Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis

Phase 4TerminatedNCT02308111

Intercept Pharmaceuticals334 enrolled

Overview

Primary Biliary Cholangitis (PBC) is a serious, life-threatening, bile acid related liver disease of unknown cause. Without treatment, it frequently progresses to liver fibrosis and eventual cirrhosis requiring liver transplantation or resulting in death. The investigational drug, Obeticholic Acid (OCA) is a modified bile acid and FXR agonist that is derived from the primary human bile acid chenodeoxycholic acid. The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. The study will assess the effect of OCA compared to placebo, combined with stable standard care, on clinical outcomes in PBC participants.

This Phase 4, double-blind, randomized, placebo-controlled, multicenter study is being undertaken at up to 170 sites internationally to evaluate the effect of OCA on clinical outcomes in 428 participants with PBC. The study will include a screening period of up to 8 weeks, requiring two clinic visits. Eligible participants will be randomly allocated (1:1) to treatment with either OCA 5 mg or matching placebo tablets, taken orally once daily for the majority of participants; dose and frequency will be modified for participants with cirrhosis and classified as Child-Pugh (CP) B or C. Randomization will be stratified by standard treatment with UDCA (yes/no) and baseline liver function. The treatment period involves clinic visits approximately every 3 months. At the 3 month visit or any study visit thereafter, if study treatment is tolerated, participants' dose should be titrated per protocol in a blinded manner eg for participants who are non-cirrhotic or classified as CP A and randomized to OCA, they should receive the maximum daily dose of 10 mg OCA, those on placebo continue to receive placebo. Subsequently, daily dosage may return to 5 mg if necessary for these participants who are non-cirrhotic or classified as CP A, but should be increased to 10 mg if possible, based on tolerability and clinical judgment. Safety and tolerability will be assessed by monitoring adverse events and vital signs, and blood and urine testing. The study is event driven and total duration will be determined by the time required to accrue approximately 127 primary endpoint events, estimated to be approximately 10 years. Participants are expected to have a minimum follow-up time of approximately 6 years.

Study Type

INTERVENTIONAL

Interventions

Obeticholic Acid (OCA)DRUG

Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants). Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, subsequently titrating up to a maximum dose and frequency of 10 mg OCA twice weekly based on tolerability and biochemical response for the duration of the study.

PlaceboDRUG

One tablet daily (or a lower frequency depending on CP score) for the remainder of the study

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Diseases \[AASLD\] and the European Association for the Study of the Liver \[EASL\] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥2 of the following 3 diagnostic factors: * History of elevated Alkaline phosphatase levels for at least 6 months * Positive antimitochondrial antibody (AMA) titer or if AMA negative or in 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 2. A mean total bilirubin \>ULN and ≤5x ULN and/or a mean ALP \>3x ULN 3. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0 Exclusion Criteria: 1. History or presence of other concomitant liver diseases including: * Hepatitis C virus infection * Active Hepatitis B infection; however, subjects 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 (PSC) * Alcoholic liver disease * Definite autoimmune liver disease or overlap hepatitis * Nonalcoholic steatohepatitis (NASH) * Gilbert's Syndrome 2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including: * History of liver transplant, current placement on a liver transplant list, or current Model of End Stage Liver Disease (MELD) score \>12. Subjects who are placed on a transplant list despite a relatively early disease stage (for example per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria * Cirrhosis with complications, including history (within the past 12 months) or presence of: * Variceal bleed * Uncontrolled ascites * Encephalopathy * Spontaneous bacterial peritonitis * Known or suspected HCC * Prior transjugular intrahepatic portosystemic shunt procedure * Hepatorenal syndrome (type I or II) or screening (Visit 1 or 2) serum creatinine \>2 mg/dL (178 μmol/L) 3. Mean total bilirubin \>5x ULN 4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures 5. Other medical conditions that may diminish life expectancy, including known cancers (except carcinomas in situ or other stable, relatively benign conditions) 6. If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating 7. Known history of human immunodeficiency virus infection 8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 3 months) 9. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the study 10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 11. Participation in another investigational product, biologic, or medical device study within 30 days prior to Screening. Participation in a previous study of OCA is allowed with 3 months washout prior to enrollment in this study 12. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain 13. History of known or suspected clinically significant hypersensitivity to OCA or any of its components 14. UDCA naïve (unless contraindicated)

Locations (181)

Mayo Clinic Arizona

Phoenix, Arizona, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

Inland Empire Liver Foundation

Rialto, California, United States

University of California Davis, Davis Medical Center

Sacramento, California, United States

Stanford University

Stanford, California, United States

Outcomes

Primary Outcomes

Time to the First Occurrence of Composite Endpoint

To assess the effect of OCA, compared to placebo in conjunction with the established local standard of care, on clinical outcomes in participants with PBC as measured by time to the first occurrence of any of the following adjudicated events, derived as a composite event endpoint of death, liver transplant, model of end-stage liver disease (MELD) ≥15, uncontrolled ascites, or hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy (as defined by a West Haven score of \>=2), or spontaneous bacterial peritonitis. The clinical events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% confidence intervals (CIs) for the clinical events distribution percentiles (25th and 50th) are provided.

Time frame: Time to first occurrence from date of randomization until the time to accrue approximately 127 primary endpoint events (up to 7 years)

Time to the First Occurrence of Primary Clinical Event (Expanded Endpoint)

Primary clinical outcome event is the first occurrence of the following events: death, liver transplant, MELD score \>=15 (MELD-Na score \>=12 baseline), MELD-Na score \>=15 (MELD-Na score \<12 baseline), hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis), or bacterial empyema, uncontrolled or refractory ascites (requiring large volume paracentesis), portal hypertension syndromes, progression to decompensated liver disease, and progression to clinical evidence of portal hypertension without decompensation (for participants without decompensation or clinical evidence of portal hypertension at baseline). 71 endpoint events were observed in the OCA arm, and 80 were observed in the Placebo arm. The clinical events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the clinical events distribution percentiles (25th and 50th) are provided.

Time frame: Time to first occurrence from date of randomization until the time to accrue approximately 127 primary endpoint events (up to 7 years)

Secondary Outcomes

Time To First Occurrence Of Severe Decompensating Events of Expanded Composite Endpoint

The first occurrence of the key secondary clinical event refers to the first occurrence of the following events: death, liver transplant, MELD-Na score \>=15 if MELD-Na\< 12 at baseline, MELD score \>=15 if MELD-Na \>=12 at baseline, uncontrolled or refractory ascites, portal hypertension syndromes (hepatorenal syndrome, portopulmonary syndrome, hepatopulmonary syndrome) or hospitalization for new onset or recurrence of variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis, or bacterial empyema. The clinical events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the clinical events distribution percentiles (25th and 50th) are provided.

Time frame: Time to first occurrence from date of randomization until the date of first documented progression or date of death from any cause, whichever came first (up to 7 years)

Time To Liver Transplant Or Death (All-cause)

The effect of OCA compared to placebo on time to liver transplant or death (all-cause) was assessed. The events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the clinical events distribution percentiles (25th and 50th) are provided.

Time frame: Time to first occurrence from date of randomization until the date of first documented liver transplant or date of death from any cause (up to 7 years)

Time to First Occurrence of Fatal Event (All-Cause)

The results represent the ratio of OCA to placebo. The fatal events distribution was estimated using the Kaplan-Meier methodology. Point estimates and 95% CIs for the fatal events distribution percentiles (25th and 50th) are provided

Time frame: Time to first occurrence from date of randomization until the date of death from any cause (up to 7 years)

Time to First Occurrence of Liver Transplant

The effect of OCA compared to placebo on time to occurrence of a liver transplant was assessed. The results represented the ratio of OCA to placebo. A hazard ratio \<1 indicated an advantage for OCA. The event of interest was summarized through Cumulative Incidence Function (CIF) estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first documented liver transplant or date of death from any cause (up to 5 years)

Time to First Occurrence of Hospitalization Due to Hepatic Events

Hospitalization events include new onset or recurrent variceal bleed, hepatic encephalopathy (as defined by a West Haven score of \>=2), spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis OR presence of \>250/mm\^3 polymorph leucocytes \[PMNs\] in the ascitic fluid), bacterial empyema is confirmed by diagnostic thoracentesis OR presence of \>250/mm\^3 PMNs in the pleural fluid. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of hospitalization, liver transplant or death from any cause, whichever came first (up to 5 years)

Time to First Occurrence of Uncontrolled or Refractory Ascites

Uncontrolled or refractory ascites are defined as diuretic-resistant ascites requiring large-volume paracentesis. The effect of OCA compared to placebo on time to the first occurrence of uncontrolled or refractory ascites was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first documented uncontrolled or refractory ascites, liver transplant or date of death from any cause, whichever came first (up to 5 years)

Time to First Occurrence of MELD Score ≥15

The MELD score is useful in assessing participants with significant decompensation. The MELD score is now used by the United Network for Organ Sharing in the United States and Eurotransplants to manage organ allocation for liver transplantation. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and International Normalized Ratio (INR), as appropriate, to predict survival. The MELD score ranges from 6 to 40. The higher the score, the more likely a participant will receive a liver from a deceased donor when an organ becomes available. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first documented MELD Score ≥15, liver transplant or date of death from any cause, whichever came first (up to 5 years)

Time To Development Of Varix/Varices

The effect of OCA compared to placebo on time to development of varix/varices was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first documented development of varix/varices, liver transplant or death from any cause, whichever came first (up to 5 years)

Time To Liver-Related Death

The effect of OCA compared to placebo on time to liver-related death was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of first liver-related or non-liver- related death, whichever came first (up to 5 years)

Time To Liver-Related Death Or Liver Transplant

The effect of OCA compared to placebo on time to liver-related death or liver transplant was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of liver transplant, liver-related death or non-liver-related death from any cause, whichever came first (up to 5 years)

Time To Liver-Related Death, Liver Transplant, Or MELD Score ≥15

The effect of OCA compared to placebo on time to liver-related death, liver transplant, or MELD Score ≥15 was assessed. The MELD score is useful in assessing participants with significant decompensation. The MELD score is now used by the United Network for Organ Sharing in the United States and Eurotransplants to manage organ allocation for liver transplantation. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and INR, as appropriate, to predict survival. The MELD score ranges from 6 to 40. The higher the score, the more likely a participant will receive a liver from a deceased donor when an organ becomes available. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of liver transplant, liver-related death, non-liver-related death from any cause or MELD Score ≥15, whichever came first (up to 5 years)

Progression To Cirrhosis (for Noncirrhotic Subjects at Baseline)

When a participant is identified as noncirrhotic at the Baseline and exhibited any signs or symptoms associated with progression to cirrhosis, the participant was assessed by Fibroscan® TE where available. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of cirrhosis, liver transplant or death from any cause, whichever came first (up to 5 years)

Time To Occurrence Of Hepatocellular Carcinoma (HCC)

The effect of OCA compared to placebo on time to occurrence of HCC was assessed. The event of interest was summarized through CIF estimate at 5 years.

Time frame: Time to first occurrence from date of randomization until the date of HCC diagnosis, liver transplant or death from any cause, whichever came first (up to 5 years)

Change From Baseline To Month 24 Of Total Bilirubin

Liver biochemistry, which includes total bilirubin, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using mixed model repeated measures (MMRM), including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Change From Baseline To Month 24 Of Direct Bilirubin

Liver biochemistry, which includes direct bilirubin, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Change From Baseline To Month 24 Of Aspartate Aminotransferase (AST)

Liver biochemistry, which includes AST, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Change From Baseline To Month 24 Of Alanine Aminotransferase (ALT)

Liver biochemistry, which includes ALT, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Change From Baseline To Month 24 Of Alkaline Phosphatase (ALP)

Liver biochemistry, which includes ALP, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Change From Baseline To Month 24 Of Gamma-glutamyl Transferase (GGT)

Liver biochemistry, which includes GGT, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Change From Baseline To Month 24 Of Albumin

Liver biochemistry, which includes albumin, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Change From Baseline To Month 24 Of INR

The coagulation test, which includes INR, was assessed to evaluate biochemical triggers that would prompt an immediate reevaluation of participants for potential hepatic injury or hepatic decompensation. INR is the ratio of tested prothrombin time to normal prothrombin time, to a power designated the international sensitivity index (ISI). INR normal range is 0.8 to 1.2 (female and male). Analysis was performed using MMRM, including treatment group, time, treatment group by time interaction, and randomization stratification factors as entered in the IWRS as fixed effects and baseline values as a covariate.

Time frame: Baseline up to Month 24

Change From Baseline To Month 72 Of MELD Score

The MELD score is useful in assessing participants with significant decompensation. The MELD score is now used by the United Network for Organ Sharing in the United States and Eurotransplants to manage organ allocation for liver transplantation. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and INR, as appropriate, to predict survival. The MELD score ranges from 6 to 40. The higher the score, the more likely a participant will receive a liver from a deceased donor when an organ becomes available.