Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis

NCT01473524 | Completed Phase 3 Results DMC

• 1 other identifier: 747-301
• Study Type: interventional
• Target: 217
• Locations: 12 countries
• Sites: 56

Brief Summary

The main objectives of the study were to assess the effects of Obeticholic Acid (OCA) on serum alkaline phosphatase (ALP) and total bilirubin, together as a composite endpoint and on safety in participants with primary biliary cirrhosis (PBC).

Conditions

Primary Biliary Cirrhosis

Keywords

Primary Biliary Cholangitis; Primary Biliary Cirrhosis; PBC; Cirrhosis; Liver

Outcome Measures

Primary Outcomes (2)

• DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo

  Percentage of participants at Month 12 with ALP \< 1.67 x upper limit of normal (ULN) and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.

  DB Month 12

• LTSE Phase: Composite Endpoint ALP And Total Bilirubin

  Percentage of participants at Months 24, 36, 48, and 60 with ALP \< 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline. DB Month 12 is the baseline for the LTSE phase.

  Baseline (DB Month 12), LTSE Months 24, 36, 48, and 60

Secondary Outcomes (11)

• DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo

  DB Month 6

• DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo

  DB Month 12

• DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo

  DB Month 6

• DB Phase: ALP Absolute Change From Baseline To Month 12

  Baseline, DB Month 12

• DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12

  Baseline, DB Month 12

Study Arms (4)

DB OCA 5-10 mg

EXPERIMENTAL

OCA 5 milligram (mg) for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.

Drug: Obeticholic Acid (OCA)

DB OCA 10 mg

EXPERIMENTAL

OCA 10 mg for 12 months during the DB phase.

Drug: Obeticholic Acid (OCA)

DB Placebo

PLACEBO COMPARATOR

Matching placebo for 12 months during the DB phase.

Drug: Placebo

LTSE OCA

EXPERIMENTAL

After completion of the 12-month DB phase all participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. Participants who were previously titrated above 10 mg OCA daily were down-titrated to ≤10 mg OCA daily.

Drug: Obeticholic Acid (OCA)

Interventions

Obeticholic Acid (OCA) DRUG

OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.

Also known as: 6α-ethyl chenodeoxycholic acid (6-ECDCA), INT-747

DB OCA 10 mg; DB OCA 5-10 mg; LTSE OCA

Placebo DRUG

Matching placebo tablets were administered orally once daily.

DB Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Disease \[AASLD\] and European Association for Study of the Liver \[EASL\] Practice Guidelines; \[Lindor 2009; EASL 2009\]), as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors:
• History of elevated alkaline phosphatase (ALP) levels for at least 6 months
• Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in low titer (\<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components (pyruvate dehydrogenase complex-E2 \[PDC-E2\], 2-oxo-glutaric acid dehydrogenase complex)
• Liver biopsy consistent with PBC
• At least 1 of the following qualifying biochemistry values:
• ALP ≥ 1.67x upper limit of normal (ULN)
• Total bilirubin \> ULN but \< 2x ULN
• Age ≥ 18 years
• Taking ursodeoxycholic acid (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 be postmenopausal, surgically sterile, or if premenopausal, be prepared to use ≥ 1 effective (≤ 1% failure rate) method of contraception during the trial and for 30 days after the end of treatment (EOT) visit. Effective methods of contraception are considered to be:
• Hormonal (for example, contraceptive pill, patch, intramuscular implant or injection); or
• Double barrier method, that is, (a) condom (male or female) or (b) diaphragm, with spermicide; or
• Intrauterine device (IUD); or
• Vasectomy (partner); or
• Sexual abstinence

You may not qualify if:

• History or presence of other concomitant liver diseases including:
• Hepatitis C virus (HCV) infection; participants with active hepatitis B (HBV) infection will be excluded, however, participants who have seroconverted (hepatitis B surface antigen \[Hbs Ag\] and hepatitis B e antigen \[Hbe Ag\] negative) may be included after consultation with the medical monitor.
• Primary sclerosing cholangitis (PSC)
• Alcoholic liver disease
• Definite autoimmune liver disease or overlap hepatitis
• Nonalcoholic steatohepatitis (NASH)
• Gilbert's Syndrome (due to interpretability of bilirubin levels)
• Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
• History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15
• Portal hypertension with complications, including: known gastric or large esophageal varices, poorly controlled or diuretic resistant ascites, history of variceal bleeds or related therapeutic or prophylactic interventions (for example, beta blockers, insertion of variceal bands or transjugular intrahepatic portosystemic shunt \[TIPS\]), or hepatic encephalopathy
• Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin \> 2x ULN
• Hepatorenal syndrome (type I or II) or Screening serum creatinine \> 2 mg/deciliter dL) (178 micromole \[µmol\])/liter \[L\])
• Participants with severe pruritus or those requiring systemic treatment for pruritus (for example, with bile acid sequestrants \[BAS\] or rifampicin) within 2 months of Day 0 will be excluded
• Administration of the following medications is prohibited as specified below:
• Prohibited 6 months prior to Day 0 and throughout the trial (that is, to last dose and/or EOT): azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; fenofibrate or other fibrates; budesonide and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)

Sponsors & Collaborators

• Intercept Pharmaceuticals: lead

Study Sites (59)

UC Davis Medical Center

Sacramento, California, 95817, United States

Location

Scripps Clinic

San Diego, California, 92037, United States

Location

University of Colorado, Denver

Aurora, Colorado, 80045, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Indiana University School of Medicine

Indianapolis, Indiana, 46202, United States

Location

Henry Ford Health System

Detroit, Michigan, 48377, United States

Location

St. Louis University

St Louis, Missouri, 63104, United States

Location

Beth Israel Medical Center

New York, New York, 10003, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Liver Institute of Virginia

Newport News, Virginia, 23602, United States

Location

Liver Institute of Virginia

Richmond, Virginia, 23226, United States

Location

Virginia Commonwealth University/McGuire DVAMC

Richmond, Virginia, 23249, United States

Location

Swedish Medical Center

Seattle, Washington, 98101, United States

Location

Royal Prince Alfred Hospital

Camperdown, New South Wales, 2050, Australia

Location

Austin Hospital

Heidelberg, Victoria, 3084, Australia

Location

The Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

Medizinische Universität Innsbruck

Innsbruck, 6020, Austria

Location

Medizinische Universität Wien

Vienna, 1090, Austria

Location

UZ Leuven

Leuven, B-3000, Belgium

Location

Toronto Western Hospital Liver Centre

Toronto, Ontario, M5T 2S8, Canada

Location

CHUM Hôpital St-Luc

Montreal, Quebec, H2X 3J4, Canada

Location

Hopital Haut-Leveque

Pessac, 33604, France

Location

Universitätsklinikum Aachen

Aachen, D-52074, Germany

Location

Friedrich-Alexander-Universität Erlangen

Erlangen, D-91054, Germany

Location

Klinikum der Johann-Wolfgang Goethe Universität Frankfurt am Main

Frankfurt am Main, 60590, Germany

Location

Universitätsklinikum Hamburg Eppendorf

Hamburg, 20246, Germany

Location

Medizinische Hochschule Hannover

Hanover, D-30625, Germany

Location

Medizinische Universitätsklinik

Heidelberg, D-69120, Germany

Location

Gastroenterologische Gemeinschaftspraxis, Dres. Felten / Hartmann / Hüppe

Herne, D-44623, Germany

Location

Universitätsklinikum des Saarlandes

Homburg, 66421, Germany

Location

Universitätsklinikum Leipzig

Leipzig, 04103, Germany

Location

LMU Klinikum der Universität München

München, D-81377, Germany

Location

Dip. Medicina Clinica - Università di Bologna

Bologna, 40138, Italy

Location

Dip. Medicina Clinica- Università di Bologna

Bologna, 40138, Italy

Location

Azienda Ospedaliera di Padova - Gastroenterologia

Padua, 35128, Italy

Location

Istituto Clinico Humanitas

Rozzano (MI), 20089, Italy

Location

VUmc Amsterdam

Amsterdam, 1081 HV, Netherlands

Location

AMC Amsterdam

Amsterdam, 1105 AZ, Netherlands

Location

UMC St. Radboud, Nijmegen

Nijmegen, 6525, Netherlands

Location

UMC Utrecht

Utrecht, 3508 GA, Netherlands

Location

All-Medicus

Katowice, 40-660, Poland

Location

Klinika Gastroenterologii i Hepatologii SP CSK im. prof. K. Gibinskiego SUM

Katowice, 40-752, Poland

Location

Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie

Lublin, 20-954, Poland

Location

Niepubliczny Zakład Opieki Zdrowotnej "SONOMED"

Szczecin, 70-361, Poland

Location

Centrum Onkologii - Instytut im. Marii Skłodowskiej - Curie, Klinika Gastroenterologii

Warsaw, 02-781, Poland

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

Sahlgrenska University Hospital

Gothenburg, SE-41345, Sweden

Location

Queen Elizabeth Hospital

Birmingham, B15 2TH, United Kingdom

Location

Bristol Royal Infirmary

Bristol, BS2 8HW, United Kingdom

Location

Ninewells Hospital Dundee

Dundee, DD1 9SY, United Kingdom

Location

Forth Valley Royal Hospital

Larbert, FK5 4WR, United Kingdom

Location

The Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Manchester Royal Infirmary

Manchester, M13 9WL, United Kingdom

Location

Institute of Cellular Medicine, Newcastle University

Newcastle upon Tyne, NE2 4 HH, United Kingdom

Location

Nottingham University Hospitals NHS Trust

Nottingham, NG7 2UH, United Kingdom

Location

Oxford University Hospitals Trust

Oxford, OX3 9DU, United Kingdom

Location

Related Publications (6)

• 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.

  PMID: 19554543 BACKGROUND

• Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, Drenth JP, Pockros PJ, Regula J, Beuers U, Trauner M, Jones DE, Floreani A, Hohenester S, Luketic V, Shiffman M, van Erpecum KJ, Vargas V, Vincent C, Hirschfield GM, Shah H, Hansen B, Lindor KD, Marschall HU, Kowdley KV, Hooshmand-Rad R, Marmon T, Sheeron S, Pencek R, MacConell L, Pruzanski M, Shapiro D; POISE Study Group. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl J Med. 2016 Aug 18;375(7):631-43. doi: 10.1056/NEJMoa1509840.

  PMID: 27532829 RESULT

• Trauner M, Nevens F, Shiffman ML, Drenth JPH, Bowlus CL, Vargas V, Andreone P, Hirschfield GM, Pencek R, Malecha ES, MacConell L, Shapiro D. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol. 2019 Jun;4(6):445-453. doi: 10.1016/S2468-1253(19)30094-9. Epub 2019 Mar 26.

  PMID: 30922873 RESULT

• Harms MH, Hirschfield GM, Floreani A, Mayo MJ, Pares A, Liberman A, Malecha ES, Pencek R, MacConell L, Hansen BE. Obeticholic acid is associated with improvements in AST-to-platelet ratio index and GLOBE score in patients with primary biliary cholangitis. JHEP Rep. 2020 Sep 29;3(1):100191. doi: 10.1016/j.jhepr.2020.100191. eCollection 2021 Feb.

  PMID: 33319187 DERIVED

• Bowlus CL, Pockros PJ, Kremer AE, Pares A, Forman LM, Drenth JPH, Ryder SD, Terracciano L, Jin Y, Liberman A, Pencek R, Iloeje U, MacConell L, Bedossa P. Long-Term Obeticholic Acid Therapy Improves Histological Endpoints in Patients With Primary Biliary Cholangitis. Clin Gastroenterol Hepatol. 2020 May;18(5):1170-1178.e6. doi: 10.1016/j.cgh.2019.09.050. Epub 2019 Oct 10.

  PMID: 31606455 DERIVED

• Mousa HS, Lleo A, Invernizzi P, Bowlus CL, Gershwin ME. Advances in pharmacotherapy for primary biliary cirrhosis. Expert Opin Pharmacother. 2015 Apr;16(5):633-43. doi: 10.1517/14656566.2015.998650. Epub 2014 Dec 29.

  PMID: 25543678 DERIVED

MeSH Terms

Conditions

Liver Cirrhosis, Biliary; Fibrosis

Interventions

obeticholic acid

Condition Hierarchy (Ancestors)

Cholestasis, Intrahepatic; Cholestasis; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Liver Diseases; Liver Cirrhosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Medical Information
• Organization: Intercept Pharmaceuticals, Inc.

medinfo@interceptpharma.com

844-782-4278

Study Officials

• Christian Weyer, MD

  Intercept Pharmaceuticals, Inc.

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 14, 2011
• First Posted: November 17, 2011
• Study Start: January 1, 2012
• Primary Completion: December 1, 2013
• Study Completion: December 17, 2018
• Last Updated: May 6, 2021
• Results First Posted: February 13, 2017

Record last verified: 2021-04

Locations

AU (2); BE (1); CA (2); DE (10); IT (4); FR (1); PL (5); SE (1); GB (9); NL (4); US (15); ES (2)