Clinical trial NCT01473524: Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis
Official title: A Phase 3, Double-Blind, Placebo-Controlled Trial and Long-Term Safety Extension of Obeticholic Acid in Patients With Primary Biliary Cirrhosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Primary Biliary Cirrhosis
Keywords: Primary Biliary Cholangitis
Primary Biliary Cirrhosis
PBC
Cirrhosis
Liver
Lead sponsor: Intercept Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2011-11-17
Enrollment: 217
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Detailed description: The study included 2 phases: a 12-month randomized, double-blind (DB), placebo-controlled, parallel group phase, followed by a long-term safety extension (LTSE) phase up to 5 years. Participants from the 12-month DB phase, including those who received placebo, were eligible to participate in the open-label LTSE phase. The Month 12 visit from the DB phase served as the Day 1 visit of the LTSE phase. 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.

Data for the LTSE phase is reported by the randomized dose group assigned in the DB phase.

Eligibility criteria: Inclusion Criteria:

1. 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
2. At least 1 of the following qualifying biochemistry values:

   * ALP ≥ 1.67x upper limit of normal (ULN)
   * Total bilirubin \> ULN but \< 2x ULN
3. Age ≥ 18 years
4. 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.
5. 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
6. Must provide written informed consent and agree to comply with the trial protocol.

Exclusion Criteria:

1. 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)
2. 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 \[L\])
3. 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
4. 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)
   * Prohibited 12 months prior to Day 0 and throughout the trial (that is, to last dose and/or EOT): antibodies or immunotherapy directed against interleukins or other cytokines or chemokines
5. Participants who have previously participated in a clinical trial of OCA will not be allowed to participate
6. History or presence of clinically concerning cardiac arrhythmias likely to affect survival during the trial, or prolongation of Screening (pretreatment) QT or QTc interval of \> 500 milliseconds (msec)
7. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
8. Known history of human immunodeficiency virus (HIV) infection
9. Presence of any other disease or condition that is interfering with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine. Participants with inflammatory bowel disease or who have undergone gastric bypass procedures will be excluded (gastric lap band is acceptable).
10. Medical conditions that may cause nonhepatic increases in ALP (for example, Paget's disease) or which may diminish life expectancy to \< 2 years, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphatic leukemia)
11. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the trial
12. Anticipated changes to current concomitant medications during the course of the trial
13. History of alcohol abuse, defined as consumption of more than 210 mL of alcohol per week (that is, the equivalent of fourteen 4-ounce (125 mL) glasses of wine or fourteen 12 ounce cans/bottles of beer), or other substance abuse within 1 year prior to Day 0
14. Participation in another investigational drug, biologic, or medical device trial within 30 days prior to Screening
15. History of noncompliance with medical regimens, or participants who are considered to be potentially unreliable
16. Blood or plasma donation within 30 days prior to Day 0
17. Mental instability or incompetence, such that the validity of informed consent or compliance with the trial is uncertain

Primary outcomes:
measure: DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo
timeFrame: DB Month 12
measure: LTSE Phase: Composite Endpoint ALP And Total Bilirubin
timeFrame: Baseline (DB Month 12), LTSE Months 24, 36, 48, and 60
Secondary outcomes:
measure: DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo
timeFrame: DB Month 6
measure: DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo
timeFrame: DB Month 12
measure: DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo
timeFrame: DB Month 6
measure: DB Phase: ALP Absolute Change From Baseline To Month 12
timeFrame: Baseline, DB Month 12
measure: DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12
timeFrame: Baseline, DB Month 12
measure: DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12
timeFrame: Baseline, DB Month 12
measure: DB Phase: Alanine Aminotransferase (ALT) Absolute Change From Baseline To Month 12
timeFrame: Baseline, DB Month 12
measure: DB Phase: Aspartate Aminotransferase (AST) Absolute Change From Baseline To Month 12
timeFrame: Baseline, DB Month 12
measure: DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12
timeFrame: Baseline, DB Month 12
measure: LTSE Phase: ALP Levels
timeFrame: LTSE Day 0 and LTSE Months 12, 24, 36, 48, and 60
measure: LTSE Phase: ALP Change From DB Baseline
timeFrame: DB Baseline, LTSE Months 12, 24, 36, 48, and 60
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: San Diego
country: United States
facility: Scripps Clinic
state: California
city: Aurora
country: United States
facility: University of Colorado, Denver
state: Colorado
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Saint Louis
country: United States
facility: St. Louis University
state: Missouri
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Newport News
country: United States
facility: Liver Institute of Virginia
state: Virginia
city: Richmond
country: United States
facility: Liver Institute of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/McGuire DVAMC
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Leuven
country: Belgium
facility: UZ Leuven
city: Toronto
country: Canada
facility: Toronto Western Hospital Liver Centre
state: Ontario
city: Montreal
country: Canada
facility: CHUM Hôpital St-Luc
state: Quebec
city: Pessac
country: France
facility: Hopital Haut-Leveque
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen
city: Erlangen
country: Germany
facility: Friedrich-Alexander-Universität Erlangen
city: Frankfurt am Main
country: Germany
facility: Klinikum der Johann-Wolfgang Goethe Universität Frankfurt am Main
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Medizinische Universitätsklinik
city: Herne
country: Germany
facility: Gastroenterologische Gemeinschaftspraxis, Dres. Felten / Hartmann / Hüppe
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: München
country: Germany
facility: LMU Klinikum der Universität München
city: Bologna
country: Italy
facility: Dip. Medicina Clinica - Università di Bologna
city: Bologna
country: Italy
facility: Dip. Medicina Clinica- Università di Bologna
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova - Gastroenterologia
city: Rozzano (MI)
country: Italy
facility: Istituto Clinico Humanitas
city: Amsterdam
country: Netherlands
facility: VUmc Amsterdam
city: Amsterdam
country: Netherlands
facility: AMC Amsterdam
city: Nijmegen
country: Netherlands
facility: UMC St. Radboud, Nijmegen
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Katowice
country: Poland
facility: All-Medicus
city: Katowice
country: Poland
facility: Klinika Gastroenterologii i Hepatologii SP CSK im. prof. K. Gibinskiego SUM
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
city: Szczecin
country: Poland
facility: Niepubliczny Zakład Opieki Zdrowotnej "SONOMED"
city: Warszawa
country: Poland
facility: Centrum Onkologii - Instytut im. Marii Skłodowskiej - Curie, Klinika Gastroenterologii
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: Dundee
country: United Kingdom
facility: Ninewells Hospital Dundee
city: Larbert
country: United Kingdom
facility: Forth Valley Royal Hospital
city: London
country: United Kingdom
facility: The Royal Free Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Newcastle Upon Tyne
country: United Kingdom
facility: Institute of Cellular Medicine, Newcastle University
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals Trust
Study officials:
affiliation: Intercept Pharmaceuticals, Inc.
name: Christian Weyer, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.