Study of Obeticholic Acid (OCA) Evaluating Pharmacokinetics and Safety in Participants With Primary Biliary Cholangitis (PBC) and Hepatic Impairment

NCT ID: NCT03633227

Last Updated: 2022-09-06

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-22
• Study Completion Date: 2021-07-09

Brief Summary

This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the pharmacokinetics (PK) and safety of OCA treatment in participants with PBC and moderate to severe hepatic impairment over a 48-week treatment period. Participants who have completed their 48-week double blind treatment period will continue double-blind treatment until all randomized participants have completed their 48-week treatment period and the database for that period is locked. An open-label extension study in which all participants receive OCA will be considered following review of blinded safety and PK data.

Conditions

Liver Cirrhosis, Biliary

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Obeticholic Acid (OCA)

Participants will initiate treatment with OCA 5 milligrams (mg) tablets orally once weekly. At Week 12, if there are no safety concerns, the dose will be up-titrated to OCA 5 mg twice weekly. Every 6 weeks thereafter, based on tolerability assessments, further up-titration of dose will be considered. At each titration visit, the participants will start the higher dose regimen no earlier than 2 days after the prior dose. The maximum dose titration will be OCA 10 mg twice weekly at least 3 days apart. The minimum treatment duration will be 48-weeks. Participants, who complete their 48-week treatment, can continue the treatment until all randomized participants complete their 48-week treatment period and the database for that period is locked (total duration: approximately up to 3 years).

Group Type: EXPERIMENTAL

Obeticholic Acid (OCA)

Intervention Type: DRUG

OCA will be administered per dose and schedule specified in the arm description.

Placebo

Participants will receive OCA matching placebo orally once weekly or twice weekly for the duration of at least 48-weeks. Participants, who complete their 48-week treatment, can continue the treatment until all randomized participants complete their 48-week treatment period and the database for that period is locked (total duration: approximately up to 3 years).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

OCA matching placebo will be administered per the schedule specified in the arm description.

Interventions

Obeticholic Acid (OCA)

OCA will be administered per dose and schedule specified in the arm description.

Intervention Type: DRUG

Placebo

OCA matching placebo will be administered per the schedule specified in the arm description.

Intervention Type: DRUG

Other Intervention Names

6alpha-ethylchenodeoxycholic acid (6-ECDCA); INT-747

Eligibility Criteria

Inclusion Criteria

1. A definite or probable diagnosis of PBC (consistent with American Association for the Study of Liver Diseases [AASLD] and European Association for the Study of the Liver [EASL] Practice Guidelines, defined as having ≥2 of the following 3 diagnostic factors:

• History of elevated alkaline phosphatase (ALP) levels for at least 6 months
• Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer (≤1:80), PBC specific antibodies (anti-glycoprotein 210 [GP210] and/or anti-SP100) and/or antibodies against the major M2 components (E2 component of mitochondrial pyruvate dehydrogenase complex [PDC-E2], 2-oxo-glutaric acid dehydrogenase complex)
• Liver biopsy consistent with PBC (collected at any time prior to Screening)

2. Evidence of cirrhosis including at least one of the following:

• Biopsy results consistent with PBC Stage 4
• Liver stiffness as assessed by Transient Elastography (TE) Median Value ≥16.9 kilopascals (kPa)
• Clinical evidence in the absence of acute liver failure consistent with cirrhosis including: gastroesophageal varices, ascites, radiological evidence of cirrhosis (nodular liver or enlargement of portal vein and splenomegaly)
• Combined low platelet count (<140,000/cubic millimeter [mm^3]) with

• persistent decrease in serum albumin, or
• elevation in prothrombin time/international normalized ratio (INR) (not due to antithrombotic agent use), or
• elevated bilirubin (2*upper limit of normal [ULN])

3. Satisfy the criteria of the modified Child-Pugh (CP) classification for hepatic impairment during Screening:

• Moderate: CP-B (Scores 7 to 9) or
• Severe: CP-C (Scores 10 to 12)

4. Model of end-stage liver disease (MELD) score of 6 to 24 at Screening

5. Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥3 months) prior to Day 1, or unable to tolerate or unresponsive to UDCA (no UDCA for ≥3 months)

Exclusion Criteria

1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6)

2. History of liver transplant or organ transplant

3. History of alcohol or drug abuse within 12 months prior to Screening

4. Hepatic encephalopathy (as defined by a West Haven score of ≥2

5. History or presence of other concomitant liver diseases including:

• Hepatitis C virus infection and ribonucleic acid (RNA) positive
• Active hepatitis B infection; however, participants who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the medical monitor
• Primary sclerosing cholangitis
• Alcoholic liver disease
• Definite autoimmune liver disease or overlap hepatitis
• Gilbert's Syndrome

6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function prior to randomization

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Intercept Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Steven Shiff, M.D.

Role: STUDY_DIRECTOR

Intercept Pharmaceuticals

Locations

Inland Empire Liver Foundation

Rialto, California, United States

University of California, Ddavis Medical Center

Sacramento, California, United States

Schiff Center for Liver Diseases/ University of Miami

Miami, Florida, United States

Mercy Medical Center

Baltimore, Maryland, United States

University Of Michigan

Ann Arbor, Michigan, United States

Kansas City Research Institute

Kansas City, Missouri, United States

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

UPMC Center for Liver Diseases

Pittsburgh, Pennsylvania, United States

The Liver Institute at Methodist Dallas Medical Center

Dallas, Texas, United States

Baylor College of Medicine- Advanced Liver Therapies

Houston, Texas, United States

American Research Corporation at theTexas Liver Institute

San Antonio, Texas, United States

Hospital Italiano de Buenos Aires

Buenos Aires, , Argentina

Hospital Universitario Austral

Buenos Aires, , Argentina

Hospital Aleman

Caba, , Argentina

Hospital Britanico de Buenos Aires

Caba, , Argentina

Hospital de Gastroenterologia "Dr Carlos Bonorino Udaondo"

Ciudad Autonoma de Buenos Aire, , Argentina

Higea S.A.

Mendoza, , Argentina

Hospital Universitario Austral

Pilar, , Argentina

Hospital Provincial del Centenario

Rosario, , Argentina

Royal Prince Alfred Hospital

Camperdown, , Australia

Nepean Hospital

Kingswood, , Australia

CUB Hospital Erasme

Brussels, , Belgium

Universitair Ziekenhuis Antwerpen UZA

Edegem, , Belgium

University Hospital Leuven

Leuven, , Belgium

Hospital das Clínicas da Universidade Federal de Minas Gerais - UFMG

Belo Horizonte, , Brazil

Hospital de Clinicas de Porto Alegre

Rio Grande, , Brazil

Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo

São Paulo, , Brazil

Toronto General Hospital

Toronto, , Canada

West Tallinn Central Hospital

Tallinn, , Estonia

Tartu University Hospital

Tartu, , Estonia

Universitatsklinikum Leipzig AoR

Leipzig, , Germany

Bekes Megyei Kozponti Korhaz Dr. Rethy Pal Tagkorhaz, 4. Belgyogyaszat-Gasztroenterologia-Hepatologia

Békéscsaba, , Hungary

Azienda Socio Sanitaria Territoriale (ASST) di Monza

Monza, MB, Italy

AOU Ospedale Civile S. Agostino Estense - UO Medicina Metabolica

Modena, , Italy

Hospital of Lithuanian University of Health Sciences Kauno Klinikos

Kaunas, , Lithuania

Klaipeda Seamen's Hospital

Klaipėda, , Lithuania

Vilnius University Hospital Santaros Klinikos

Vilnius, , Lithuania

Paseo Vall d'Hebron

Barcelona, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

Hospital Universitari I Politecnic La Fe de Valencia

Valencia, , Spain

Countries

United States; Argentina; Australia; Belgium; Brazil; Canada; Estonia; Germany; Hungary; Italy; Lithuania; Spain

References

Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology. 2009 Jul;50(1):291-308. doi: 10.1002/hep.22906. No abstract available.

Reference Type: BACKGROUND

PMID: 19554543 (View on PubMed)

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009 Aug;51(2):237-67. doi: 10.1016/j.jhep.2009.04.009. Epub 2009 Jun 6. No abstract available.

Reference Type: BACKGROUND

PMID: 19501929 (View on PubMed)

Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. doi: 10.1002/hep.27210. Epub 2014 Jul 8. No abstract available.

Reference Type: BACKGROUND

PMID: 25042402 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

747-401

Identifier Type: -

Identifier Source: org_study_id