E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nonalcoholic steatohepatitis (NASH) |
|
E.1.1.1 | Medical condition in easily understood language |
Inflammation of the liver due to accumulation of fat, not related to alcohol consumption |
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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 |
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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 |
To evaluate the safety and tolerability of GS-9674 in subjects with NASH. |
|
E.2.2 | Secondary objectives of the trial |
The exploratory objectives of this study are as follows:
-To evaluate changes in steatosis as measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) including the proportion of subjects with >30% reduction;
-To evaluate changes in liver stiffness as measured by both Magnetic Resonance Elastography (MRE) and FibroScan®;
-To assess changes in markers of liver injury and function: ALT, AST, bilirubin, GGT and ALP;
-To assess changes in non-invasive markers of fibrosis including ELFTM test score and FibroSURE/FibroTest®;
-To assess changes in apoptosis as measured by serum CK-18 levels;
-To determine the effect of GS-9674 on metabolism and cardiovascular risk factors (insulin resistance, hyperlipidemia, obesity and blood pressure);
-To evaluate the pharmacokinetics (PK) of GS-9674;
-To evaluate the pharmacodynamics (PD) of GS-9674 as evidenced by changes in FGF19, C4, and bile acids;
-To assess changes in QoL assessments. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK and PD Substudy
For subjects who provide consent, plasma and serum samples will be collected relative to dosing of GS-9674 to measure concentrations of GS-9674 (and its metabolites, as applicable) and the PD biomarkers FGF19 and C4 for GS-9674. |
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E.3 | Principal inclusion criteria |
-Meets all of the following conditions:
a. A clinical diagnosis of nonalcoholic fatty liver disease (NAFLD), and
b. Screening magnetic resonance imaging-proton density fat fraction (MRI-PDFF) with ≥ 8% steatosis, and
c. Screening magnetic resonance elastography (MRE) with liver stiffness ≥ 2.5 kPa
Note: criterion a. must be met before evaluating criteria b. and c. OR
d. A historical liver biopsy within 12 months of Screening consistent with NASH (defined as the presence of steatosis, lobular inflammation, and hepatocellular ballooning) with fibrosis, but not cirrhosis, and
e. No documented weight loss > 5% between the date of the liver biopsy and Screening.
Note: Screening MRI-PDFF and MRE will be performed prior to the baseline visit for all subjects including those with historical liver biopsies meeting criteria 3d.
-Platelet count ≥ 150,000/mm^3;
-Albumin ≥ 3.3 g/dL;
-Serum Creatinine ≤ ULN |
|
E.4 | Principal exclusion criteria |
-Pregnant or lactating females;
-ALT > 5X ULN;
-Other causes of liver disease including autoimmune, viral, and alcoholic liver disease;
-Cirrhosis of the liver
-Body mass index (BMI) < 18 kg/m^2;
-Uncontrolled diabetes mellitus (hemoglobin A1c > 9% at screening);
-International normalized ratio (INR) > 1.2 unless on anticoagulant therapy;
-Total bilirubin > 1x ULN, except with diagnosis of Gilbert’s syndrome. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the safety of GS-9674 in subjects with NASH. Safety endpoints include adverse events and laboratory evaluations. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety will be assessed during the study through the reporting of AEs, and by clinical laboratory tests and vital sign assessments at various time points during the study (Baseline/Day1, week 1, 4, 8, 12, 16, 20, 24 and follow-up visit) |
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E.5.2 | Secondary end point(s) |
The exploratory efficacy endpoints are:
-Change from baseline in steatosis as measured by MRI-PDFF including the proportion of subjects with ≥ 30% reduction;
-Change from baseline in liver stiffness as measured by both MRE and FibroScan®;
-Change from baseline in markers of liver injury and function: ALT, AST, bilirubin, GGT and ALP;
-Change from baseline in non-invasive markers of fibrosis including the ELF™ test score and FibroSURE/FibroTest®;
-Change from baseline in apoptosis as measured by serum CK-18 levels;
-Change from baseline in homeostatic assessment of insulin resistance (HOMA-IR), serum lipid profiles, and HbA1c levels;
-Change from baseline in health related QoL;
-Change from baseline in body weight;
-Change from baseline in Pooled Cohort Risk Score. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Exploratory efficacy endpoints will be assessed at various time points during the study (Baseline/Day1, week 1, 4, 8, 12, 16, 20, 24 and follow-up visit) |
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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) | 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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Canada |
France |
Hong Kong |
New Zealand |
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
|
End of study is defined as when the last patient last visit (LPLV) for the Follow-Up visit (four weeks after their last dose of study drug) occurs, or the ET visit, whichever occurs later. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |