Obeticholic acid in patients with primary biliary cirrhosis

Phase 3

Completed

• Conditions: Primary Biliary Cirrhosis; Digestive System; Primary biliary cirrhosis

• Registration Number: ISRCTN89514817
• Lead Sponsor: Intercept Pharmaceuticals Inc. (USA)

Brief Summary

2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27532829

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2012-02-24
• Study Completion: 2018-12-17
• Last Update Posted: 13 May 2019

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 217

Inclusion Criteria

1. Definite or probable PBC diagnosis (consistent with AASLD and EASL Practice Guidelines, as demonstrated by the presence of = 2 of the following 3 diagnostic factors:
1.1. History of elevated Alkaline phosphatase (ALP) levels for at least 6 months prior to Day 0
1.2. 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 (PDC-E2, 2-oxo-glutaric acid dehydrogenase complex)
1.3. Liver biopsy consistent with PBC
2. At least 1 of the following qualifying biochemistry values:
2.1. ALP = 1.67x upper limit of normal (ULN)
2.2. 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 patients must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use = 1 effective (= 1% failure rate) method of contraception during the trial and until the EOT visit. Effective methods of contraception are considered to be:
5.1. Hormonal (e.g., contraceptive pill, patch, intramuscular implant or injection); or
5.2. Double barrier method, i.e., (a) condom (male or female) or (b) diaphragm, with spermicide; or
5.3. Intrauterine device (IUD)
5.4. Vasectomy (partner)
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:
1.1. Hepatitis B or C virus (HCV, HBV) infection
1.2. Primary sclerosing cholangitis (PSC)
1.3. Alcoholic liver disease
1.4. Definite autoimmune liver disease or overlap hepatitis
1.5. Nonalcoholic steatohepatitis (NASH)
1.6. Gilbert?s Syndrome (due to interpretability of bilirubin levels)
2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
2.1. History of liver transplantation, current placement on a liver transplant list or current Model for End-Stage Liver Disease (MELD) score = 15
2.2. Portal hypertension and complications, including: known esophageal varices, poorly controlled or diuretic resistant ascites, history of variceal bleeds or related interventions (e.g., insertion of variceal bands or transjugular intrahepatic portosystemic shunts [TIPS]), hepatic encephalopathy
2.3. Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin > 2x ULN
2.4. Hepatorenal syndrome (type I or II) or Screening serum creatinine > 2 mg/dL (178 µmol/L)
3. Patients with a history of severe pruritus requiring current or prior systemic treatment [e.g., with bile acid sequestrants (BAS) or rifampicin]
4. Administration of the following medications is prohibited as specified below:
4.1. Prohibited 6 months prior to Day 0 and throughout the trial (i.e., to last dose 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)
4.2. Prohibited 12 months prior to Day 0 and throughout the trial (i.e., to last dose to last dose and/or EOT): antibodies or immunotherapy directed against interleukins or other cytokines or chemokines
5. Patients 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, or prolongation of Screening (pretreatment) QT or QTc interval of > 500 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. History or presence of any other disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine (e.g., inflammatory bowel disease or gastric bypass procedures; [gastric lap band is acceptable])
10. Medical conditions that may cause nonhepatic increases in ALP (e.g., 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

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<br> 1.Obeticholic acid (OCA) is safe and tolerated in patients with cirrhosis and portal hypertension<br> 2. Obeticholic Acid (OCA) will reduce alkaline phosphatase (ALP) to less than 1.67 times the upper limit of normal and total bilirubin will be within normal limits, and ALP will have a total decrase of at least 15%.<br>

Secondary Outcome Measures

Name	Time	Method
<br> 1. Hepatocellular injury and liver function, including histology (inflammatory, structural [portal, parenchymal] and fibrotic assessments)<br> 2. Disease specific symptoms<br> 3. Biomarkers and noninvasive assessments of liver fibrosis<br> 4. Bile acids (BA)<br> 5. Other exploratory evaluations<br>