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Study of OCA Evaluating Pharmacokinetics and Safety in Patients With PBC and Hepatic Impairment

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ClinicalTrials.gov Identifier: NCT03633227
Recruitment Status : Recruiting
First Posted : August 16, 2018
Last Update Posted : August 16, 2019
Sponsor:
Information provided by (Responsible Party):
Intercept Pharmaceuticals

Brief Summary:
This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and safety of OCA treatment in patients with primary biliary cholangitis (PBC) and moderate to severe hepatic impairment over a 48 week treatment period. Patients who have completed their 48-week double blind treatment period will continue double-blind treatment until all randomized patients have completed their 48-week treatment period and the database for that period is locked. An open-label extension study in which all patients receive OCA will be considered following review of blinded safety and PK data.

Condition or disease Intervention/treatment Phase
Liver Cirrhosis, Biliary Drug: Obeticholic Acid (OCA) Drug: Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating the Pharmacokinetics and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment
Actual Study Start Date : June 22, 2018
Estimated Primary Completion Date : June 1, 2020
Estimated Study Completion Date : June 1, 2020


Arm Intervention/treatment
Experimental: Obeticholic Acid (OCA) 5 mg to 10 mg Drug: Obeticholic Acid (OCA)
Moderate and Severe hepatic impairment classified as Child-Pugh Class B and C: 5 mg tablet of OCA once weekly titrating up to 5 mg OCA twice weekly based on tolerability at 3 months and subsequently titrating up to a maximum dose of 10 mg OCA twice weekly based on safety and tolerability for the duration of the study.
Other Names:
  • 6alpha-ethylchenodeoxycholic acid (6-ECDCA)
  • INT-747

Placebo Comparator: Placebo Drug: Placebo
One tablet twice weekly (or a lower frequency based on safety and tolerability) for the duration of the study




Primary Outcome Measures :
  1. Evaluate maximum concentration (Cmax) of OCA, its conjugates and total OCA (sum of OCA and its conjugates) [ Time Frame: Weeks 12, 18, 24, 30 and 48: 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours at ]
  2. Evaluate area under the concentration curve versus time curve from 0 to 24 hours (AUC 0-24) of OCA, its conjugates and total OCA [ Time Frame: 24 hours at Day 1, and Weeks 12, 18, 24, 30, 36, and 48 ]
    Area under the concentration versus time curve from time 0 to 24 hours with measurable analyte concentration

  3. Evaluate safety and tolerability as assessed by the incidence of treatment emergent adverse events and serious treatment emergent adverse events comparing OCA to placebo [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]

Secondary Outcome Measures :
  1. Evaluate the effect of OCA treatment compared to placebo on the model of end-stage liver disease (MELD) and its components [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]

    MELD Scores range from 6 [low risk] to 40 [high risk]. The three components of MELD (total bilirubin [mg/dL], serum creatinine[mg/dL], and INR) are input into the following equation to generate a MELD Score:

    MELD = 3.78×ln[total bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43


  2. Evaluate the effect of OCA treatment compared to placebo on Child-Pugh score and its components [ Time Frame: At Day 1, and Weeks 6, 12, 18, 24, 30, 36, and 48 ]
    The 5 components of the Child Pugh Score are scored on a scale of 1-3 by increasing severity and then summed together to calculate the total score (range: 5 [compensated cirrhosis] - 15 [decompensated cirrhosis]). The components of the Child Pugh Score are total bilirubin [mg/dL], serum albumin [g/dL], INR, Ascites [none-severe], hepatic encephalopathy [none-grade 4]

  3. Evaluate the effect of OCA treatment compared to placebo on total bilirubin (mg/dL) and direct bilirubin (mg/dL) [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
  4. Evaluate the effect of OCA treatment compared to placebo on alkaline phosphatase (U/L), alanine aminotransferase (U/L), aspartate transaminase (U/L), and gamma glutamyl transaminase (U/L) [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
  5. Evaluate the effect of OCA treatment compared to placebo on platelets (109/L) [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
  6. Evaluate the effect of OCA treatment compared to placebo on fibroblast growth factor-19 (pg/mL) [ Time Frame: Baseline, Screening, Day 1, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
  7. . Evaluate the effect of OCA treatment compared to placebo on 7α hydroxy-4-cholesten-3-one (ng/mL) [ Time Frame: Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]
  8. Evaluate the effect of OCA treatment compared to placebo on plasma bile acids (µmol/L) [ Time Frame: Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years ]


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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. A definite or probable diagnosis of PBC (consistent with American Association for the Study of Liver Diseases [AASLD] and European Association for the Study of the Liver [EASL] Practice Guidelines [Lindor 2009, EASL 2009]), defined as having ≥2 of the following 3 diagnostic factors:

    • History of elevated ALP levels for at least 6 months
    • Positive antimitochondrial antibody (AMA) titer or if AMA negative or 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)
    • Liver biopsy consistent with PBC (collected at any time prior to Screening)
  2. Evidence of cirrhosis including at least one of the following:

    • Biopsy results consistent with PBC Stage 4
    • Liver stiffness as assessed by Transient Elastography (TE) Median Value ≥16.9kPa
    • Clinical evidence in the absence of acute liver failure consistent with cirrhosis including: gastroesophageal varices, ascites, radiological evidence of cirrhosis (nodular liver or enlargement of portal vein and splenomegaly)
    • Combined low platelet count (<140 000/mm3) with

      • persistent decrease in serum albumin, or
      • elevation in prothrombin time /INR (not due to antithrombotic agent use), or
      • elevated bilirubin (2× ULN)
  3. Satisfy the criteria of the modified CP classification for hepatic impairment during Screening:

    • Moderate: CP-B (Scores 7 to 9) or
    • Severe: CP-C (Scores 10 to 12)
  4. MELD score of 6 to 24 at Screening
  5. Taking UDCA for at least 12 months (stable dose for ≥3 months) prior to Day 1, or unable to tolerate or unresponsive to UDCA (no UDCA for ≥3 months)

Exclusion Criteria:

  1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6)
  2. History of liver transplant or organ transplant
  3. History of alcohol or drug abuse within 12 months prior to Screening
  4. Hepatic encephalopathy (as defined by a West Haven score of ≥2 [AASLD, EASL 2014])
  5. History or presence of other concomitant liver diseases including:

    • Hepatitis C virus infection and RNA positive
    • Active hepatitis B infection; however, patients who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the medical monitor
    • Primary sclerosing cholangitis
    • Alcoholic liver disease
    • Definite autoimmune liver disease or overlap hepatitis
    • Gilbert's Syndrome
  6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function prior to randomization

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): NCT03633227


Contacts
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Contact: Alberto Rodriguez +1(619)541-7426 alberto.rodriguez@interceptpharma.com

  Show 27 Study Locations
Sponsors and Collaborators
Intercept Pharmaceuticals
Investigators
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Study Director: Christian Weyer, M.D. Intercept Pharmaceuticals

Publications:
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Responsible Party: Intercept Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03633227     History of Changes
Other Study ID Numbers: 747-401
First Posted: August 16, 2018    Key Record Dates
Last Update Posted: August 16, 2019
Last Verified: August 2019

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

Keywords provided by Intercept Pharmaceuticals:
Primary Biliary Cholangitis
Primary Biliary Cirrhosis
PBC
Hepatic Impairment
Cirrhosis
Liver

Additional relevant MeSH terms:
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Fibrosis
Liver Cirrhosis
Liver Diseases
Liver Cirrhosis, Biliary
Pathologic Processes
Digestive System Diseases
Cholestasis, Intrahepatic
Cholestasis
Bile Duct Diseases
Biliary Tract Diseases
Chenodeoxycholic Acid
Cathartics
Gastrointestinal Agents