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels
  • Subjects will satisfy the criteria of the modified Child-Pugh classification for hepatic impairment during Screening:

    1. Mild hepatic impairment: Class A (Child-Pugh Scores 5-6 points)
    2. Moderate hepatic impairment: Class B (Child-Pugh Scores 7-9 points)
    3. Severe hepatic impairment: Class C (Child Pugh Scores 10-15 points)

Healthy volunteers:

  • Absence of clinically-relevant abnormalities identified by a detailed medical history, full physical examination, 12-lead ECG
  • Clinical laboratory tests within the normal reference range
  • Subjects must be within ± 10 years of the mean age and within 20% of the mean BMI of the hepatic impaired subjects (Child-Pugh category A, B, and C)

Subject Exclusion Criteria All Subjects

  • Positive test for human immunodeficiency virus (HIV)-1 or HIV-2 at screening
  • Presence or history of malignancy, with the exception of basal cell carcinoma
  • Received an investigational drug, including OCA, within 30 days or t½=5 prior to dosing
  • Blood or plasma donation within 30 days prior to dosing
  • History of non-compliance to medical regimens, or subjects who are considered to be potentially unreliable
  • Presence or history of clinically significant cardiac arrhythmias that may prohibit the subject from participating in the trial
  • Female subjects who are pregnant or lactating
  • Subjects who have irritable bowel disease or other GI disorders that have the potential to alter drug or bile acid absorption.
  • Subjects who have a history of gall bladder removal, gastric bypass or other GI surgery that may affect drug absorption or the enterohepatic circulation.

Subjects with Hepatic Impairment

  • History of alcohol or drug abuse 3 months prior to dosing
  • In the opinion of the Investigator and medical monitor, fluctuating or rapidly deteriorating hepatic function within the screening period
  • In the opinion of the Investigator, any evidence of additional severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding likely to affect the conduct of the trial or interpretation of the data
  • Subjects who have a transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting
  • Subjects with Wilson's disease, alpha-1 antitrypsin deficiency, glycogen storage diseases and galactosemia
  • Heavy smoker or use of tobacco or nicotine products

Healthy Volunteers

  • Presence of significant uncontrolled disease that will complicate execution of the trial or interfere with the absorption, distribution, metabolism, or excretion of drugs via the gut
  • Evidence of chronic or acute liver disease as documented by medical history, physical examination or diagnostic tests that it likely to affect the conduct of the trial or interpretation of the data
  • History of and/or current alcohol abuse (defined as consumption of more than 210 mL of alcohol per week; or the equivalent of fourteen 4-oz glasses of wine, or fourteen 12-oz cans/bottles of beer or wine coolers per week) or drug abuse within the prior two years
  • Smoke or use tobacco or nicotine products

Sites / Locations

  • Clinical Pharmacology of Miami, Inc.
  • Orlando Clinical Research Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Healthy Volunteer

Mild Hepatic Impairment

Moderate Hepatic Impairment

Severe Hepatic Impairment

Arm Description

Healthy volunteers receiving a single dose of obeticholic acid 10 mg.

Subjects with mild hepatic impairment defined as Child-Pugh class A receiving a single dose of obeticholic acid 10mg.

Subjects with moderate hepatic impairment defined as Child-Pugh class B receiving obeticholic acid 10mg.

Subjects with severe hepatic impairment defined as Child-Pugh class C receiving obeticholic acid 10 mg.

Outcomes

Primary Outcome Measures

Peak plasma concentration (Cmax) of OCA and conjugates
maximum concentration
Area under the concentration versus time curve from time 0 to the last sampling time with measurable analyte concentration (AUCt) of OCA and conjugates
Time to Cmax (Tmax) of OCA and conjugates
Area under the concentration versus time curve from time 0-24 hours with measurable analyte concentration of OCA and conjugates. (AUC 0-24)

Secondary Outcome Measures

Urine concentration of unchanged OCA and conjugates
Amount of OCA and conjugates excretion in urine
Total amount of OCA and conjugates excreted in urine
Protein Binding

Full Information

First Posted
May 23, 2013
Last Updated
October 23, 2013
Sponsor
Intercept Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01904539
Brief Title
Hepatic Impairment Trial of Obeticholic Acid
Official Title
An Open-Label, Single-Dose Trial to Assess the Effects of Hepatic Impairment on the Pharmacokinetics of Obeticholic Acid (OCA)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2013
Overall Recruitment Status
Completed
Study Start Date
June 2013 (undefined)
Primary Completion Date
October 2013 (Actual)
Study Completion Date
October 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Intercept Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a phase 1 study to evaluate the safety of a single 10 mg dose of obeticholic acid (OCA) in healthy volunteers and patients with liver disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatic Impairment

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Healthy Volunteer
Arm Type
Experimental
Arm Description
Healthy volunteers receiving a single dose of obeticholic acid 10 mg.
Arm Title
Mild Hepatic Impairment
Arm Type
Experimental
Arm Description
Subjects with mild hepatic impairment defined as Child-Pugh class A receiving a single dose of obeticholic acid 10mg.
Arm Title
Moderate Hepatic Impairment
Arm Type
Experimental
Arm Description
Subjects with moderate hepatic impairment defined as Child-Pugh class B receiving obeticholic acid 10mg.
Arm Title
Severe Hepatic Impairment
Arm Type
Experimental
Arm Description
Subjects with severe hepatic impairment defined as Child-Pugh class C receiving obeticholic acid 10 mg.
Intervention Type
Drug
Intervention Name(s)
obeticholic acid 10 mg
Other Intervention Name(s)
INT-747, 6α-ethyl chenodeoxycholic acid, 6-ECDCA
Intervention Description
Single dose OCA 10mg in each arm
Primary Outcome Measure Information:
Title
Peak plasma concentration (Cmax) of OCA and conjugates
Description
maximum concentration
Time Frame
Up to 48 hours
Title
Area under the concentration versus time curve from time 0 to the last sampling time with measurable analyte concentration (AUCt) of OCA and conjugates
Time Frame
Post-dose 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 216 hours post-dose
Title
Time to Cmax (Tmax) of OCA and conjugates
Time Frame
Up to 48 hours
Title
Area under the concentration versus time curve from time 0-24 hours with measurable analyte concentration of OCA and conjugates. (AUC 0-24)
Time Frame
24 hours
Secondary Outcome Measure Information:
Title
Urine concentration of unchanged OCA and conjugates
Time Frame
0, 6, 12, 24, 30 hours
Title
Amount of OCA and conjugates excretion in urine
Time Frame
-6to 0, 0 to 6, 6 to 12, 12 to 24, and 24 to 30 hours
Title
Total amount of OCA and conjugates excreted in urine
Time Frame
0 to 30 hours
Title
Protein Binding
Time Frame
0, 0.75, 1.5, 6, and 24 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Subject Inclusion Criteria All Subjects Female and male subjects ≥ 18 years of age Subjects will have a minimum body weight of 45 kg or body mass index (BMI)> 18 kg/m2. Contraception: Female subjects must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use ≥ 1 effective method of contraception during the trial and until at least 30 days after administration of OCA. Subjects must provide written informed consent and agree to comply with the trial protocol. Subjects with Hepatic Impairment: Evidence of hepatic disease Score ≥ 2 on one of the Child-Pugh parameters, or Histological diagnosis of cirrhosis or presence of esophageal varices, or Abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels Subjects will satisfy the criteria of the modified Child-Pugh classification for hepatic impairment during Screening: Mild hepatic impairment: Class A (Child-Pugh Scores 5-6 points) Moderate hepatic impairment: Class B (Child-Pugh Scores 7-9 points) Severe hepatic impairment: Class C (Child Pugh Scores 10-15 points) Healthy volunteers: Absence of clinically-relevant abnormalities identified by a detailed medical history, full physical examination, 12-lead ECG Clinical laboratory tests within the normal reference range Subjects must be within ± 10 years of the mean age and within 20% of the mean BMI of the hepatic impaired subjects (Child-Pugh category A, B, and C) Subject Exclusion Criteria All Subjects Positive test for human immunodeficiency virus (HIV)-1 or HIV-2 at screening Presence or history of malignancy, with the exception of basal cell carcinoma Received an investigational drug, including OCA, within 30 days or t½=5 prior to dosing Blood or plasma donation within 30 days prior to dosing History of non-compliance to medical regimens, or subjects who are considered to be potentially unreliable Presence or history of clinically significant cardiac arrhythmias that may prohibit the subject from participating in the trial Female subjects who are pregnant or lactating Subjects who have irritable bowel disease or other GI disorders that have the potential to alter drug or bile acid absorption. Subjects who have a history of gall bladder removal, gastric bypass or other GI surgery that may affect drug absorption or the enterohepatic circulation. Subjects with Hepatic Impairment History of alcohol or drug abuse 3 months prior to dosing In the opinion of the Investigator and medical monitor, fluctuating or rapidly deteriorating hepatic function within the screening period In the opinion of the Investigator, any evidence of additional severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding likely to affect the conduct of the trial or interpretation of the data Subjects who have a transjugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting Subjects with Wilson's disease, alpha-1 antitrypsin deficiency, glycogen storage diseases and galactosemia Heavy smoker or use of tobacco or nicotine products Healthy Volunteers Presence of significant uncontrolled disease that will complicate execution of the trial or interfere with the absorption, distribution, metabolism, or excretion of drugs via the gut Evidence of chronic or acute liver disease as documented by medical history, physical examination or diagnostic tests that it likely to affect the conduct of the trial or interpretation of the data History of and/or current alcohol abuse (defined as consumption of more than 210 mL of alcohol per week; or the equivalent of fourteen 4-oz glasses of wine, or fourteen 12-oz cans/bottles of beer or wine coolers per week) or drug abuse within the prior two years Smoke or use tobacco or nicotine products
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Shapiro, MD
Organizational Affiliation
Intercept Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Pharmacology of Miami, Inc.
City
Miami
State/Province
Florida
ZIP/Postal Code
33014
Country
United States
Facility Name
Orlando Clinical Research Center
City
Orlando
State/Province
Florida
ZIP/Postal Code
32809
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
27743502
Citation
Edwards JE, LaCerte C, Peyret T, Gosselin NH, Marier JF, Hofmann AF, Shapiro D. Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage. Clin Transl Sci. 2016 Dec;9(6):328-336. doi: 10.1111/cts.12421. Epub 2016 Oct 15.
Results Reference
derived

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Hepatic Impairment Trial of Obeticholic Acid

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