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 | 20.1 |
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 |
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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 change in alanine aminotransferase (ALT) levels - To evaluate the safety and tolerability of EDP-305
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of EDP-305 on liver fat - To evaluate the effect of EDP-305 on fibrosis (liver stiffness) - To evaluate the effect of EDP-305 on noninvasive liver fibrosis markers - To evaluate the effects of EDP-305 on lipids - To evaluate the effects of EDP-305 on glucose metabolism - To evaluate the effects of EDP-305 on inflammatory markers - To evaluate the pharmacokinetics (PK) of EDP-305 and its metabolites in plasma - To evaluate the effect of EDP-305 on body weight - To evaluate the effect of EDP-305 on waist to hip (WTH) ratio - To evaluate the pharmacodynamics of EDP-305
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female subjects of any ethnic origin between the ages of 18 and 75 years, inclusive 2. Male or female with presence of NASH by: - Histologic evidence on a historical liver biopsy within 24 months of Screening consistent with NASH with fibrosis (no cirrhosis), and elevated ALT at Screening OR - Phenotypic diagnosis of NASH based on elevated ALT and diagnosis of T2DM or pre-diabetes AND - Screening MRI PDFF with >8% steatosis 3. Body mass index (BMI) >25 kg/m2. NOTE: for Asian-Americans, BMI >23 kg/m2 4. 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. 5. Female subjects of childbearing potential must agree to use two effective methods of contraception from the date of Screening until 90 days after the last dose of EDP-305. 6. All male participants who have not had a vasectomy must use effective contraception from Day −1 to 90 days after their last dose of study drug. 7. Male subjects must agree to refrain from sperm donation from the date of Screening until 90 days after their last dose of study drug. 8. Subject must be willing and able to adhere to the assessments, visit schedules, prohibitions and restrictions, as described in this protocol.
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E.4 | Principal exclusion criteria |
1. Laboratory Screening Results: - Total bilirubin >ULN (normal range 0.2–1.2 mg/dL) - Total white blood cells (WBC) <3,000 cells/mm3 - Absolute neutrophil count (ANC) <1,500 cells/mm3 - Platelet count <140,000/mm3 - Prothrombin time (international normalized ratio, INR)>1.2 - Creatine kinase above the upper limit of normal (ULN) except when in relation with intense exercise - Serum creatinine >2 mg/dL or clearance creatinine <60 ml/min (based on Cockroft Gault method) 2. Known history of alpha-1-antitrypsin deficiency 3. Use of an experimental treatment for NASH within the past 6 months 4. Prior use and/or concurrent treatment with obeticholic acid 5. Use of immunosuppressant (eg, corticosteroids) for more than 2 weeks in duration within 1 year prior to Screening and during the course of the study 6. Use of experimental or unapproved drugs within a year of Screening 7. Any other condition(s) (including cardiovascular diseases) that would compromise the safety of the subject or compromise the quality of the clinical study, as judged by the Principal Investigator 8. Pregnant or nursing females 9. Recipients of liver or other organ transplantation or anticipated need for orthotropic organ transplantation in one year as determined by a Model for End-Stage Liver Disease Score ≥15 10. Clinical suspicion of advanced liver disease or cirrhosis 11. Coexisting liver or biliary diseases, such as primary sclerosing cholangitis, choledocholithiasis, acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver disease, acute infection of bile duct system or gall bladder, history of gastrointestinal bleeding (secondary to portal hypertension), cirrhosis 12. Suspicion of cancer (eg, liver cancer) with the exception of basal cell carcinoma that has been resected 13. Cirrhosis with or without complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin >2 × ULN 14. Hepatorenal syndrome (type I or II) or Screening serum creatinine > 2 mg/dL (178 μmol/L) 15. Prior variceal hemorrhage, uncontrolled encephalopathy, Child-Pugh Class A, B, and C, esophageal varices, or refractory ascites within the previous 6 months of Screening 16. Any condition possibly affecting drug absorption (eg, gastrectomy <3 years prior to Screening) 17. History of regular alcohol consumption exceeding 14 drinks/week for females and 21 drinks/week for males within 6 months of Screening. 18. Subject has received an investigational agent or vaccine within 30 days, or a biological product within 3 months or 5 elimination half-lives (whichever is longer) prior to the planned intake of study drug. 19. Clinically significant electrocardiogram abnormalities or QTcF greater than 450 ms for males and 470 ms for females at either Screening or Baseline, or any prior history of QT abnormality 20. Use of cytochrome P450 (CYP)3A4 and P-glycoprotein (P-gp) inducers and inhibitors within 14 days prior to the first dose of study medication and throughout study duration 21. Use of a new statin regimen from Screening and throughout study duration. 22. Current use of fibrates. 23. Clinically significant history of drug sensitivity or allergy, as determined by the PI 24. Uncontrolled diabetes mellitus (ie, HbA1c ≥9% or higher) 60 days prior to Day 1 25. Use of a new antidiabetic regimen from Screening and throughout study duration 26. Subjects with contraindications to MRI imaging, or not being able to have the MRI performed |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Change from baseline in ALT levels at Week 12 - Frequency of adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation through Week 12
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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) |
- Change from Baseline in percentage of fat in the liver as assessed by magnetic resonance imaging-estimated proton density fat fraction (MRI PDFF) at Week 12 - Change from Baseline in liver stiffness as assessed by magnetic resonance elastography (MRE) at Week 12 - Change from Baseline of noninvasive liver fibrosis markers (Enhanced Liver Fibrosis [ELF] panel) and PRO C3 at Week 12 - Change from Baseline in non-alcoholic fatty liver disease (NAFLD) Fibrosis Score (NFS), AST to Platelet Ratio Index (APRI), and fibrosis 4 (FIB-4) at Week 12 - Change form Baseline in triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), adiponectin and apolipoproteins (Apo)A1, B, C3 at Week 12 - Change from Baseline in fasting glucose and insulin, homeostasis model assessment (HOMA) index (in nondiabetic subjects) and glycated hemoglobin (HbA1c) in subjects with Type 2 diabetes mellitus (T2DM) at Week 12 - Change from Baseline in fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β , alpha2 macroglobulin and haptoglobin levels at Week 12 - Pharmacokinetic parameters of EDP-305 (and metabolites): Cmax, tmax, and AUClast - Change from Baseline in body weight at Week 12 - Change in WTH ratio at Week 12 - Pharmacodynamic parameters of EDP-305: FGF19, C4, and bile acid (BA) at Week 12 |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Canada |
France |
Germany |
New Zealand |
United Kingdom |
United States |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
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 | 3 |