Nonalcoholic Steatohepatitis
Conditions
Keywords
Non-alcoholic Fatty Liver Disease, NAFLD, Fatty Liver Disease, NASH
Brief summary
This Phase 2, double-blind, randomized, placebo-controlled, multicenter study, with an open-label long-term safety extension (LTSE), will evaluate the effect of Obeticholic Acid, and the subsequent addition of statin therapy, on lipoprotein metabolism in subjects with nonalcoholic steatohepatitis (NASH) with fibrosis stage 1 to 4, but no evidence of hepatic decompensation.
Interventions
DRUGObeticholic Acid
Once a day (QD) by mouth (PO)
DRUGAtorvastatin
Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO). Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated. Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated.
DRUGPlacebo
Once a day (QD) by mouth (PO)
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. Age ≥18 years 2. Histologic evidence of NASH, as assessed by central reading of a liver biopsy obtained no more than 1 year prior to randomization, defined by the presence of all 3 key histological features of NASH with a score of at least 1 for each and a combined score of 4 or greater out of a possible 8 points according to NASH Clinical Research Network (CRN) criteria. 3. Histologic evidence of fibrosis stage 1 to stage 4 (as defined by NASH CRN scoring of fibrosis) without any evidence of hepatic decompensation. 4. If subject has type 2 diabetes, is on stable dose of anti-diabetic medication (except thiazolidinediones \[TZDs\]) for ≥3 months prior to Day 1. 5. Is either not taking or is on stable doses of TZDs and/or Vitamin E for ≥6 months prior to Day 1. 6. Contraception: Female subjects of childbearing potential must use ≥1 effective method of contraception during the study and until 30 days following the last dose of investigational product. Effective methods of contraception are considered to be the following: barrier method, ie, condom (male or female) with spermicide or diaphragm with spermicide, intrauterine device, vasectomy (partner), hormonal (eg, contraceptive pill, patch, intramuscular implant or injection), abstinence (defined as refraining from heterosexual intercourse). 7. Must provide written informed consent and agree to comply with the study protocol, including adherence to protocol-described statin withdrawal and statin therapy.
Exclusion criteria
1. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening Visit 1 (significant alcohol consumption is defined as more than 2 units/day in females and more than 4 units/day in males, on average) 2. Prior intolerance to treatment with atorvastatin or other 3-hydroxy-3-methyl-glutaryl (HMG) Coenzyme A reductase inhibitors (including but not limited to rhabdomyolysis). 3. LDL cholesterol ≥190 mg/dL and already on statin therapy at Screening Visit 1. 4. LDL cholesterol \>200 mg/dL at any Screening Visit in subjects who are not on statin therapy, or at Screening Visit 2 in statin washout subjects. 5. Planned change in diet or exercise habits during participation in the double-blind period, or a significant weight change of \>5% in the prior 6 months. 6. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures. 7. History of biliary diversion 8. Uncontrolled diabetes defined as HbA1c ≥9.5% within 60 days prior to randomization (Day 1). 9. Administration of any of the following medications as specified below: * Prohibited 30 days prior to Day 1: * bile acid sequestrants (BAS) including cholestyramine and its derivatives, colesevelam, colestipol, or * omega-3 fatty acid-containing dietary supplements * Prohibited 3 months prior to Day 1: * nicotinic acid and derivatives, ezetimibe * any prescription or over-the-counter (OTC) medication or herbal remedy with putative NASH efficacy (except Vitamin E or TZDs) * ursodeoxycholic acid * fenofibrate or other fibrates * any OTC or health food used to treat lipids including plant sterols and berberine * Prohibited 6 months prior to Day 1: * azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate, mofetil, pentoxifylline; budesonide and other systemic corticosteroids, or * potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin) * Prohibited 12 months prior to Day 1: * antibodies or immunotherapy directed against interleukins, or * other cytokines or chemokines 10. Evidence of other forms of chronic liver disease including but not limited to: * Positive test result at Screening for hepatitis B surface antigen * Active hepatitis C virus (HCV) infection (positive for HCV ribonucleic acid \[RNA\] at Screening) or history of positive HCV RNA test result * Primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis or overlap syndrome * Alcoholic liver disease * Wilson's disease or hemochromatosis or iron overload * Alpha-1-antitrypsin (A1AT) deficiency * Prior known drug-induced liver injury within 5 years before Day 1 * Known or suspected hepatocellular carcinoma 11. History of liver transplant, current placement on a liver transplant list, or current Model for End-Stage Liver Disease (MELD) score \>12. Subjects who are placed on a transplant list despite relatively early disease stage (eg, per regional guidelines) may be eligible as long as they do not meet any of the other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Effect of Obeticholic Acid on Low-density Lipoprotein (LDL) Concentration (Least Squares Mean Change From Baseline at Week 16) | Baseline and Week 16 | The effect of Obeticholic Acid on LDL metabolism in subjects with biopsy confirmed nonalcoholic steatohepatitis (NASH) and the ability of atorvastatin to modulate this effect as measured by change (least squares mean) from baseline at week 16 in LDL concentration |
| The Effect of Obeticholic Acid on LDL Particle Size (Least Squares Mean Change From Baseline at Week 16) | Baseline and Week 16 | The effect of Obeticholic Acid on LDL metabolism in subjects with biopsy confirmed NASH and the ability of atorvastatin to modulate this effect as measured by change from baseline (least squares mean) at week 16 in LDL particle size. It is LDL particle diameter size (nm) that is reported. |
| The Effect of Obeticholic Acid on LDL Particle Concentration (Total) (Least Squares Mean Change From Baseline at Week 16) | Baseline and Week 16 | The effect of Obeticholic Acid on LDL metabolism in subjects with biopsy confirmed nonalcoholic NASH and the ability of atorvastatin to modulate this effect as measured by change (least squares mean) from baseline at week 16 in LDL particle concentration (total) |
Countries
United States
Participant flow
Pre-assignment details
Subjects using statins within 30 days of the initial Screening visit (Screening Visit 1) are required to stop statin therapy immediately following this initial visit and must undergo a 4-week statin washout period prior to Screening Visit 2.
Participants by arm
| Arm | Count |
|---|---|
| 5 mg Obeticholic Acid 5 mg Obeticholic Acid daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg.
Obeticholic Acid: Once a day (QD) by mouth (PO)
Atorvastatin: Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO).
Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated.
Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated. | 20 |
| 10 mg Obeticholic Acid 10 mg Obeticholic Acid daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg.
Obeticholic Acid: Once a day (QD) by mouth (PO)
Atorvastatin: Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO).
Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated.
Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated. | 21 |
| 25 mg Obeticholic Acid 25 mg Obeticholic Acid daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg.
Obeticholic Acid: Once a day (QD) by mouth (PO)
Atorvastatin: Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO).
Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated.
Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated. | 22 |
| Placebo One tablet daily for the double-blind treatment period. 10 mg Atorvastatin titrating to 20mg.
Atorvastatin: Initiate treatment with Atorvastatin at Week 4 visit with a dose of 10 mg once daily (QD) by mouth (PO).
Increase Atorvastatin to 20 mg once daily (QD) by mouth (PO) at Week 8 visit if 10 mg daily is tolerated.
Atorvastatin may be titrated up or down at Week 12 visit as clinically indicated.
Placebo: Once a day (QD) by mouth (PO) | 21 |
| Total | 84 |
Baseline characteristics
| Characteristic | Total | 10 mg Obeticholic Acid | Placebo | 5 mg Obeticholic Acid | 25 mg Obeticholic Acid |
|---|---|---|---|---|---|
| Age, Continuous | 58.1 years STANDARD_DEVIATION 11.07 | 57.1 years STANDARD_DEVIATION 11.62 | 59.8 years STANDARD_DEVIATION 9.88 | 52.9 years STANDARD_DEVIATION 10.13 | 62.2 years STANDARD_DEVIATION 11.06 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 4 Participants | 4 Participants | 7 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 17 Participants | 17 Participants | 13 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fibrosis stage (NASH Clinical Research Network (CRN) categories) Stage 1 and 2 | 41 Participants | 10 Participants | 10 Participants | 10 Participants | 11 Participants |
| Fibrosis stage (NASH Clinical Research Network (CRN) categories) Stage 3 and 4 | 43 Participants | 11 Participants | 11 Participants | 10 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 74 Participants | 20 Participants | 16 Participants | 19 Participants | 19 Participants |
| Screening LDL Greater than 125 mg/dL | 38 Participants | 10 Participants | 10 Participants | 9 Participants | 9 Participants |
| Screening LDL Less than or equal 125 mg/dL | 46 Participants | 11 Participants | 11 Participants | 11 Participants | 13 Participants |
| Sex: Female, Male Female | 51 Participants | 12 Participants | 13 Participants | 16 Participants | 10 Participants |
| Sex: Female, Male Male | 33 Participants | 9 Participants | 8 Participants | 4 Participants | 12 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 | 0 / 20 | 0 / 21 | 0 / 22 | 0 / 21 |
| other Total, other adverse events | 13 / 20 | 9 / 21 | 19 / 22 | 9 / 21 |
| serious Total, serious adverse events | 2 / 20 | 1 / 21 | 1 / 22 | 0 / 21 |
Outcome results
Primary
The Effect of Obeticholic Acid on LDL Particle Concentration (Total) (Least Squares Mean Change From Baseline at Week 16)
The effect of Obeticholic Acid on LDL metabolism in subjects with biopsy confirmed nonalcoholic NASH and the ability of atorvastatin to modulate this effect as measured by change (least squares mean) from baseline at week 16 in LDL particle concentration (total)
Time frame: Baseline and Week 16
Population: Efficacy evaluable population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Obeticholic Acid | The Effect of Obeticholic Acid on LDL Particle Concentration (Total) (Least Squares Mean Change From Baseline at Week 16) | -224.79 nmol/L | Standard Error 62.58 |
| 10 mg Obeticholic Acid | The Effect of Obeticholic Acid on LDL Particle Concentration (Total) (Least Squares Mean Change From Baseline at Week 16) | -325.04 nmol/L | Standard Error 49.81 |
| 25 mg Obeticholic Acid | The Effect of Obeticholic Acid on LDL Particle Concentration (Total) (Least Squares Mean Change From Baseline at Week 16) | -336.22 nmol/L | Standard Error 51.4 |
| Placebo | The Effect of Obeticholic Acid on LDL Particle Concentration (Total) (Least Squares Mean Change From Baseline at Week 16) | -439.84 nmol/L | Standard Error 47.7 |
95% CI: [-35.58, 242.81]
95% CI: [-21.53, 251.13]
95% CI: [55.84, 374.26]
Primary
The Effect of Obeticholic Acid on LDL Particle Size (Least Squares Mean Change From Baseline at Week 16)
The effect of Obeticholic Acid on LDL metabolism in subjects with biopsy confirmed NASH and the ability of atorvastatin to modulate this effect as measured by change from baseline (least squares mean) at week 16 in LDL particle size. It is LDL particle diameter size (nm) that is reported.
Time frame: Baseline and Week 16
Population: Efficacy evaluable population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Obeticholic Acid | The Effect of Obeticholic Acid on LDL Particle Size (Least Squares Mean Change From Baseline at Week 16) | 0.02 nm | Standard Error 0.15 |
| 10 mg Obeticholic Acid | The Effect of Obeticholic Acid on LDL Particle Size (Least Squares Mean Change From Baseline at Week 16) | -0.41 nm | Standard Error 0.12 |
| 25 mg Obeticholic Acid | The Effect of Obeticholic Acid on LDL Particle Size (Least Squares Mean Change From Baseline at Week 16) | -0.09 nm | Standard Error 0.12 |
| Placebo | The Effect of Obeticholic Acid on LDL Particle Size (Least Squares Mean Change From Baseline at Week 16) | -0.49 nm | Standard Error 0.12 |
95% CI: [0.07, 0.75]
95% CI: [-0.25, 0.42]
95% CI: [0.14, 0.89]
Primary
The Effect of Obeticholic Acid on Low-density Lipoprotein (LDL) Concentration (Least Squares Mean Change From Baseline at Week 16)
The effect of Obeticholic Acid on LDL metabolism in subjects with biopsy confirmed nonalcoholic steatohepatitis (NASH) and the ability of atorvastatin to modulate this effect as measured by change (least squares mean) from baseline at week 16 in LDL concentration
Time frame: Baseline and Week 16
Population: Efficacy evaluable population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Obeticholic Acid | The Effect of Obeticholic Acid on Low-density Lipoprotein (LDL) Concentration (Least Squares Mean Change From Baseline at Week 16) | -33.2 mg/dL | Standard Error 4.93 |
| 10 mg Obeticholic Acid | The Effect of Obeticholic Acid on Low-density Lipoprotein (LDL) Concentration (Least Squares Mean Change From Baseline at Week 16) | -44.27 mg/dL | Standard Error 4.1 |
| 25 mg Obeticholic Acid | The Effect of Obeticholic Acid on Low-density Lipoprotein (LDL) Concentration (Least Squares Mean Change From Baseline at Week 16) | -39.54 mg/dL | Standard Error 4.24 |
| Placebo | The Effect of Obeticholic Acid on Low-density Lipoprotein (LDL) Concentration (Least Squares Mean Change From Baseline at Week 16) | -53.33 mg/dL | Standard Error 3.93 |
95% CI: [2.28, 25.3]
95% CI: [-2.18, 20.3]
95% CI: [7.33, 32.92]