E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nonalcoholic steatohepatitis |
|
E.1.1.1 | Medical condition in easily understood language |
Fatty liver disease not related to alcohol intake |
|
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 | 22.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029530 |
E.1.2 | Term | Non-alcoholic fatty liver |
E.1.2 | System Organ Class | 100000004871 |
|
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 the Months 18 Interim Analysis:
1. Evaluate the effect of OCA compared to placebo on liver histology in
non-cirrhotic NASH subjects with stage 2 or 3 fibrosis by assessing the
following endpoints:
a. The proportion of OCA treated patients relative to placebo achieving at
least one stage of liver fibrosis improvement with no worsening of NASH
OR
b. The proportion of OCA treated patients relative to placebo achieving
NASH resolution with no worsening of liver fibrosis
Primary objective assessed at the 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 of first
occurrence of any adjudicated events (clinical outcomes composite
endpoint) |
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives at the Month 18 Interim Analysis:
1. Evaluate the effect of OCA compared to placebo on histological improvement in NASH by assessing endpoints using NASH CRN scoring criteria
2. Evaluate the effect of OCA compared to placebo on liver biochemistry and markers of liver function
Secondary objectives at end of study:
1. Evaluate the effect of OCA compared to placebo on histological improvement in NASH by assessing endpoints using NASH CRN scoring criteria
2. Evaluate the effect of OCA compared to placebo on liver biochemistry and markers of liver function |
|
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 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, or 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. |
|
E.4 | Principal exclusion criteria |
Key Exclusion Criteria:
1. Model for End-stage Liver Disease (MELD) score >12
2. ALT ≥10x 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- atitrypsin 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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
At 18 months:
a. Improvement in fibrosis with no worsening of NASH OR
b.Resolution of NASH with no worsening of fibrosis
At the end of study:
a. Clinical outcomes composite endpoint |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints at the Month 18 Interim Analysis:
• Improvement of fibrosis by at lease 1 stage AND/OR resolution of
NASH, without worsening of either
• No worsening of fibrosis AND no worsening of NASH
• Improvement in each histological feature of NASH by at least 1 point
• Improvement of fibrosis by at least 2 stages
• Improvement in NAS by at least 2 points with no worsening of fibrosis
• Improvement of fibrosis and resolution of NASH as a composite
endpoint and as defined by both endpoints being met in the same
subject
• Resolution of fibrosis
• Histological progression to cirrhosis
Secondary efficacy endpoints at EOS:
• Improvement in fibrosis by at least 1 stage with no worsening of NASH
• NASH resolution with no worsening of fibrosis
• Improvement of fibrosis by at lease 1 stage AND/OR resolution of
NASH, without worsening of either
• No worsening of fibrosis AND no worsening of NASH
• Improvement in each histological feature of NASH by at least 1 point
• Improvement of fibrosis by at least 2 stages
• Improvement in NAS by at least 2 points with no worsening of fibrosis
• Improvement of fibrosis and resolution of NASH as a composite endpoint and as defined by both endpoints being met in the same
subject
• Resolution of fibrosis |
|
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 130 |
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 |
Australia |
Serbia |
Austria |
Belgium |
Canada |
Denmark |
Finland |
Germany |
Hungary |
Israel |
Italy |
New Zealand |
Poland |
Portugal |
Spain |
Sweden |
Switzerland |
United Kingdom |
United States |
France |
|
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 | 10 |
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 | 10 |
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 |