Non Alcoholic Steatohepatitis (NASH)
Conditions
Keywords
Non Alcoholic Steatohepatitis, fatty liver disease, NASH
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.
Interventions
DRUGObeticholic Acid
DRUGPlacebo
Sponsors
Intercept Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Portugal, Puerto Rico, Serbia, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
This was a phase 3, double-blind, randomized, long-term, placebo-controlled, multicenter study evaluating the safety and efficacy of Obeticholic Acid (OCA) in Participants with Nonalcoholic Steatohepatitis (NASH).
Pre-assignment details
The study was conducted at approximately 350 investigational sites globally.
Participants by arm
| Arm | Count |
|---|---|
| OCA 10 Milligrams (mg) Participants were randomized to receive OCA 10 mg once daily orally with water. | 825 |
| OCA 25 mg Participants were randomized to receive OCA 25 mg once daily orally with water. | 827 |
| Placebo Participants were randomized to receive matching placebo once daily orally with water. | 825 |
| Total | 2,477 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 22 | 56 | 36 |
| Overall Study | Death | 11 | 15 | 12 |
| Overall Study | Lost to Follow-up | 43 | 50 | 57 |
| Overall Study | Missing | 1 | 1 | 0 |
| Overall Study | Non-compliance with Study Drug | 4 | 2 | 0 |
| Overall Study | Other | 19 | 16 | 20 |
| Overall Study | Physician Decision | 11 | 18 | 11 |
| Overall Study | Protocol Violation | 2 | 1 | 2 |
| Overall Study | Site Closure | 14 | 5 | 7 |
| Overall Study | Study Terminated by Sponsor | 549 | 509 | 528 |
| Overall Study | Withdrawal by Subject | 149 | 154 | 152 |
Baseline characteristics
| Characteristic | Total | OCA 10 Milligrams (mg) | OCA 25 mg | Placebo |
|---|---|---|---|---|
| Age, Continuous | 55.3 Years STANDARD_DEVIATION 11.24 | 55.3 Years STANDARD_DEVIATION 10.76 | 55.3 Years STANDARD_DEVIATION 11.71 | 54.4 Years STANDARD_DEVIATION 11.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 425 Participants | 129 Participants | 149 Participants | 147 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1806 Participants | 620 Participants | 594 Participants | 592 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 246 Participants | 76 Participants | 84 Participants | 86 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 19 Participants | 5 Participants | 8 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 119 Participants | 47 Participants | 43 Participants | 29 Participants |
| Race (NIH/OMB) Black or African American | 46 Participants | 14 Participants | 20 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 14 Participants | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 10 Participants | 4 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 231 Participants | 72 Participants | 75 Participants | 84 Participants |
| Race (NIH/OMB) White | 2038 Participants | 679 Participants | 674 Participants | 685 Participants |
| Sex: Female, Male Female | 1447 Participants | 475 Participants | 494 Participants | 478 Participants |
| Sex: Female, Male Male | 1030 Participants | 350 Participants | 333 Participants | 347 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 825 | 19 / 827 | 14 / 825 |
| other Total, other adverse events | 798 / 825 | 813 / 827 | 781 / 825 |
| serious Total, serious adverse events | 273 / 825 | 276 / 827 | 248 / 825 |
Outcome results
Primary
Time to the First Adjudicated Event for Clinical Outcome Composite Endpoint: Percentage of Participants With an Event
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.
Time frame: Up to 7 years
Population: Intent-to-Treat (ITT) Population comprised of all randomized participants with fibrosis stage 2 or stage 3 who receive at least 1 dose of investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OCA 10 Milligrams (mg) | Time to the First Adjudicated Event for Clinical Outcome Composite Endpoint: Percentage of Participants With an Event | 15.8 Percentage of participants |
| OCA 25 mg | Time to the First Adjudicated Event for Clinical Outcome Composite Endpoint: Percentage of Participants With an Event | 14.7 Percentage of participants |
| Placebo | Time to the First Adjudicated Event for Clinical Outcome Composite Endpoint: Percentage of Participants With an Event | 18.8 Percentage of participants |
p-value: 0.102895% CI: [0.635, 1.043]Log Rank
p-value: 0.044495% CI: [0.6, 0.994]Log Rank
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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.
Time frame: Up to 7 years
Population: Safety Population comprised all randomized participants, all fibrosis stages, who receive at least 1 dose of investigational product (OCA or placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| OCA 10 Milligrams (mg) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 798 Participants |
| OCA 10 Milligrams (mg) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 273 Participants |
| OCA 25 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 813 Participants |
| OCA 25 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 276 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 781 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 248 Participants |
Secondary
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
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.
Time frame: Up to 7 years
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OCA 10 Milligrams (mg) | 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 | 18.5 Percentage of participants |
| OCA 25 mg | 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 | 20.8 Percentage of participants |
| Placebo | 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 | 11.8 Percentage of participants |
p-value: 0.000495% CI: [3, 10.4]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [5.2, 12.8]Cochran-Mantel-Haenszel
Secondary
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
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.
Time frame: Up to 7 years
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OCA 10 Milligrams (mg) | 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 | 17.1 Percentage of participants |
| OCA 25 mg | 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 | 19.5 Percentage of participants |
| Placebo | 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 | 10.0 Percentage of participants |
p-value: <0.000195% CI: [3.6, 10.6]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [5.8, 13]Cochran-Mantel-Haenszel