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

Primary Biliary Cirrhosis Clinical Trial

— POISE  

Official title:

A Phase 3, Double-Blind, Placebo-Controlled Trial and Long-Term Safety Extension of Obeticholic Acid in Patients With Primary Biliary Cirrhosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01473524
• Other study ID #: 747-301
• Status: Completed
• Phase: Phase 3
• Start date: January 2012
• Est. completion date: December 17, 2018

Study information

• Verified date: April 2021
• Source: Intercept Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 217
• Est. completion date: December 17, 2018
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 a-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

Related Conditions & MeSH terms

• Fibrosis
• Liver Cirrhosis
• Liver Cirrhosis, Biliary
• Primary Biliary Cirrhosis

Intervention

Drug:
• Obeticholic Acid (OCA)
OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.
• Placebo
Matching placebo tablets were administered orally once daily.

Locations

Country	Name	City	State
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Austin Hospital	Heidelberg	Victoria
Australia	The Alfred Hospital	Melbourne	Victoria
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	Medizinische Universität Wien	Wien
Belgium	UZ Leuven	Leuven
Canada	CHUM Hôpital St-Luc	Montreal	Quebec
Canada	Toronto Western Hospital Liver Centre	Toronto	Ontario
France	Hopital Haut-Leveque	Pessac
Germany	Universitätsklinikum Aachen	Aachen
Germany	Friedrich-Alexander-Universität Erlangen	Erlangen
Germany	Klinikum der Johann-Wolfgang Goethe Universität Frankfurt am Main	Frankfurt am Main
Germany	Universitätsklinikum Hamburg Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Medizinische Universitätsklinik	Heidelberg
Germany	Gastroenterologische Gemeinschaftspraxis, Dres. Felten / Hartmann / Hüppe	Herne
Germany	Universitätsklinikum des Saarlandes	Homburg
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	LMU Klinikum der Universität München	München
Italy	Dip. Medicina Clinica - Università di Bologna	Bologna
Italy	Dip. Medicina Clinica- Università di Bologna	Bologna
Italy	Azienda Ospedaliera di Padova - Gastroenterologia	Padova
Italy	Istituto Clinico Humanitas	Rozzano (MI)
Netherlands	AMC Amsterdam	Amsterdam
Netherlands	VUmc Amsterdam	Amsterdam
Netherlands	UMC St. Radboud, Nijmegen	Nijmegen
Netherlands	UMC Utrecht	Utrecht
Poland	All-Medicus	Katowice
Poland	Klinika Gastroenterologii i Hepatologii SP CSK im. prof. K. Gibinskiego SUM	Katowice
Poland	Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie	Lublin
Poland	Niepubliczny Zaklad Opieki Zdrowotnej "SONOMED"	Szczecin
Poland	Centrum Onkologii - Instytut im. Marii Sklodowskiej - Curie, Klinika Gastroenterologii	Warszawa
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Sweden	Sahlgrenska University Hospital	Gothenburg
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Bristol Royal Infirmary	Bristol
United Kingdom	Ninewells Hospital Dundee	Dundee
United Kingdom	Forth Valley Royal Hospital	Larbert
United Kingdom	The Royal Free Hospital	London
United Kingdom	Manchester Royal Infirmary	Manchester
United Kingdom	Institute of Cellular Medicine, Newcastle University	Newcastle Upon Tyne
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Oxford University Hospitals Trust	Oxford
United States	University of Colorado, Denver	Aurora	Colorado
United States	University of Chicago	Chicago	Illinois
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	Beth Israel Medical Center	New York	New York
United States	Liver Institute of Virginia	Newport News	Virginia
United States	Liver Institute of Virginia	Richmond	Virginia
United States	Virginia Commonwealth University/McGuire DVAMC	Richmond	Virginia
United States	UC Davis Medical Center	Sacramento	California
United States	St. Louis University	Saint Louis	Missouri
United States	Scripps Clinic	San Diego	California
United States	Swedish Medical Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Intercept Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Italy,  Netherlands,  Poland,  Spain,  Sweden,  United Kingdom, 

References & Publications (3)

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. — View 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, — View 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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo	Percentage of participants at Month 6 with ALP < 1.67x ULN and total bilirubin = ULN and ALP decrease of = 15% from baseline.	DB Month 6
Secondary	DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo	Percentage of participants at Month 12 with ALP < 1.67x ULN and total bilirubin = ULN and ALP decrease of = 15% from baseline.	DB Month 12
Secondary	DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo	Percentage of participants at Month 6 with ALP < 1.67x ULN and total bilirubin = ULN and ALP decrease of = 15% from baseline.	DB Month 6
Secondary	DB Phase: ALP Absolute Change From Baseline To Month 12	Blood samples were evaluated for ALP levels. ALP Absolute Change From Baseline (ALP at Month 12 - ALP at Baseline) is presented.	Baseline, DB Month 12
Secondary	DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12	Blood samples were evaluated for bilirubin levels. Total bilirubin absolute change from baseline (total bilirubin at Month 12 - total bilirubin at Baseline) is presented.	Baseline, DB Month 12
Secondary	DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12	Blood samples were evaluated for bilirubin levels. Direct bilirubin absolute change from baseline (direct bilirubin at Month 12 - direct bilirubin at Baseline) is presented.	Baseline, DB Month 12
Secondary	DB Phase: Alanine Aminotransferase (ALT) Absolute Change From Baseline To Month 12	Blood samples were evaluated for ALT levels. ALT absolute change from baseline (ALT at Month 12 - ALT at Baseline) is presented.	Baseline, DB Month 12
Secondary	DB Phase: Aspartate Aminotransferase (AST) Absolute Change From Baseline To Month 12	Blood samples were evaluated for AST levels. AST absolute change from baseline (AST at Month 12 - AST at Baseline) is presented.	Baseline, DB Month 12
Secondary	DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12	Blood samples were evaluated for GGT levels. GGT absolute change from baseline (GGT at Month 12 - GGT at Baseline) is presented.	Baseline, DB Month 12
Secondary	LTSE Phase: ALP Levels	Blood samples were evaluated for ALP levels.	LTSE Day 0 and LTSE Months 12, 24, 36, 48, and 60
Secondary	LTSE Phase: ALP Change From DB Baseline	Blood samples were evaluated for ALP levels. ALP Change From Baseline (ALP at LTSE Months 12, 24, 36, 48, and 60 - ALP at Baseline) is presented. DB baseline is the mean of all available evaluations prior to DB treatment.	DB Baseline, LTSE Months 12, 24, 36, 48, and 60