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 |
Liver inflammation caused by a buildup of fat in the liver |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
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 |
Evaluate hepatic histological improvement in nonalcoholic fatty liver disease (NAFLD) activity score (NAS) at Year 1, relative to the Screening biopsy, defined by a minimum 2-point improvement in NAS with at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning AND with no concurrent worsening of fibrosis stage (worsening defined as progression of NASH Clinical Research Network [CRN] fibrosis stage) at Year 1. |
|
E.2.2 | Secondary objectives of the trial |
• Evaluate the complete resolution of steatohepatitis (histopathologic interpretation of fatty liver disease or simple or isolated steatosis with no steatohepatitis) AND no concurrent worsening of fibrosis stage (worsening defined as progression of NASH CRN fibrosis stage) at Year 1
• Evaluate the improvement in fibrosis by at least 1 stage (NASH CRN system) AND no worsening of steatohepatitis (no worsening of lobular inflammation or hepatocellular ballooning grade) at Year 1 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
--Histological evidence of NASH, based on Screening biopsy, with a NAS of ≥ 4 with at least 1 in each component of NAS
--Histological evidence of liver fibrosis defined as NASH CRN System Stage 1 to 3, inclusive, based on Screening biopsy
--Meeting any of the 3 following major criteria (a, b, c):
a. Documented evidence of type 2 diabetes mellitus (T2DM)
b. High BMI (> 25 kg/m2) with at least 1 of the following criteria of the metabolic syndrome, as defined by the NCEP:
i. Central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 35 inches (female)
ii. Dyslipidemia: TG ≥ 1.7 mmol/L (150 mg/dL)
iii. Dyslipidemia: HDL-cholesterol < 40 mg/dL (male), < 50 mg/dL (female)
iv. Blood pressure ≥ 130/85 mmHg (or treated for hypertension)
v. Fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dL)
c. Bridging fibrosis (NASH CRN Stage 3) and/or definite NASH (NAS ≥ 5)
--Agree to have one liver biopsy at Screening, one at Year 1, and one at the end
of study treatment (Year 2) |
|
E.4 | Principal exclusion criteria |
--Hepatitis B surface antigen (HBsAg) positive
--Hepatitis C antibody (HCVAb) positive with the following 2 exceptions:
a. Subjects previously treated for viral hepatitis C with at least a 1-year period since documented sustained virologic response at Week 12 (post-treatment) may be eligible if all other eligibility criteria are met
b. Subjects with presence of hepatitis C antibody but negative hepatitis C virus RNA without treatment (i.e., spontaneous clearance) may be eligible if all other eligibility criteria are met
--Prior or planned liver transplantation
--Other known causes of chronic liver disease, including alcoholic liver disease
--History of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding
--Alcohol consumption greater than 21 units/week for males or 14 units/week for females (one unit of alcohol is ½ pint of beer [285 mL], 1 glass of spirits
[25 mL] or 1 glass of wine [125 mL]) |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Hepatic histological improvement in NAS at Year 1, relative to the Screening biopsy, defined as a decrease (improvement) in NAS by ≥ 2
with at least a 1-point reduction in either lobular inflammation of hepatocellular ballooning AND with no concurrent worsening of fibrosis stage (worsening defined as progression of NASH CRN fibrosis stage) at Year 1 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Biopsies will be performed at Screening, Year 1, and Year 2 |
|
E.5.2 | Secondary end point(s) |
• Complete resolution of steatohepatitis histopathologic interpretation of fatty liver disease or simple or isolated steatosis with no steatohepatitis) AND no concurrent worsening of fibrosis stage (worsening defined as progression of NASH CRN fibrosis stage) at Year 1
• Improvement in fibrosis by at least 1 stage (NASH CRN system) AND no
worsening of steatohepatitis (no worsening of lobular inflammation or hepatocellular ballooning grade) at Year 1 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessments will be performed every three months for two years. |
|
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.6 | Cross over | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
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 |
Belgium |
France |
Germany |
Hong Kong |
Israel |
Italy |
Moldova, Republic of |
Poland |
Romania |
Spain |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
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 |