| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nonalcoholic steatohepatitis |
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| E.1.1.1 | Medical condition in easily understood language |
| Fatty liver disease not related to alcohol intake |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029530 |
| E.1.2 | Term | Non-alcoholic fatty liver |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective assessed at 18 months:
1. Evaluate the effect of OCA compared to placebo on histological improvement in NASH by assessing the following as co-primary endpoints using NASH CRN scoring criteria:
a. Improvement in fibrosis by at least 1 stage with no worsening of NASH defined as no increase in hepatocellular ballooning or lobular inflammation
b. Resolution of NASH as defined by overall histopathological interpretation with no worsening of fibrosis
Primary Objective assessed at end of trial:
1. Evaluate the effect of OCA compared to placebo on all-cause mortality and liver-related clinical outcomes as measured by the time to first occurrence of any of adjudicated events (clinical outcomes composite endpoint)
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|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives at 18 months:
To evaluate the effect of OCA compared to placebo on histological improvement in NASH by using NASH CRN scoring criteria
Exploratory objectives at 18 months:
To evaluate the effect of OCA compared to placebo on liver histology
Exploratory objectives at end of trial:
1. To evaluate the effect of OCA compared to placebo
2. To evaluate the correlation between histology and noninvasive scores of liver fibrosis with clinical outcomes at the end of the study |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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 CRN criteria.
2. Histologic evidence of fibrosis stage 2 (perisinusoidal and portal/periportal) or stage 3 (bridging fibrosis) as defined by the NASH CRN scoring of fibrosis, or Histologic evidence of fibrosis stage 1a or stage 1b (mild or moderate, zone 3 perisinusoidal) as defined by
the NASH CRN scoring of fibrosis if accompanied by ≥1 of the following risk factors:
− Obesity (BMI ≥30 kg/m2)
− Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria (hemoglobin A1c [HbA1c]
≥6.5%, fasting plasma glucose ≥126 mg/dL, 2-hour plasma glucose ≥200 mg/dL during oral glucose tolerance test, or random plasma glucose ≥200 mg/dL)
− 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 (ie, not varying by >10% for at least 3 months) before Day 1.
5. Age ≥18 years.
6. 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 those listed below:
− 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. |
|
| E.4 | Principal exclusion criteria |
1. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year before Screening (significant alcohol consumption is defined as more than 2 units/day for females and more than 4 units/day for males, on average).
2. Prior (at any point) or planned (during the study period) ileal resection, or prior (within 5 years before Screening) or planned (during the study period) bariatric surgery (eg, gastric bands, gastroplasty, roux-en-Y gastric bypass).
3. HbA1c >9.5% within 60 days before Day 1.
4. Evidence of other forms of known chronic liver disease including:
− 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, hemochromatosis, or iron overload
− Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver histology (confirmed
by A1AT level below the lower limit of normal or exclusion at the Investigator’s discretion)
− Prior known drug-induced liver injury within 5 years before Day 1
− Known or suspected HCC
− History of liver transplant, current placement on a liver transplant list, or MELD score >12.
5. Histological presence of cirrhosis.
6. Total bilirubin >1.5 mg/dL (subjects with Gilbert’s syndrome may be enrolled despite a total bilirubin level
>1.5 mg/dL if their conjugated bilirubin is <1.5× ULN).
7. AST or ALT ≥10× ULN, international normalized ratio (INR) >1.5, or serum creatinine ≥1.5 mg/dL.
8. Creatine phosphokinase >5x ULN.
9. Platelet count <100 000/mm3.
10. LDL ≥190 mg/dL and already on a stable dose of statin and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for ≥30 days at Screening.
11. Inability to safely undergo a liver biopsy.
12. History of biliary diversion.
13. Known positivity for human immunodeficiency virus infection.
14. Subjects with recent history (within 1 year of Day 1) of significant atherosclerotic cardiovascular disease (myocardial infarction, unstable angina, acute coronary syndrome, cerebrovascular accident [stroke], cerebrovascular ischemia, transient ischemic attack, or peripheral vascular disease requiring intervention). Such subjects may be identified by different means, including but not limited to, an abnormal ECG, a history or planned cardiovascular intervention such as coronary revascularization (eg, percutaneous
coronary intervention or coronary artery bypass graft), coronary angioplasty, stenting, carotid atherectomy, or placement of a cardiac pacemaker or defibrillator.
− Controlled hypertension without other recent manifestations of significant atherosclerotic
cardiovascular disease and placement of cardiac pacemaker or defibrillator for reasons other than atherosclerotic cardiovascular disease (eg, for treatment of atrial fibrillation subsequent to nodal ablation) is not exclusionary.
15. Other medical conditions that may diminish life expectancy to <2 years, including known cancers (except carcinomas in situ or other stable, relatively benign carcinomas).
16. Known substance abuse in the year before Screening.
17. Pregnancy, planned pregnancy, potential for pregnancy (ie, unwillingness to use effective birth control during the study), or current or planned breast feeding.
18. Participated in a clinical research study with any investigational product being evaluated for the treatment of diabetes, weight loss, or NASH in the 6 months before Day 1.
19. Received any investigational product not being evaluated for the treatment of diabetes, weight loss, or NASH from Screening to Day 1, within 30 days before Day 1, or within 5 half-lives of the compound (whichever was longer) before Day 1.
20. Previous exposure to OCA.
21. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study, is uncertain.
22. History of known or suspected clinically significant hypersensitivity to OCA or any of its components.
23. Any other condition that, in the opinion of the Investigator, would impede compliance or hinder completion of the study.
24. Acute cholecystitis or acute biliary obstruction.
25. BMI >45 kg/m2 with at least 1 of the following comorbidities:
− Hypertension with a blood pressure ≥140/90 mmHg if <60 years, ≥150/90 mmHg if ≥60 years, or on antihypertensive medication
− Hyperlipidemia defined as LDL cholesterol ≥160 mg/dL, total cholesterol ≥200 mg/dL, or on lipid lowering medication
− Type 2 diabetes per 2013 American Diabetes Association criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
At 18 months:
a. Improvement in fibrosis with no worsening of NASH
b. Resolution of NASH with no worsening of fibrosis
End of Study:
a. Clinical outcomes composite endpoint
Exploratory Outcomes at end of study:
a. Individual components of the clinical outcomes composite endpoint and liver-related death
b. Health-related quality of life
c. Measure of health status for the assessment of health utilities
d. Non-invasive scores of liver fibrosis
e. Adjudicated cardiovascular events for cardiovascular outcomes assessment
f. Long-term safety and tolerability
g. Correlations between histology and noninvasive scores of liver fibrosis with clinical outcomes
Exploratory outcomes at end of study in a subset of patients:
a. Non-invasive radiological liver fibrosis measurements
Safety
Efficacy Analyses
Primary and key secondary efficacy hypothesis testing will be based on the ITT population including only fibrosis stage 2 and stage 3 subjects only. Exploratory analyses will be conducted using PP population and all fibrosis stages (mITT Population).
The total 2-sided alpha allocated to all testing conducted (ie, at Month 18, Month 48, and EOS) in this single study will be 0.05. In order to control the overall family-wise type I error at these 2 different timepoints while also adjusting for multiplicity, the total 2-sided alpha will be split between the 2 different timepoints with an alpha level of 0.01 at Month 18 and an alpha level of 0.04 at EOS. In addition, the alpha will be further split between the 2 doses at Month 18 with an alpha level of 0.005 for each dose. At the end of the study, doses will be tested in a closed sequential testing procedure.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Interim Key Secondary Efficacy Analyses:
Key secondary efficacy endpoints at Month 18 are:
a. Improvement of fibrosis and NASH as a composite endpoint and as defined by improvement in fibrosis by at least 1 stage and improvement in NAS by at least 2 points with at least 1 point improvement each for hepatocellular ballooning and lobular inflammation from baseline
b. Resolution of fibrosis
Interim Analyses of Clinical Outcomes:
Two additional planned interim analyses of the clinical outcomes composite endpoint, including all-cause mortality and liver-related clinical outcomes at approximately 18 Months and 48 Months will be conducted using group sequential approach in accordance to the statistical analysis plan (SAP) and DMC Charter. The SAP will specify the methods and alpha levels for interim analyses and EOS final analyses. The DMC will review the interim criterion for efficacy in conjunction with detailed safety data and other relevant information to determine whether to continue the study.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 135 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Canada |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Serbia |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Subjects who discontinue investigational product due to Investigator or
Sponsor decision are expected to be followed through to study closure
(or at the discretion of the Sponsor).
Last patient last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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