E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nonalcoholic steatohepatitis with likely stage F2 to F3 fibrosis |
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E.1.1.1 | Medical condition in easily understood language |
Nonalcoholic steatohepatitis, a disease characterized by the presence of an abnormal 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 | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10019805 |
E.1.2 | Term | Hepatobiliary disorders |
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 |
The primary objective is to determine the efficacy and safety profiles of 2 doses and 2 dosing regimens of EYP001a versus placebo on liver fat content (LFC) from baseline to Week 12 in patients with NASH. |
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E.2.2 | Secondary objectives of the trial |
• To explore the pharmacokinetics (PK) of 2 doses and 2 dosing regimens of EYP001a • To evaluate pharmacodynamic (PD) effects of 2 doses and 2 dosing regimens of EYP001a on bile acid-related markers as appropriate • To assess the effects of 2 doses and 2 dosing regimens of EYP001a on lipid and metabolic profiles • To assess the safety of 2 doses and 2 dosing regimens of EYP001a with statin coadministration
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provides signed written informed consent and agrees to comply with the study protocol. 2. Is a male or female aged 18 years or older. 3. Has a suspected diagnosis of NASH during the Screening Period (up to 60 days before dosing), defined as follows: a. The average baseline serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values should be established by at least 2 samples obtained at least 4 weeks and no more than 12 weeks apart. One sample can be obtained from the patient's medical history and 1 sample can be obtained during the Screening Period, or both samples can be obtained during the Screening Period. Unless both samples are within normal ranges, to be eligible for study entry, the difference between the first and second measurement of ALT and AST should be =< 30%. A third sample will be collected if the variability between the first 2 values exceeds the 30% limit. If the third sample exceeds the 30% limit (compared to the first result), the isolated ALT or AST increase shall prompt the search for signs of worsening of liver injury to be further evaluated under Exclusion Criterion 2. If the third sample is within the 30% variability limit, the patient will be eligible for enrollment. If the values of ALT or AST in both samples are within normal ranges, the variability of the marker is assumed adequate for randomization. Baseline AST values should be >=0.6 x upper limit of normal (ULN) (ie, >20 U/L). b. Normal average baseline levels of alkaline phosphatase (ALP). Total bilirubin (TBL) levels should be =< 22.2 umol/L (1.3 mg/dL). c. Liver stiffness compatible with liver fibrosis stage F2 or F3 determined by FibroScan® vibration-controlled transient elastography assessment cut-off value >= 8.5 kPa. d. FibroScan controlled attenuation parameter (CAP) for steatosis with cut-off values >300 dB/m. e. LFC >=10% as measured by MRI PDFF. 4. Is not of childbearing potential (as defined in Inclusion Criterion 5) or, if of childbearing potential, is not pregnant as confirmed by a negative serum human chorionic gonadotropin test at screening and is not planning a pregnancy during the course of the study. 5. Women of childbearing potential and male patients with female partners must agree to use a dual method of contraception as defined in the study protocol or practice complete abstinence from sexual intercourse if this is the patient's usual and preferred lifestyle throughout the duration of the study and for 90 days after stopping study drug. Patients who are using hormonal contraceptives should be instructed to use an additional contraceptive measure during the study. |
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E.4 | Principal exclusion criteria |
1. Is an employee of a clinical research organization, vendor, or Sponsor involved with this study 2. Shows evidence of worsening liver injury, defined as either an increase of >30% between 2 baseline values of ALT or AST or an increase of >20% between 2 baseline values of TBL or ALP and when such values are above the ULN or associated with clinical signs or symptoms of liver impairment 3. Has known non-NASH liver disease, including, but not limited to, alcoholic liver disease, autoimmune disease, human immunodeficiency virus, hepatitis B virus, active hepatitis C virus (HCV), Wilson's disease, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, drug-induced liver injury, bile duct obstruction, or suspected or known liver cancer 4. Has history of cirrhosis or liver decompensation, including ascites, hepatic encephalopathy, or presence of esophageal varices 5. Has known history of alcohol abuse or daily heavy alcohol consumption. Has an Alcohol Use Disorders Identification Test-Concise (AUDIT-C) score of >=3 points for men and women AND a full Alcohol Use Disorders Identification Test (AUDIT) score of >=8 points at screening 6. Has Gilbert's syndrome with direct bilirubin >1x ULN 7. Is pregnant or breastfeeding 8. Has clinically relevant immunosuppression, including, but not limited to, immunodeficiency conditions 9. Has a known preexisting medical or psychiatric condition that could interfere with the patient's ability to provide informed consent or participate in study conduct, or that may confound study findings 10. Has, in the opinion of the Investigator, clinically significant cardiovascular or cerebrovascular disease within 90 days prior to the first study drug administration 11. Has participated in any drug study within 90 days prior to the first study drug administration in the current study 12. Has had major surgery within 90 days prior to the first study drug administration in the current study 13. Has a history of relevant drug and/or food allergies 14. Unable to undergo an MRI PDFF due to: a. Contraindication to MRI examination b. Severe claustrophobia impacting ability to perform MRI during the study, despite mild sedation/treatment with a short half life (ie, <20 hours) anxiolytic c. Body weight or girth exceeding the scanner capacities 15. Is using any of the following disallowed medications: a. Anticancer drug(s), immunomodulator(s), or immunosuppressant(s) within 90 days or 5 half lives prior to screening, whichever is longer, or any drug historically associated with NAFLD with known liver toxicity for >2 weeks in the year prior to screening b. Vitamin E (>400 IU/day), glitazones, glucagon-like peptide 1 receptor agonists, ursodeoxycholic acid, or obeticholic acid within 90 days prior to screening c. Agents (including herbal over-the-counter weight loss preparations) or medications known to significantly impact body weight within 90 days prior to screening d. Statins other than rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, or lovastatin e. Agents that are substrates for cytochrome P450 (CYP) 2C8 or CYP2C9 and have a narrow therapeutic index 16. Has prior or planned (during the study period) bariatric surgery 17. Has type 1 diabetes mellitus 18. Has type 2 diabetes mellitus and hemoglobin A1c >9.5% or has not been on a stable dose of antidiabetic medication for at least 90 days prior to screening 19. Has had total body weight loss of >5% within 6 months or since a liver biopsy, if applicable 20. Has any of the following exclusionary laboratory results at screening: a. ALT >5x ULN, AST >5x ULN b. International normalized ratio >=1.3, unless on anticoagulant therapy c. Platelet count <lower limit of normal d. Estimated glomerular filtration rate <60 mL/min/1.73 m2 (the Modification of Diet in Renal Disease formula) e. Creatine kinase (CK) >ULN in patients on concomitant statin therapy and CK >3x ULN in all other patients f. Thyroid stimulating hormone >1.5x ULN or abnormal free triiodothyronine or free thyroxine 21. Has history of clinically significant gastrointestinal disease, especially peptic ulcerations, gastrointestinal bleeding, inflammatory bowel disease, bariatric surgery, renal, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, or cardiovascular disease or any other condition, which, in the opinion of the Investigator, would jeopardize the safety of the patient or impact the validity of the study results |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end point is the efficacy of EYP001a, being the absolute change in Liver Fat Content as measured by MRI-PDFF from baseline to 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) |
Efficacy: • Proportion of patients with >=5% absolute reduction in LFC as measured by MRI-PDFF from baseline to Week 12 • Proportion of patients with >=5% or <10% absolute reduction in LFC as measured by MRI PDFF at Week 12 • Proportion of patients with >=10% or <20% absolute reduction in LFC as measured by MRI PDFF at Week 12 • Proportion of patients with a relative reduction in LFC >=20% as measured by MRI PDFF at Week 12 • Proportion of patients with a relative reduction in LFC >=30% as measured by MRI PDFF at Week 12 • Percent change (relative reduction) in LFC as measured by MRI-PDFF from baseline to Week 12 • Change and percent change in imaging-derived mean cT1 from baseline to Week 12 • Change in the following biomarkers of liver fibrosis and inflammation: ALT, AST, AST/ALT ratio, adiponectin, high sensitivity C-reactive protein, interleukin 6, tumor necrosis factor alpha, cytokeratin-18, fibronectin, hyaluronic acid, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases-1 (and derived enhanced liver fibrosis score), Pro C3, and chitinase 3 like protein 1 (also known as YKL-40) from baseline to Week 4, Week 8, and Week 14/Early Termination (ET), as applicable
Pharmacokinetic (EYP001a concentrations) and Pharmacodynamic (C4 and FGF19 concentrations)
Safety and tolerability : monitoring of adverse events, AESIs (ie, pruritus, drug induced liver injury, and all muscle related adverse events), and SAEs, and findings from physical examinations, vital signs, ECGs, and clinical laboratory parameters
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: From baseline to Week 12
PK: Part A: Day 1, Day 14 at 0 (predose), 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose, End of Study (EOS) and Early Termination (ET) Visits. Optional sampling at 6 hours postdose at : Days 7, 21, 28, 56, and 84. Part B: predose and 2 hours postdose (an optional sample at 6 hours postdose) at : Days 1, 14, 28, 56, 84, EOS and ET Visits.
PD: Part A: Day 1 and Day 14 at: 0 (predose), 4, 6, 10, 12, and 24 hours postdose, at the EOS and ET Visit . Sparse PD sampling will also occur predose and 2 hours postdose at Days 28, 56, and 84. Part B: predose and 2 hours postdose (an optional sample at 6 hours postdose) at Days 1, 14, 28, 56, and 84, EOS and ET Visits.
Safety: throughout the study |
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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 | 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 | 4 |
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 | 7 |
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 |
Belgium |
France |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 24 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 24 |