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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03633227




Registration number
NCT03633227
Ethics application status
Date submitted
8/04/2018
Date registered
16/08/2018
Date last updated
16/08/2019

Titles & IDs
Public title
Study of OCA Evaluating Pharmacokinetics and Safety in Patients With PBC and Hepatic Impairment
Scientific 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
Secondary ID [1] 0 0
747-401
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver Cirrhosis, Biliary 0 0
Condition category
Condition code
Inflammatory and Immune System 0 0 0 0
Connective tissue diseases
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Cancer 0 0 0 0
Liver

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Obeticholic Acid (OCA)
Treatment: Drugs - Placebo

Experimental: Obeticholic Acid (OCA) 5 mg to 10 mg -

Placebo Comparator: Placebo -


Treatment: Drugs: 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.

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

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Evaluate maximum concentration (Cmax) of OCA, its conjugates and total OCA (sum of OCA and its conjugates)
Timepoint [1] 0 0
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
Primary outcome [2] 0 0
Evaluate area under the concentration curve versus time curve from 0 to 24 hours (AUC 0-24) of OCA, its conjugates and total OCA - Area under the concentration versus time curve from time 0 to 24 hours with measurable analyte concentration
Timepoint [2] 0 0
24 hours at Day 1, and Weeks 12, 18, 24, 30, 36, and 48
Primary outcome [3] 0 0
Evaluate safety and tolerability as assessed by the incidence of treatment emergent adverse events and serious treatment emergent adverse events comparing OCA to placebo
Timepoint [3] 0 0
Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years
Secondary outcome [1] 0 0
Evaluate the effect of OCA treatment compared to placebo on the model of end-stage liver disease (MELD) and its components - 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
Timepoint [1] 0 0
Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years
Secondary outcome [2] 0 0
Evaluate the effect of OCA treatment compared to placebo on Child-Pugh score and its components - 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]
Timepoint [2] 0 0
At Day 1, and Weeks 6, 12, 18, 24, 30, 36, and 48
Secondary outcome [3] 0 0
Evaluate the effect of OCA treatment compared to placebo on total bilirubin (mg/dL) and direct bilirubin (mg/dL)
Timepoint [3] 0 0
Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years
Secondary outcome [4] 0 0
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)
Timepoint [4] 0 0
Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years
Secondary outcome [5] 0 0
Evaluate the effect of OCA treatment compared to placebo on platelets (109/L)
Timepoint [5] 0 0
Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years
Secondary outcome [6] 0 0
Evaluate the effect of OCA treatment compared to placebo on fibroblast growth factor-19 (pg/mL)
Timepoint [6] 0 0
Baseline, Screening, Day 1, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years
Secondary outcome [7] 0 0
. Evaluate the effect of OCA treatment compared to placebo on 7a hydroxy-4-cholesten-3-one (ng/mL)
Timepoint [7] 0 0
Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years
Secondary outcome [8] 0 0
Evaluate the effect of OCA treatment compared to placebo on plasma bile acids (µmol/L)
Timepoint [8] 0 0
Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years

Eligibility
Key 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)
Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 0 0
Nepean Hospital - Kingswood
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2747 - Kingswood
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Michigan
Country [5] 0 0
United States of America
State/province [5] 0 0
Missouri
Country [6] 0 0
United States of America
State/province [6] 0 0
Ohio
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Washington
Country [10] 0 0
Argentina
State/province [10] 0 0
Caba
Country [11] 0 0
Belgium
State/province [11] 0 0
Brussels
Country [12] 0 0
Belgium
State/province [12] 0 0
Leuven
Country [13] 0 0
Brazil
State/province [13] 0 0
Rio Grande
Country [14] 0 0
Estonia
State/province [14] 0 0
Tallinn
Country [15] 0 0
Estonia
State/province [15] 0 0
Tartu
Country [16] 0 0
Germany
State/province [16] 0 0
Leipzig
Country [17] 0 0
Italy
State/province [17] 0 0
MB
Country [18] 0 0
Lithuania
State/province [18] 0 0
Kaunas
Country [19] 0 0
Lithuania
State/province [19] 0 0
Vilnius
Country [20] 0 0
Spain
State/province [20] 0 0
Barcelona
Country [21] 0 0
Spain
State/province [21] 0 0
Sevilla
Country [22] 0 0
Spain
State/province [22] 0 0
Valencia

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Intercept Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT03633227
Trial related presentations / publications
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.
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009 Aug;51(2):237-67. doi: 10.1016/j.jhep.2009.04.009. Epub 2009 Jun 6.
Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. doi: 10.1002/hep.27210. Epub 2014 Jul 8.
Public notes

Contacts
Principal investigator
Name 0 0
Christian Weyer, M.D.
Address 0 0
Intercept Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Alberto Rodriguez
Address 0 0
Country 0 0
Phone 0 0
+1(619)541-7426
Fax 0 0
Email 0 0
alberto.rodriguez@interceptpharma.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03633227