| 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 |
|
| 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 |
|
| 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 |
|
| 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 EYP001a versus placebo on liver fat content (LFC) from baseline to Week 12 in patients with NASH. |
|
| E.2.2 | Secondary objectives of the trial |
• To explore the pharmacokinetics (PK) of EYP001a
• To evaluate pharmacodynamic (PD) effects of EYP001a on bile acid-related markers as appropriate
• To assess the effects of EYP001a on lipid and metabolic profiles
• To assess the safety of EYP001a with statin coadministration
• To assess the effects of EYP001a on noninvasive biomarkers of liver fibrosis and inflammation
|
|
| 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 12 weeks 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. If the values of ALT or AST in both samples are within normal ranges, the variability of the marker is assumed adequate for randomization. If the values of ALT or AST are higher than normal values, the patient will be eligible for enrollment provided the increase from the first to second sample is =< 40%. If the values from sample 1 are higher than those from sample 2 (ie. there is a decrease), the patient will be eligible despite a > 40% limit. A third sample can be collected if an increase from sample 1 to sample 2 exceeds the 40% limit. If sample 3 exceeds the 40% limit (compared to sample 1), this increase shall prompt to the search of clinical signs or symptoms of liver impairment, and the patient will not be eligible for enrollment. Baseline AST values should be > 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).
Note: Baseline serum ALP and TBL 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. If the values of ALP or TBL in both samples are within normal ranges, the variability of the marker is assumed adequate for randomization. If the values of ALP or TBL are higher than normal values, the patient will be eligible for enrollment provided the increase from the first to second sample is =<40%. If the values from sample 1 are higher than those from sample 2 (ie, there is a decrease), the patient will be eligible despite a >40% difference. A third sample can be collected if an increase from sample 1 to sample 2 exceeds the 40% limit. If sample 3 exceeds the 40% limit (compared to sample 1), this increase shall prompt the search for clinical signs or symptoms of liver impairment, and the patient will not be eligible for enrollment.
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.
Note: Patients do not need to undergo a CAP assessment if their medical records indicate a magnetic resonance imaging (MRI) proton density fat fraction (MRI PDFF) LFC ≥ 10% within 12 months prior to screening.
Note: Histology within 12 months prior to screening will supersede FibroScan entry criteria if the following criteria are met: NASH with fibrosis stage F2 to F3, defined as portal fibrosis with few septa (F2) or bridging septa between central and portal veins (F3), and nonalcoholic fatty liver disease (NAFLD) activity score ≥ 4, including a minimum of 1 point each for ballooning and inflammation. However, if a patient participated in a previous study with a NASH investigational drug between 365 and 60 days prior to being screened for this study, the histology information will only be considered if the biopsy was performed after the end of the patient's participation in the previous study.
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 highly effective birth control throughout the duration of the study and for 90 days after stopping study drug. Patients who are using hormonal contraceptives or intrauterine devices should be instructed to use an additional contraceptive measure during the study such as a male or female condom with spermicide or diaphragm. Highly effective is defined as birth control methods that result in a failure rate of <1% per year when used consistently and correctly. |
|
| E.4 | Principal exclusion criteria |
1. Is an employee of a clinical research organization, vendor, or Sponsor involved with this study
2. 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
3. Has history of cirrhosis or liver decompensation, including ascites, hepatic encephalopathy, or presence of esophageal varices
4. 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
5. Has Gilbert's syndrome with direct bilirubin >1x ULN
6. Is pregnant or breastfeeding
7. Has clinically relevant immunosuppression, including, but not limited to, immunodeficiency conditions
8. 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
9. Has, in the opinion of the Investigator, clinically significant cardiovascular or cerebrovascular disease within 90 days prior to the first study drug administration
10. Has participated in any drug study within 90 days prior to the first study drug administration in the current study
11. Has had major surgery within 90 days prior to the first study drug administration in the current study
12. Has a history of relevant drug and/or food allergies
13. Has a history of hypersensitivity to the study drug or any of te excipients or placebo
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: cholecystectomy prior to age 25 years, peptic ulcerations, gastrointestinal bleeding, inflammatory bowel disease, or bariatric surgery); renal, hematologic, endocrine, oncologic, pulmonary, immunologic, or cardiovascular disease; neurologic or psychiatric disease (including any use of addictive substances such as regular opioid treatment and/or any use of illicit drugs); 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.
22. Has a body mass index >45 kg/m2. |
|
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| 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 >=10% absolute reduction in LFC as measured by MRI PDFF at Week 12
• Proportion of patients with >=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 and percent change in waist to hip ratio from baseline to Week 12 (Part B only)
• Change and percent change in waist to height ratio from baseline to Week 12 (Part B only)
• 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, [Part A only], drug induced liver injury, [Part A only], elevation of transaminases [Part B only], and all muscle related adverse events), and SAEs, and findings from physical examinations, vital signs, ECGs, and clinical laboratory parameters
|
|
| 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.
Part B: predose and 2 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 at Days 1, 14, 28, 56, and 84, EOS and ET Visits.
Safety: throughout the study |
|
| 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 | 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 | 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 |
| Puerto Rico |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 7 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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