Brief Summary
The primary objectives of this study are to evaluate the effect of Obeticholic Acid treatment compared to placebo on 1) histological improvement and 2) liver-related clinical outcomes in patients with non-cirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis.
Brief Title
Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment
Completion Date
Completion Date Type
Actual
Conditions
Non Alcoholic Steatohepatitis (NASH)
Eligibility Criteria
Inclusion Criteria:
1. Histologic evidence of NASH upon central read of a liver biopsy obtained no more than 6 months before Day 1 defined by presence of all 3 key histological features of NASH according to NASH CRN criteria.
2. Histologic evidence of fibrosis stage 2 or stage 3 as defined by the NASH CRN scoring of fibrosis, or
Histologic evidence of fibrosis stage 1a or stage 1b if accompanied by ≥1 of the following risk factors:
* Obesity (BMI ≥30 kg/m2)
* Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria
* ALT \>1.5× upper limit of normal (ULN).
3. For subjects with a historical biopsy, is either not taking or is on stable doses of TZDs/glitazones or vitamin E for 6 months before Day 1.
4. Stable body weight.
Exclusion Criteria:
1. Model for End-stage Liver Disease (MELD) score \>12
2. ALT ≥10× ULN
3. HbA1c \>9.5%
4. Total bilirubin \>1.5 mg/dL
5. Evidence of other known forms of known chronic liver disease such as alcoholic liver disease, hepatitis B, hepatitis C, PBC, PSC, autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC)
6. History of liver transplant, or current placement on a liver transplant list
7. Current or history of significant alcohol consumption
8. Prior or planned ileal resection, or prior or planned bariatric surgery
9. Histological presence of cirrhosis
10. History of biliary diversion
11. Known positivity for human immunodeficiency virus infection.
12. Acute cholecystitis or acute biliary obstruction.
13. BMI \>45 kg/m2
1. Histologic evidence of NASH upon central read of a liver biopsy obtained no more than 6 months before Day 1 defined by presence of all 3 key histological features of NASH according to NASH CRN criteria.
2. Histologic evidence of fibrosis stage 2 or stage 3 as defined by the NASH CRN scoring of fibrosis, or
Histologic evidence of fibrosis stage 1a or stage 1b if accompanied by ≥1 of the following risk factors:
* Obesity (BMI ≥30 kg/m2)
* Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria
* ALT \>1.5× upper limit of normal (ULN).
3. For subjects with a historical biopsy, is either not taking or is on stable doses of TZDs/glitazones or vitamin E for 6 months before Day 1.
4. Stable body weight.
Exclusion Criteria:
1. Model for End-stage Liver Disease (MELD) score \>12
2. ALT ≥10× ULN
3. HbA1c \>9.5%
4. Total bilirubin \>1.5 mg/dL
5. Evidence of other known forms of known chronic liver disease such as alcoholic liver disease, hepatitis B, hepatitis C, PBC, PSC, autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC)
6. History of liver transplant, or current placement on a liver transplant list
7. Current or history of significant alcohol consumption
8. Prior or planned ileal resection, or prior or planned bariatric surgery
9. Histological presence of cirrhosis
10. History of biliary diversion
11. Known positivity for human immunodeficiency virus infection.
12. Acute cholecystitis or acute biliary obstruction.
13. BMI \>45 kg/m2
Inclusion Criteria
Inclusion Criteria:
1. Histologic evidence of NASH upon central read of a liver biopsy obtained no more than 6 months before Day 1 defined by presence of all 3 key histological features of NASH according to NASH CRN criteria.
2. Histologic evidence of fibrosis stage 2 or stage 3 as defined by the NASH CRN scoring of fibrosis, or
Histologic evidence of fibrosis stage 1a or stage 1b if accompanied by ≥1 of the following risk factors:
* Obesity (BMI ≥30 kg/m2)
* Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria
* ALT \>1.5× upper limit of normal (ULN).
3. For subjects with a historical biopsy, is either not taking or is on stable doses of TZDs/glitazones or vitamin E for 6 months before Day 1.
4. Stable body weight.
1. Histologic evidence of NASH upon central read of a liver biopsy obtained no more than 6 months before Day 1 defined by presence of all 3 key histological features of NASH according to NASH CRN criteria.
2. Histologic evidence of fibrosis stage 2 or stage 3 as defined by the NASH CRN scoring of fibrosis, or
Histologic evidence of fibrosis stage 1a or stage 1b if accompanied by ≥1 of the following risk factors:
* Obesity (BMI ≥30 kg/m2)
* Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria
* ALT \>1.5× upper limit of normal (ULN).
3. For subjects with a historical biopsy, is either not taking or is on stable doses of TZDs/glitazones or vitamin E for 6 months before Day 1.
4. Stable body weight.
Gender
All
Gender Based
false
Keywords
Non Alcoholic Steatohepatitis, fatty liver disease, NASH
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
85 Years
Minimum Age
18 Years
NCT Id
NCT02548351
Org Class
Industry
Org Full Name
Intercept Pharmaceuticals
Org Study Id
747-303
Overall Status
Terminated
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 3, Double-Blind, Randomized, Long-Term, Placebo-Controlled, Multicenter Study Evaluating the Safety and Efficacy of Obeticholic Acid in Subjects With Nonalcoholic Steatohepatitis
Primary Outcomes
Outcome Description
All potential liver-related clinical outcomes that occurred after administration of first dose of investigational product were reviewed and adjudicated by blinded, independent Hepatic Outcomes Committee(HOC). Adjudicated results were used to assess effect of OCA, compared to placebo in conjunction with established local standard of care, on clinical outcomes in participants with NASH as measured by time to first occurrence of any of following adjudicated events, derived as a composite event endpoint of death(all-cause), liver transplant, Model of End-stage Liver Disease(MELD)≥15 Score, hospitalization(defined by a stay of 24 hours or greater) for onset of: variceal bleed, hepatic encephalopathy(defined by a West Haven score of ≥2), and spontaneous bacterial peritonitis(confirmed by diagnostic paracentesis), ascites secondary to cirrhosis requiring medical intervention, and histological progression to Cirrhosis. Clinical events distribution was estimated using Kaplan-Meier methodology.
Outcome Measure
Time to the First Adjudicated Event for Clinical Outcome Composite Endpoint: Percentage of Participants With an Event
Outcome Time Frame
Up to 7 years
Secondary Outcomes
Outcome Description
Fibrosis stage was evaluated by NASH Clinical Research Network (CRN) Fibrosis Staging System as follows: Stage 0: No fibrosis, Stage 1: Perisinusoidal/periportal fibrosis, Stage 1A: Mild, zone 3, perisinusoidal fibrosis, Stage 1B: Moderate, zone 3, perisinusoidal fibrosis, Stage 1C: Portal/periportal fibrosis, Stage 2: Perisinusoidal and portal/periportal fibrosis, Stage 3: Bridging fibrosis and Stage 4: Cirrhosis. No worsening of NASH was defined as no worsening of hepatocellular ballooning, no worsening of lobular inflammation, and no worsening of steatosis. Responders are defined as participants who did not discontinue treatment due to Adverse event (AE) or did not die and had evaluable post-Baseline biopsy assessment. Mantel-Haenszel method is used to construct the confidence intervals.
Outcome Time Frame
Up to 7 years
Outcome Measure
Percentage of Responders With Improvement of Fibrosis by at Least One Stage With no Worsening of NASH Using Consensus Read Method of Scheduled Liver Biopsies
Outcome Description
Fibrosis stage was evaluated by NASH Clinical Research Network(CRN) Fibrosis Staging System as follows: Stage 0:No fibrosis, Stage 1:Perisinusoidal/periportal fibrosis, Stage 1A:Mild, zone 3, perisinusoidal fibrosis, Stage 1B:Moderate, zone3, perisinusoidal fibrosis, Stage 1C:Portal/periportal fibrosis, Stage 2:Perisinusoidal and portal/periportal fibrosis, Stage 3:Bridging fibrosis and Stage 4:Cirrhosis. Resolution of NASH (Nonalcoholic Steatohepatitis) is defined as absence of fatty liver disease, or presence of simple or isolated steatosis without steatohepatitis, with a NAS(NAFLD Activity Score) of 0 for ballooning and 0 to 1 for inflammation. NAS ranges from 0-12; 0: no features of fatty liver disease and 12: highest degree of fatty liver disease. Higher signify worse symptoms. Responders are who did not discontinue treatment due to Adverse event(AE) or did not die and had evaluable post-Baseline biopsy assessment. Mantel-Haenszel method is used to construct confidence intervals.
Outcome Time Frame
Up to 7 years
Outcome Measure
Percentage of Participants Who Showed Improvement in Fibrosis by at Least 1 Stage and/or Resolution of NASH Without Worsening of Either Using Consensus Read Method
Outcome Description
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A TEAE was defined as any AE that either newly appeared, increased in frequency, or worsened in severity following treatment up to 30 days from last dose of permanent investigational product discontinuation. Serious AE (SAE) was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event.
Outcome Time Frame
Up to 7 years
Outcome Measure
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
85
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Samuel Sigal
Investigator Email
ssigal@montefiore.org
Investigator Phone
718-920-6240