Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment

Phase 3

Terminated

• Conditions: Non Alcoholic Steatohepatitis (NASH)
• Interventions: Drug: Obeticholic Acid; Drug: Placebo

• Registration Number: NCT02548351
• Lead Sponsor: Intercept Pharmaceuticals

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-09-01
• Study First Submitted QC: 2015-09-10
• Study First Posted: 2015-09-14
• Study Start: 2015-09-22
• Primary Completion: 2023-09-15
• Study Completion: 2023-09-15
• Results First Submitted: 2024-08-14
• Results First Submitted QC: 2024-08-14
• Status Verified: 2024-09
• Results First Posted: 2024-09-05
• Last Update Submitted: 2024-09-05
• Last Update Posted: 2024-10-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 2477

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
10 mg Obeticholic Acid	Obeticholic Acid	10 mg Obeticholic Acid daily for the remainder of the study
Placebo	Placebo	One tablet daily for the remainder of the study
25 mg Obeticholic Acid	Obeticholic Acid	25 mg Obeticholic Acid daily for the remainder of the study

Primary Outcome Measures

Name	Time	Method
Time to the First Adjudicated Event for Clinical Outcome Composite Endpoint: Percentage of Participants With an Event	Up to 7 years	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.

Secondary Outcome Measures

Name	Time	Method
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	Up to 7 years	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.
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	Up to 7 years	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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Up to 7 years	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.

Trial Locations

Locations (343)

The University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Digestive Health Specialists of the Southeast; 🇺🇸 Dothan, Alabama, United States

Institute for Liver Health DBA Arizona Liver Health; 🇺🇸 Chandler, Arizona, United States

Arizona Liver Health - Glendale; 🇺🇸 Glendale, Arizona, United States

St. Joseph's Hospital and Medical Center; 🇺🇸 Phoenix, Arizona, United States

Mayo Clinic Arizona; 🇺🇸 Phoenix, Arizona, United States

Arizona Liver Clinic - Tucson; 🇺🇸 Tucson, Arizona, United States

Liver Wellness Center; 🇺🇸 Little Rock, Arkansas, United States

Arkansas Gastroenterology; 🇺🇸 North Little Rock, Arkansas, United States

GW Research Inc.; 🇺🇸 Chula Vista, California, United States

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