E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-alcoholic Steatohepatitis (NASH) |
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E.1.1.1 | Medical condition in easily understood language |
Accumulation of fat in the liver |
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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 | 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 |
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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 effect of EDP-305 compared to placebo on liver histology in non-cirrhotic NASH subjects with stage 2 or 3 fibrosis |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of EDP-305 on liver histology with assessments including: - Improvement of fibrosis by at least 1 stage and/or resolution of NASH, without worsening of either - No worsening of fibrosis and no worsening of NASH - Resolution of fibrosis - Improvement in each histological feature of NASH by at least 1 point - Improvement of fibrosis by ≥ 2 stages - Improvement in non-alcoholic fatty liver disease activity score by at least 2 points with no worsening of fibrosis - Histological progression to cirrhosis based on the overall assessment made • To evaluate the safety of EDP-305 • To evaluate the effect of EDP-305 on pruritus • To evaluate the effect of EDP-305 on hepatic steatosis • To evaluate the effect of EDP-305 on liver stiffness • To evaluate the effect of EDP-305 on lipid profile • To evaluate the pharmacokinetics of EDP-305 and its metabolites in plasma
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male and female subjects, of all ethnic origins, between the ages of 18 and 75 years, inclusive. • Subjects of all ethnic origins should have a Body Mass Index (BMI) > 25 kg/m2 and ≤45 except for Asian subjects who qualify for the study with BMI > 23kg/m2. • Histological evidence of definite NASH based on NASH Clinical Research Network (CRN) criteria obtained from assessment of a liver biopsy by the central histopathologist. • Non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS) of 4 or greater with a score of at least 1 in each component of the NAS (steatosis scored 0-3, lobular inflammation scored 0-3, ballooning scored 0-2). • Fibrosis stage 2 or 3 using the NASH CRN Histologic Scoring System. • For subjects taking Vitamin E or pioglitazone, the following three criteria apply: -subjects must have been on a stable dose for at least 12 weeks prior to the qualifying biopsy, and -treatment with Vitamin E or pioglitazone cannot have started after the qualifying biopsy, and -it is expected that subjects will continue on the same dosing regimen throughout study participation unless required to adjust doses due to safety reasons. • Subjects who had previously been taking Vitamin E or pioglitazone (but are no longer taking either one), must have discontinued Vitamin E or pioglitazone a minimum of 12 weeks prior to the qualifying biopsy. • Weight change <5% after the qualifying biopsy. • Subjects must have Screening laboratory values for Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and HCV RNA, and Human Immunodeficiency Virus (HIV) 1 and 2 antibodies (Ab) as seronegative. • For hypertensive patients, blood pressure should be controlled by stable dose of anti-hypertensive medication for at least 8 weeks prior to Screening with the intention to keep the regimen stable during the study. • A woman of childbearing potential who is sexually active with a male must agree to use two effective methods of contraception from the date of Screening until 30 days after the last dose of study drug. • A male subject who has not had a vasectomy and is sexually active with a woman of childbearing potential must agree to use effective contraception from the date of Screening to 90 days after the last dose of study drug. • Aspartate aminotransferase > 30 IU/L • Magnetic resonance imaging - proton density fat fraction ≥8%
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E.4 | Principal exclusion criteria |
• Laboratory Screening results as indicated below: - Total white blood cells (WBC) <3000 cells/mm3 - Absolute neutrophil count (ANC) <1500 cells/mm3 - Platelet count <140,000/mm3 - International Normalized Ratio, INR >1.2 (unless due to use of anticoagulants) - Estimated glomerular filtration rate (eGFR) < 60 mL/min according to the Modification of Diet in Renal Disease (MDRD) equation - Aspartate aminotransferase ≥5× upper limit of normal (ULN) - Alanine aminotransferase ≥5× ULN - Alkaline phosphatase ≥ 2x ULN - Total bilirubin > 1.5 times ULN during Screening. • Pregnant or nursing females. • MELD: Model for End-stage Liver Disease score >12. • Clinical or laboratory evidence of known chronic liver disease such as alcoholic liver disease, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, Wilson disease, iron overload, alpha- 1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma. • History of acute liver complications due to gallstones (e.g., acute cholecystitis or acute biliary obstruction), unless the subject has had a cholecystectomy (more than 12 weeks prior to Screening). • History of liver transplant, or current placement on a liver transplant list. • Hepatorenal syndrome (type I or II). • Prior variceal hemorrhage, uncontrolled encephalopathy, liver cirrhosis Child-Pugh Class A, B, and C, esophageal varices, or refractory ascites within the previous 26 weeks of Screening and/or histological presence of liver cirrhosis. • Prior or planned ileal resection, or prior or planned bariatric surgery. • Subjects with clinically or otherwise documented cardiovascular or cerebrovascular disease including clinically significant anomalies of rhythm or pattern of ECG, that in the judgement of the Principal Investigator could affect the safety of the subject or their ability to comply with the study requirements. • Glycated hemoglobin (HbA1c) ≥ 9.5% within 60 days prior to Day 1. • Use of a new antidiabetic regimen in the months prior to Screening, including metformin, glucagon-like peptide-1 (GLP-1) agonists, sodium glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, or dipeptidyl peptidase 4 (DPP4) inhibitors, insulin or peroxisome proliferatoractivated receptor γ agonists (e.g. pioglitazone or rosiglitazone). For pre-existing antidiabetic treatment, subjects should be on a stable dose of antidiabetic drugs: (1) for at least 8 weeks (for metformin and/or sulfonylureas), (2) 12 weeks (for SGLT2 or DPP4 inhibitors), or (3) 12 weeks (for GLP-1 receptor agonists and thiazolidinediones) prior to Screening with the intention to keep the regimen stable during the study. • Use of a new statin regimen or other lipid lowering agents from 12 weeks prior to Screening. • Use of a new fibrate regimen from 12 weeks prior to Screening. • Subjects with contraindications to MRI imaging, or not being able to have the MRI performed. • Subject has received any investigational agent (including investigational vaccine) or biological product within 30 days or 5 times the half-life (whichever is longer) prior to the planned first dose of study drug. • Use of an experimental or approved treatment for NASH within 26 weeks of Screening. • Prior use of obeticholic acid (OCA) within 26 weeks of Screening and/or concurrent treatment with OCA (or any other farnesoid X receptor agonists). • Use of systemic immunosuppressant (e.g., corticosteroids) for more than 4 weeks in duration within 1 year prior to Screening with the intention to continue during the study (chronic use of inhaled, topical, ophthalmological, nasal corticosteroids is allowed). • Use of medication for weight loss or appetite reduction (e.g. orlistat, bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin, non-prescription supplements) at Screening. Refer to protocol for additional exclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects who achieve ≥1 stage improvement in fibrosis without worsening of steatohepatitis and/or resolution of steatohepatitis and no worsening of liver fibrosis as determined by liver biopsy at 72 weeks
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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) |
• Proportion of subjects with improvement of fibrosis by at least 1 stage and/or resolution of NASH without worsening of either as determined by liver biopsy at Week 72 • Proportion of subjects with no worsening of fibrosis combined with no worsening of NASH as determined by liver biopsy at Week 72 • Proportion of subjects with resolution of fibrosis as determined by liver biopsy at Week 72 • Proportion of subjects with improvement in each histologic feature of NASH, by at least 1 point as determined by liver biopsy at Week 72 • Proportion of subjects with improvement of fibrosis by ≥ 2 stages by liver biopsy at Week 72 • Proportion of subjects with improvement in NAS by at least 2 points with no worsening of fibrosis as determined by liver biopsy at Week 72 • Proportion of subjects with improvement of fibrosis and resolution of NASH as a composite endpoint as defined by both endpoints being met in the same subject • Proportion of subjects with resolution of NASH and no worsening of liver fibrosis • Proportion of subjects with histological progression to cirrhosis as determined by liver biopsy at Week 72 • Frequency of adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation through Week 72 and 4-week follow-up period • Change from Baseline in 5D-itch scale and Visual Analog Score through Week 72 • Change from Baseline in percentage of fat in the liver as assessed by magnetic resonance imaging proton density fat fraction at Week 12 and Week 72 • Change from Baseline in liver stiffness as assessed by magnetic resonance elastography at Week 12 and Week 72 • Change from Baseline in triglycerides, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and adiponectin through Week 72 • Pharmacokinetic concentrations of EDP-305 (and metabolites)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | Yes |
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
| 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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 |
Canada |
Korea, Republic of |
Mexico |
United States |
France |
Germany |
United Kingdom |
Argentina |
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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
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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 | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |