Study evaluating safety, tolerability and efficacy of the experimental drug EYP001a in patients with non-alcoholic steatohepatitis

Phase 1

Conditions: onalcoholic steatohepatitis with likely stage F2 to F3 fibrosis
MedDRA version: 20.0Level: SOCClassification code 10019805Term: Hepatobiliary disordersSystem Organ Class: 10019805 - Hepatobiliary disorders
Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Registration Number: EUCTR2018-003119-22-BE

Lead Sponsor: ENYO Pharma SA

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 114

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 infl

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. Plat

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 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. ;Secondary Objective: • To explore the pharmacokinetics (PK) of EYP001a <br>• To evaluate pharmacodynamic (PD) effects of EYP001a on bile acid-related markers as appropriate <br>• To assess the effects of EYP001a on lipid and metabolic profiles<br>• To assess the safety of EYP001a with statin coadministration <br>• To assess the effects of EYP001a on noninvasive biomarkers of liver fibrosis and inflammation<br>;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.;Timepoint(s) of evaluation of this end point: baseline to Week 12

Secondary Outcome Measures

Name	Time	Method

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