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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00570765

Enrollment

Registered

2007-12-11

Start date

2008-01-17

Completion date

2017-09-25

Last updated

2021-06-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Liver Cirrhosis, Biliary

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.

Interventions

DRUGPlacebo

Matching placebo tablets were administered orally once daily.

DRUGObeticholic Acid (OCA)

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
DB Phase: Mean Percent Change In Serum Alkaline Phosphatase (ALP) From Baseline To Day 85	Baseline, 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.

Secondary

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

Countries

Austria, Canada, France, Germany, Spain, United Kingdom, United States

Participant flow

Recruitment details

Recruitment started Dec. 2007 and completed June 2010. Due to positive Phase 2 data in another study (NCT00550862), power calculations were revised and recruitment ended early. Eligible participants who received treatment in the double-blind (DB) phase could continue receiving obeticholic acid (OCA) in the long-term safety extension (LTSE) phase.

Pre-assignment details

Screening interim allowed for pre-randomization eligibility assessment of 1 to 4 weeks. Other than 3-month (pre-Screening) washout for ursodeoxycholic acid and other medications, no washout or run-in period was defined between Screening and Randomization. During LTSE, OCA dosing (milligrams \[mg\]) remained oral once daily.

Participants by arm

Arm	Count
DB OCA 10 mg OCA 10 mg for 3 months during the DB phase. 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.	20
DB OCA 50 mg OCA 50 mg for 3 months during the DB phase. 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.	16
DB OCA Placebo Matching placebo for 3 months during the DB phase. 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.	23
Total	59

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
DB Phase	Adverse Event	3	6	0	0
DB Phase	Did Not Receive Study Drug	0	0	1	0
DB Phase	Protocol Violation	0	1	0	0
DB Phase	Withdrawal by Subject	1	0	0	0
LTSE Phase	Adverse Event	0	0	0	7
LTSE Phase	Physician Decision	0	0	0	4
LTSE Phase	Withdrawal by Subject	0	0	0	1

Baseline characteristics

Characteristic	DB OCA 10 mg	DB OCA 50 mg	DB OCA Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	4 Participants	1 Participants	5 Participants	10 Participants
Age, Categorical Between 18 and 65 years	16 Participants	15 Participants	18 Participants	49 Participants
Age, Continuous	54.8 years STANDARD_DEVIATION 10.9	54.1 years STANDARD_DEVIATION 7.3	55.3 years STANDARD_DEVIATION 10	54.8 years STANDARD_DEVIATION 9.5
Region of Enrollment Canada	3 participants	2 participants	4 participants	9 participants
Region of Enrollment France	2 participants	1 participants	1 participants	4 participants
Region of Enrollment Germany	4 participants	1 participants	3 participants	8 participants
Region of Enrollment Spain	0 participants	1 participants	1 participants	2 participants
Region of Enrollment United Kingdom	7 participants	6 participants	6 participants	19 participants
Region of Enrollment United States	4 participants	5 participants	8 participants	17 participants
Sex: Female, Male Female	14 Participants	16 Participants	20 Participants	50 Participants
Sex: Female, Male Male	6 Participants	0 Participants	3 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	18 / 20	15 / 16	19 / 23	28 / 28
serious Total, serious adverse events	0 / 20	0 / 16	1 / 23	9 / 28

Outcome results

Primary

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.

Time frame: Baseline, Day 85

Population: Intention-to-treat (ITT): participants randomized to receive investigational product regardless of their actual treatment status.

Arm	Measure	Value (MEAN)	Dispersion
DB OCA 10 mg	DB Phase: Mean Percent Change In Serum Alkaline Phosphatase (ALP) From Baseline To Day 85	-44.5 Percent change	Standard Deviation 24.4
DB OCA 50 mg	DB Phase: Mean Percent Change In Serum Alkaline Phosphatase (ALP) From Baseline To Day 85	-37.6 Percent change	Standard Deviation 21
DB OCA Placebo	DB Phase: Mean Percent Change In Serum Alkaline Phosphatase (ALP) From Baseline To Day 85	0.4 Percent change	Standard Deviation 15.3

Comparison: Hierarchical testing strategy was proposed to account for multiple comparisons. Statistical significance was evaluated as follows: if statistical significance at alpha=0.05 is shown for the 10 mg OCA versus placebo, then the statistical significance at alpha=0.05 for the 50 mg OCA versus placebo was evaluated. If no statistical significance was shown at alpha=0.05 at the first step, then the subsequent comparison was not considered statistically significant.p-value: <0.0001Wilcoxon (Mann-Whitney)

Secondary

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.

Time frame: Baseline, Day 85

Population: Intention-to-treat (ITT): participants randomized to receive investigational product regardless of their actual treatment status.

Arm	Measure	Value (MEAN)	Dispersion
DB OCA 10 mg	DB Phase: Mean Percent Change In Alanine Transaminase (ALT) From Baseline To Day 85	-37 Percent change	Standard Deviation 35
DB OCA 50 mg	DB Phase: Mean Percent Change In Alanine Transaminase (ALT) From Baseline To Day 85	-35 Percent change	Standard Deviation 25
DB OCA Placebo	DB Phase: Mean Percent Change In Alanine Transaminase (ALT) From Baseline To Day 85	-4 Percent change	Standard Deviation 40

p-value: <0.01Wilcoxon (Mann-Whitney)

Secondary

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.

Time frame: Baseline, Day 85

Population: Intention-to-treat (ITT): participants randomized to receive investigational product regardless of their actual treatment status.

Arm	Measure	Value (MEAN)	Dispersion
DB OCA 10 mg	DB Phase: Mean Percent Change In Conjugated Bilirubin From Baseline To Day 85	0.7 Percent Change	Standard Deviation 67.3
DB OCA 50 mg	DB Phase: Mean Percent Change In Conjugated Bilirubin From Baseline To Day 85	-1.7 Percent Change	Standard Deviation 39.9
DB OCA Placebo	DB Phase: Mean Percent Change In Conjugated Bilirubin From Baseline To Day 85	30.3 Percent Change	Standard Deviation 69.8

Secondary

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.

Time frame: Baseline, Day 85

Population: Intention-to-treat (ITT): participants randomized to receive investigational product regardless of their actual treatment status.

Arm	Measure	Value (MEAN)	Dispersion
DB OCA 10 mg	DB Phase: Mean Percent Change In Gamma-glutamyl Transferase (GGT) From Baseline To Day 85	-73 Percent change	Standard Deviation 18
DB OCA 50 mg	DB Phase: Mean Percent Change In Gamma-glutamyl Transferase (GGT) From Baseline To Day 85	-65 Percent change	Standard Deviation 25
DB OCA Placebo	DB Phase: Mean Percent Change In Gamma-glutamyl Transferase (GGT) From Baseline To Day 85	-3 Percent change	Standard Deviation 22

p-value: <0.0001Wilcoxon (Mann-Whitney)

Secondary

DB: Plasma Trough Concentrations Of OCA And Its Major, Known Metabolites

Time frame: 12 weeks

Population: OCA and its conjugates were quantified by an assay using an extended and improved protocol initially described in peer reviewed literature. The assay was not validated when the study was conducted. A validated assay was established using plasma after the study. But because only serum samples, not plasma samples, were acquired in the study, the levels of OCA and its conjugates were not summarized in the clinical study report, and thus, not used to draw conclusions on exposure.

Secondary

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.

Time frame: Baseline (DB), Last Available Visit (up to 96 months)