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Obeticholic Acid (OCA) in Primary Sclerosing Cholangitis (PSC) (AESOP)

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ClinicalTrials.gov Identifier: NCT02177136
Recruitment Status : Completed
First Posted : June 27, 2014
Results First Posted : May 30, 2018
Last Update Posted : May 30, 2018
Sponsor:
Information provided by (Responsible Party):
Intercept Pharmaceuticals

Brief Summary:
This is a phase 2, double-blind, placebo controlled trial in patients with primary sclerosing cholangitis to evaluate the effect of obeticholic acid on liver biochemistry, in particular, serum alkaline phosphatase; and, safety.

Condition or disease Intervention/treatment Phase
Primary Sclerosing Cholangitis (PSC) Drug: OCA Drug: Placebo Phase 2

Detailed Description:

This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding evaluation of the efficacy and safety of OCA in subjects with PSC. Approximately 75 subjects who provide written informed consent and meet all of the inclusion and none of the exclusion criteria will be randomized to 1 of 3 treatment groups as follows: 1.5 mg titrating to 3 mg OCA, 5 mg titrating to 10 mg OCA, or placebo, in a 1:1:1 ratio. Subjects will administer investigational product (IP) orally, once daily for 2 consecutive 12-week periods.

For the first 12 weeks, the subject's dose will be 1.5 mg OCA, 5 mg OCA, or placebo. After 12 weeks, the subject's dose will be titrated as follows, providing there are no limiting safety or tolerability concerns in the opinion of the investigator, while maintaining the trial blind: the 1.5 mg OCA treatment group will titrate to 3 mg, the 5 mg OCA treatment group will titrate to 10 mg OCA, and the placebo group will remain on placebo. Double-blind treatment will continue for a further 12 weeks at that dose.

Any subjects whose dose is not titrated, due to safety or tolerability concerns, will remain on their starting treatment (1.5 mg OCA, 5 mg OCA, or placebo) for the remainder of the double-blind phase to Week 24.

Randomization will be stratified by the presence or absence of concomitant ursodeoxycholic acid (UDCA) use and total bilirubin level (≤ 1.5x upper limit of normal [ULN] or > 1.5x ULN but < 2.5x ULN).


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 77 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Clinical Trial Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects With Primary Sclerosing Cholangitis
Actual Study Start Date : February 9, 2015
Actual Primary Completion Date : March 7, 2017
Actual Study Completion Date : March 22, 2018


Arm Intervention/treatment
Experimental: 1.5 mg OCA titrating to 3 mg OCA
Subjects randomized to 1.5 mg OCA will take 1.5 mg OCA daily for 12 weeks. If tolerated, the dose will be increased to 3 mg OCA daily for an additional 12 weeks.
Drug: OCA
Other Names:
  • Obeticholic Acid
  • 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
  • INT-747

Experimental: 5 mg OCA titrating to 10 mg OCA
Subjects randomized to 5 mg OCA will take 5 mg OCA daily for 12 weeks. If tolerated, the dose will be increased to 10 mg OCA daily for an additional 12 weeks.
Drug: OCA
Other Names:
  • Obeticholic Acid
  • 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
  • INT-747

Experimental: Placebo
Subjects randomized to placebo will take placebo for 24 weeks.
Drug: Placebo



Primary Outcome Measures :
  1. Change From Baseline in Serum Alkaline Phosphatase (ALP) [ Time Frame: Baseline and 24 weeks ]
    The primary efficacy analysis will compare the Week 24 change from Baseline in ALP between OCA treatment group and placebo using an analysis of covariance (ANCOVA) model with fixed effects for treatment group and randomization strata, and Baseline as a covariate.


Secondary Outcome Measures :
  1. Change From Baseline in Serum Alanine Transaminase (ALT) [ Time Frame: Baseline and 24 weeks ]
  2. Change From Baseline in Serum Aspartate Aminotransferase (AST) [ Time Frame: Baseline and 24 weeks ]
  3. Change From Baseline in Serum Total Bilirubin [ Time Frame: Baseline and 24 weeks ]
  4. Change From Baseline in Serum Direct Bilirubin [ Time Frame: Baseline and 24 weeks ]
  5. Change From Baseline in Serum Gamma-Glutamyl Transferase (GGT) [ Time Frame: Baseline and 24 weeks ]
  6. Change From Baseline in Plasma Fibroblast Growth Factor-19 (FGF-19) [ Time Frame: Baseline and 24 weeks ]
  7. Change From Baseline in Plasma C4 [ Time Frame: Baseline and 24 weeks ]


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female aged 18 to 75 years
  • Must provide written informed consent and agree to comply with the trial protocol
  • Must have a diagnosis of PSC (based on cholangiography at any point in time)
  • Alkaline phosphatase (ALP) at Screening ≥ 2x ULN
  • Total bilirubin at Screening < 2.5x ULN.
  • For subjects with concomitant inflammatory bowel disease (IBD):

    1. Colonoscopy (if subject has a colon) or other appropriate endoscopic procedure within 12 months of Day 0 confirming no dysplasia or colorectal cancer
    2. Subjects with Crohn's Disease (CD) must be in remission as defined by a Crohn's Disease Activity Index (CDAI) <150.
    3. Subjects with ulcerative colitis (UC) must either be in remission or have mild disease. Remission is defined as a partial Mayo score of ≤2 with no individual sub-score exceeding 1. Mild disease is defined as a partial Mayo score ≤3 with no individual sub-score exceeding 1 point.
  • For subjects being administered UDCA as part of their standard of care, the dose must have been stable for ≥ 3 months prior to, and including, Day 0 and must not have exceeded 20 mg/kg/day during this time.
  • Subjects being administered biologic treatments (eg, anti-tumor necrosis factor (TNF) or anti-integrin monoclonal antibodies), immunosuppressants, systemic corticosteroids, or statins, must have been on a stable dose for ≥ 3 months prior to, and including, Day 0 and should plan to remain on a stable dose throughout the trial.
  • Contraception: female subjects of childbearing potential must use ≥ 1 effective method (≤1% failure rate) of contraception during the trial and until 4 weeks following the last dose of IP (including long term safety extension doses).

Exclusion Criteria:

  • Evidence of a secondary cause of sclerosing cholangitis at Screening
  • Immunoglobulin G4 (IgG4) > 4x ULN at Screening or evidence of IgG4 sclerosing cholangitis
  • Small duct cholangitis in the absence of large duct disease
  • Presence of clinical complications of chronic liver disease or clinically significant hepatic decompensation, including:
  • Current Child Pugh classification B or C
  • History of, or current diagnosis or suspicion of, cholangiocarcinoma or other hepatobiliary malignancy, or biliary tract dysplasia.
  • History of liver transplantation, or current model of end stage liver disease score ≥ 12
  • History of, or current, cirrhosis with complications, including history or presence of spontaneous bacterial peritonitis hepatocellular carcinoma or hepatic encephalopathy (as assessed by the investigator)
  • Current known 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 (e.g., beta blockers, insertion of variceal bands or transjugular intrahepatic portosystemic shunt [TIPS])
  • History of, or current, hepatorenal syndrome (type I or II) or Screening serum creatinine > 2 mg/dL (178 μmol/L)
  • Platelet count < 50 x 10⁹/L
  • Current clinical evidence of dominant strictures that are considered clinically relevant in the opinion of the Investigator or current biliary stent at Screening
  • Current cholecystitis or evidence of current biliary obstruction due to gallstones. Asymptomatic gallstones that are not considered a safety risk in the opinion of the Investigator might be acceptable subject to discussion and agreement with the Medical Monitor.
  • Colonic dysplasia within ≤ 5 years prior to Day 0
  • History of small bowel resection
  • History of other chronic liver diseases, including, but not limited to, primary biliary cirrhosis (PBC), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), autoimmune hepatitis, hepatitis B virus (unless seroconverted and no positive Hepatitis B Virus DNA), hepatitis C virus and overlap syndrome
  • Known Gilbert's syndrome or history of elevations in unconjugated (indirect) bilirubin >ULN or unconjugated (indirect) bilirubin >ULN at Screening
  • Known history of human immunodeficiency virus (HIV) infection
  • Currently experiencing, or experienced within ≤ 3 months of Screening, pruritus requiring systemic or enteral treatment
  • Known or suspected acute cholangitis in the 3 months prior to, and including, Day 0 including cholangitis treated with antibiotics
  • Administration of antibiotics is prohibited ≤1 month of Day 0 (unless subject is on a stable prophylaxis dose for at least 3 months prior to Day 0).
  • Administration of the following medications is prohibited ≤ 6 months of Day 0 and throughout the trial: fenofibrate or other fibrates and potentially hepatotoxic medications (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin).
  • IBD flare during Screening (up to and including Day 0), where "flare" is defined as follows:

    • UC flare: partial Mayo Score ≥5, and
    • CD flare: CDAI ≥250
  • Evidence of deleterious effects of alcohol abuse (as assessed by the investigator) or excessive alcohol consumption (>4 units/day for males, >2 units/day for females)
  • Known or suspected use of illicit drugs or drugs of abuse (allowed if medically prescribed or indicated) within 3 months of Day 0
  • If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
  • Other concomitant disease, malignancy, or condition likely to significantly decrease life expectancy to less than the duration of the trial (e.g., moderate to severe congestive heart failure)
  • Participation in another investigational drug, biologic, or medical device trial within 30 days prior to Screening
  • History of noncompliance with medical regimens, or subjects who are considered to be potentially unreliable
  • Blood or plasma donation within 30 days prior to Day 0
  • Mental instability or incompetence such that the validity of informed consent or compliance with the trial is uncertain.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02177136


  Show 35 Study Locations
Sponsors and Collaborators
Intercept Pharmaceuticals
Investigators
Study Director: David Shapiro, MD Intercept Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Intercept Pharmaceuticals:
Study Protocol  [PDF] March 18, 2016
Statistical Analysis Plan  [PDF] April 5, 2017


Responsible Party: Intercept Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02177136     History of Changes
Other Study ID Numbers: 747-207
First Posted: June 27, 2014    Key Record Dates
Results First Posted: May 30, 2018
Last Update Posted: May 30, 2018
Last Verified: April 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Intercept Pharmaceuticals:
PSC

Additional relevant MeSH terms:
Cholangitis
Cholangitis, Sclerosing
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Chenodeoxycholic Acid
Cathartics
Gastrointestinal Agents