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

Sponsor

Intercept Pharmaceuticals (Industry)

Overall Status

Terminated

CT.gov ID

NCT03633227

Collaborator

(none)

Enrollment

Locations

Arms

36.6

Actual Duration (Months)

0.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Actual Enrollment :

22 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 :

Jun 22, 2018

Actual Primary Completion Date :

Jul 9, 2021

Actual Study Completion Date :

Jul 9, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Evaluate maximum concentration (Cmax) of OCA, its conjugates and total OCA (sum of OCA and its conjugates) [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]
Evaluate area under the concentration curve versus time curve from 0 to 24 hours (AUC 0-24) of OCA, its conjugates and total OCA [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
Evaluate safety and tolerability as assessed by the incidence of treatment emergent adverse events and serious treatment emergent adverse events comparing OCA to placebo [Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years]

Secondary Outcome Measures

Evaluate the effect of OCA treatment compared to placebo on the model of end-stage liver disease (MELD) and its components [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
Evaluate the effect of OCA treatment compared to placebo on Child-Pugh score and its components [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]
Evaluate the effect of OCA treatment compared to placebo on total bilirubin (mg/dL) and direct bilirubin (mg/dL) [Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years]
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) [Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years]
Evaluate the effect of OCA treatment compared to placebo on platelets (109/L) [Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years]
Evaluate the effect of OCA treatment compared to placebo on fibroblast growth factor-19 (pg/mL) [Baseline, Screening, Day 1, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years]
. Evaluate the effect of OCA treatment compared to placebo on 7α hydroxy-4-cholesten-3-one (ng/mL) [Baseline, Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years]
Evaluate the effect of OCA treatment compared to placebo on plasma bile acids (µmol/L) [Weeks 3, 6, 12, 18, 24, 30, 36, 42, 48, and every 3 months thereafter through approximately 3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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)

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)

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)

MELD score of 6 to 24 at Screening
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:

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

In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function prior to randomization

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Inland Empire Liver Foundation	Rialto	California	United States	92377
2	University of California, Ddavis Medical Center	Sacramento	California	United States	95817
3	Schiff Center for Liver Diseases/ University of Miami	Miami	Florida	United States	33136
4	Mercy Medical Center	Baltimore	Maryland	United States	21202
5	University Of Michigan	Ann Arbor	Michigan	United States	48109
6	Kansas City Research Institute	Kansas City	Missouri	United States	64131
7	The Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
8	UPMC Center for Liver Diseases	Pittsburgh	Pennsylvania	United States	15213
9	The Liver Institute at Methodist Dallas Medical Center	Dallas	Texas	United States	75203
10	Baylor College of Medicine- Advanced Liver Therapies	Houston	Texas	United States	77030
11	American Research Corporation at theTexas Liver Institute	San Antonio	Texas	United States	78215
12	Hospital Italiano de Buenos Aires	Buenos Aires		Argentina
13	Hospital Universitario Austral	Buenos Aires		Argentina
14	Hospital Aleman	Caba		Argentina
15	Hospital Britanico de Buenos Aires	Caba		Argentina
16	Hospital de Gastroenterologia "Dr Carlos Bonorino Udaondo"	Ciudad Autonoma de Buenos Aire		Argentina
17	Higea S.A.	Mendoza		Argentina	M5500DPS
18	Hospital Universitario Austral	Pilar		Argentina
19	Hospital Provincial del Centenario	Rosario		Argentina
20	Royal Prince Alfred Hospital	Camperdown		Australia	2050
21	Nepean Hospital	Kingswood		Australia	2747
22	CUB Hospital Erasme	Brussels		Belgium	1070
23	Universitair Ziekenhuis Antwerpen UZA	Edegem		Belgium
24	University Hospital Leuven	Leuven		Belgium	3000
25	Hospital das Clínicas da Universidade Federal de Minas Gerais - UFMG	Belo Horizonte		Brazil
26	Hospital de Clinicas de Porto Alegre	Rio Grande		Brazil
27	Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo	São Paulo		Brazil	054003-000
28	Toronto General Hospital	Toronto		Canada
29	West Tallinn Central Hospital	Tallinn		Estonia	10617
30	Tartu University Hospital	Tartu		Estonia
31	Universitatsklinikum Leipzig AoR	Leipzig		Germany	04103
32	Bekes Megyei Kozponti Korhaz Dr. Rethy Pal Tagkorhaz, 4. Belgyogyaszat-Gasztroenterologia-Hepatologia	Bekescsaba		Hungary
33	Azienda Socio Sanitaria Territoriale (ASST) di Monza	Monza	MB	Italy	20900
34	AOU Ospedale Civile S. Agostino Estense - UO Medicina Metabolica	Modena		Italy	41126
35	Hospital of Lithuanian University of Health Sciences Kauno Klinikos	Kaunas		Lithuania
36	Klaipeda Seamen's Hospital	Klaipeda		Lithuania	LT-92288
37	Vilnius University Hospital Santaros Klinikos	Vilnius		Lithuania
38	Paseo Vall d'Hebron	Barcelona		Spain	8035
39	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
40	Hospital Universitari I Politecnic La Fe de Valencia	Valencia		Spain	46026