Study of INT-747 as Monotherapy in Participants With Primary Biliary Cirrhosis (PBC)

Study Overview
=================
Brief Summary
-----------------
The primary hypothesis was that obeticholic acid (OCA) will cause a reduction in alkaline phosphatase levels in PBC participants, over a 12-week treatment period, as compared to placebo.

Detailed Description
-----------------
The study included 2 phases: a 3-month randomized, double-blind (DB), placebo-controlled, parallel group phase, followed by a long-term safety extension (LTSE). The planned duration of the LTSE phase was country-specific, ranging from 108 months to indefinitely. On-site visits occurred at least every 6 months. Following completion of the 3-month DB phase, participants who continued to meet protocol requirements were given the opportunity to enroll in the LTSE phase of the study at selected study sites. The participants who enrolled in the LTSE phase started OCA administration, from a starting dose (10 or 50 milligrams [mg]) based on the dose of OCA or placebo received in the DB phase or on the timing of entry into the LTSE phase. Because the LTSE phase was not planned in the original study design, participants had varied gaps between the end of the DB phase and the start of the LTSE phase. Moreover, some participants initiated ursodeoxycholic acid during the course of that break.

Official Title
-----------------
A Study of INT-747 (6-ECDCA) Monotherapy in Patients With Primary Biliary Cirrhosis

Conditions
-----------------
Liver Cirrhosis, Biliary

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Obeticholic Acid (OCA)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female participants must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use 1 effective method of contraception with all sexual partners during the study and for 14 days after the end of dosing. Male participants must be prepared to use 1 effective method of contraception with all sexual partners during the study during the study unless they had a prior vasectomy. Proven or likely PBC, as demonstrated by the participant presenting with at least 2 of the following 3 diagnostic factors: History of increased alkaline phosphatase (ALP) levels for at least 6 months; Positive antimitochondrial antibody titer (>1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay) or PBC-specific antinuclear antibodies (antinuclear dot and nuclear rim positive); Liver biopsy consistent with PBC Screening ALP level between 1.5 and 10 × upper limit of normal (ULN). Exclusion Criteria: Administration of the following drugs at any time during the 3 months prior to screening for the study: ursodeoxycholic acid, colchicine, methotrexate, azathioprine, or systemic corticosteroids. Screening conjugated (direct) bilirubin >2 × ULN. Screening alanine aminotransferase or aspartate aminotransferase >5 × ULN. Screening serum creatinine >133 micromoles/liter (1.5 mg/deciliter). History or presence of hepatic decompensation (for example, variceal bleeds, encephalopathy, or poorly controlled ascites). History or presence of other concomitant liver diseases including hepatitis due to hepatitis B or C virus infection, primary sclerosing cholangitis, alcoholic liver disease, definite autoimmune liver disease or biopsy proven nonalcoholic steatohepatitis. Pregnancy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DB OCA 10 mg<br>OCA 10 mg for 3 months during the DB phase. | Drug: Obeticholic Acid (OCA)<br>* Starting dose of 10 or 50 mg administered orally once daily, followed by dose titration planned from 10 mg to 25 mg to 50 mg once daily, which could be modified for safety and tolerability issues or to achieve adequate therapeutic response.<br>* Other names: 6α-ethyl-chenodeoxycholic acid (6-ECDCA);|
| Experimental: DB OCA 50 mg<br>OCA 50 mg for 3 months during the DB phase. | Drug: Obeticholic Acid (OCA)<br>* Starting dose of 10 or 50 mg administered orally once daily, followed by dose titration planned from 10 mg to 25 mg to 50 mg once daily, which could be modified for safety and tolerability issues or to achieve adequate therapeutic response.<br>* Other names: 6α-ethyl-chenodeoxycholic acid (6-ECDCA);|
| Placebo Comparator: DB OCA Placebo<br>Matching placebo for 3 months during the DB phase. | Drug: Placebo<br>* Matching placebo tablets were administered orally once daily.<br>|
| Experimental: LTSE OCA Total<br>After completion of the 3-month DB phase, all eligible participants were offered the opportunity to enter an open-label LTSE for up to 96 months beginning at 10 mg OCA. Doses up to 50 mg daily were evaluated. | Drug: Obeticholic Acid (OCA)<br>* Starting dose of 10 or 50 mg administered orally once daily, followed by dose titration planned from 10 mg to 25 mg to 50 mg once daily, which could be modified for safety and tolerability issues or to achieve adequate therapeutic response.<br>* Other names: 6α-ethyl-chenodeoxycholic acid (6-ECDCA);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DB Phase: Mean Percent Change In Serum Alkaline Phosphatase (ALP) From Baseline To Day 85 | The percent change in serum ALP from baseline to Day 85 is reported. The baseline value used was the mean of the pretreatment Screening and Day 0 evaluations. | Baseline, Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DB Phase: Mean Percent Change In Gamma-glutamyl Transferase (GGT) From Baseline To Day 85 | As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to Day 85 is reported. | Baseline, Day 85 | 
| DB Phase: Mean Percent Change In Alanine Transaminase (ALT) From Baseline To Day 85 | As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to Day 85 is reported. | Baseline, Day 85 | 
| DB: Plasma Trough Concentrations Of OCA And Its Major, Known Metabolites |  | 12 weeks | 
| DB Phase: Mean Percent Change In Conjugated Bilirubin From Baseline To Day 85 | As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to Day 85 is reported. | Baseline, Day 85 | 
| LTSE Phase: Median Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit | The percent change in serum ALP from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Month 24, Month 48, Month 72, Last Available Visit (up to 96 months) | 
| LTSE Phase: Mean Percent Change In Serum ALP From Baseline To Month 24, Month 48, Month 72, And Last Available Visit | The percent change in serum ALP from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Month 24, Month 48, Month 72, Last Available Visit (up to 96 months) | 
| LTSE: Median Percent Change In GGT From Baseline To Last Available Visit | As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Last Available Visit (up to 96 months) | 
| LTSE: Mean Percent Change In GGT From Baseline To Last Available Visit | As a marker of hepatocellular injury and liver function, the percent change in GGT from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Last Available Visit (up to 96 months) | 
| LTSE: Median Percent Change In ALT From Baseline To Last Available Visit | As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Last Available Visit (up to 96 months) | 
| LTSE: Mean Percent Change In ALT From Baseline To Last Available Visit | As a marker of hepatocellular injury and liver function, the percent change in ALT from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Last Available Visit (up to 96 months) | 
| LTSE: Median Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit | As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Last Available Visit (up to 96 months) | 
| LTSE: Mean Percent Change In Conjugated Bilirubin From Baseline To Last Available Visit | As a marker of hepatocellular injury and liver function, the percent change in conjugated bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Last Available Visit (up to 96 months) | 
| LTSE: Median Percent Change In Total Bilirubin From Baseline To Last Available Visit | As a marker of hepatocellular injury and liver function, the percent change in total bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Last Available Visit (up to 96 months) | 
| LTSE: Mean Percent Change In Total Bilirubin From Baseline To Last Available Visit | As a marker of hepatocellular injury and liver function, the percent change in total bilirubin from baseline to the last available visit is reported. The DB baseline value was used as the baseline. | Baseline (DB), Last Available Visit (up to 96 months) |