Safety And Efficacy Study Of Orally Administered Epeleuton In Patients With NAFLD
A Randomised, Double-Blind, Placebo-Controlled, Exploratory Phase IIa Study To Assess The Safety And Efficacy Of Orally Administered Epeleuton In NAFLD Patients.
The purpose of this randomised, double-blind, placebo-controlled, parallel group study is to assess the safety and efficacy of orally administered Epeleuton capsules versus placebo in the treatment of adult patients with Non Alcoholic Fatty Liver Disease (NAFLD)
2 x placebo 500 mg capsules orally administered twice a day (4 capsules daily) for 16 weeks
1 x Epeleuton 500 mg capsule and 1 x placebo 500 mg capsule orally administered twice a day (4 capsules daily) for 16 weeks
2 x Epeleuton 500 mg capsules orally administered twice a day (4 capsules daily) for 16 weeks
Inclusion Criteria: Patients diagnosed with NAFLD by the presence of hepatic steatosis on imaging or histology in the absence of any secondary causes. Patients with an ALT ≥ 1.5 upper limit of normal (ULN) and < 5 ULN on two occasions 7 or more days apart during screening. Patients with historical liver biopsy showing NASH and/or ≥ F1 fibrosis OR NFS ≥ -1.455 OR Fib- 4 ≥ 1.3 OR Fibroscan ≥8kPa within 3 months of screening. Patients with a body mass index (BMI) between 25.0 and 40.0 kg/m² inclusive. Patients with a history of controlled obesity or controlled diabetes are allowed on the study. Patients whose pre-study clinical laboratory findings do not interfere with their participation in the study, in the opinion of the Investigator. Patients aged between 18 and 75 years inclusive. Female patients and male patients with female partners of child bearing potential must use adequate contraception or have a sterilized partner for the duration of the study. Adequate contraception is defined as: systemic hormonal contraceptives; intrauterine device or barrier method of contraception in conjunction with spermicide; or agree to sexual abstinence, defined as a patient refraining from heterosexual intercourse during the entire period of risk associated with the study treatments and in line with their preferred and usual lifestyle. Hormonal contraceptives must be on a stable dose for at least one month before baseline. Patients who are able to communicate well with the Investigator, to understand and comply with the requirements of the study, and understand and sign the written informed consent. Exclusion Criteria: Patients with an unstable metabolic condition such as weight change > 5% in the 3 months prior to inclusion. Patients with medical/surgical history of gastric bypass surgery, orthotopic liver transplant (OLT) or listed for OLT. Patients with uncontrolled diabetes mellitus type 2, i.e. HbA1c ≥ 9% (75 mmol/mol) at the time of screening. Patients with decompensated or severe liver disease as evidenced by one or more of the following: confirmed cirrhosis or suspicion of cirrhosis, esophageal varices, ascites, suspicion of portal hypertension, hospitalization for liver disease within 60 days of screening, bilirubin ≥ 2 x ULN, or ALT or AST ≥ 5 x ULN. Patients with Gilbert's syndrome are eligible if the conjugated bilirubin is ≤ 1.5 x ULN. Patients with inflammatory bowel disease that is either active or requiring medical therapy. Patients with diagnosed or suspected autoimmune diseases such as systemic lupus erythematosus and/or rheumatoid arthritis. Patients with a history of or active non-liver malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas). Patients with a significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal insufficiency, serious psychiatric disease, respiratory or hypertensive disease, as well as diabetes and arthritis that, in the opinion of the Investigator, would preclude the patient from participating in and completing the study. Patients requiring anti-diabetic treatment (including insulin sensitizing agents), and/or lipid lowering treatment, and who are not on a stable dose for at least 3 months prior to screening should be excluded. If patients are insulin dependent this treatment should have commenced at least 3 months prior to screening, however changes in dose are permitted. Patients with known hypersensitivity to any ingredients of the study treatment. Patients with a positive test for human immunodeficiency virus antibodies, Hepatitis B surface antigen or Hepatitis C antibodies at screening. Patients with liver disease of other etiologies such as drug-induced, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, haemochromatosis, alpha-1 antitrypsin deficiency or Wilson's disease. Patients with a significant history of drug/solvent abuse, in the opinion of the investigator. Patients with a history of alcohol abuse in the opinion of the Investigator, or who currently drinks in excess of 21 units per week (males) or 14 units per week (females), whereby a unit consists of 10ml or 8mg of pure alcohol. Patients who have used dietary supplements rich in omega-3 or omega-6 fatty acids in the 4 weeks prior to baseline. Patients who have participated in any other clinical study with an investigational drug within 3 months before the first day of administration of study treatment. Patients who are pregnant, planning pregnancy, breastfeeding and/or are unwilling to use adequate contraception (as specified in inclusion criterion 7) during the study. Patients, in the opinion of the Investigator, not suitable to participate in the study.
|Event Type||Organ System||Event Term||Placebo||1000 mg Epeleuton||2000 mg Epeleuton|
Change in serum ALT from baseline to Week 16 using ANCOVA.
To evaluate change in liver stiffness measurements using Transient Elastography from baseline to Week 16 using FibroScan® 502 Touch model or equivalent.
Subjects with at least 1 TEAE leading to treatment discontinuation
Change in serum ALT from baseline to weeks 2, 4, 8 and 12.
Change in serum AST from baseline to weeks 2, 4, 8, 12 and 16.
Change in AST: ALT ratio from baseline to weeks 2, 4, 8, 12 and 16.
Change in FIB-4 Index from baseline to week 16. This index is based on age, platelet count, ALT level, and AST level and will be assessed at Baseline (Visit 2) and week 16 (Visit 10). FIB-4 was calculated using the following formula: FIB4 = (Age (years) x AST (U/L))/(Platelet count (10^9/L) x √ALT (U/L)). A decrease in FIB-4 represents a positive outcome. A FIB-4 Index of <1.45 indicates none to moderate fibrosis and an Index of >3.25 indicates advanced fibrosis.
Change in NAFLD fibrosis score (NFS) from baseline to week 16. The NFS is based on age, hyperglycemia, BMI, platelet count, albumin level, and AST/ALT ratio. NFS was calculated using the following formula: NAFLD fibrosis score = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m^2) + 1.13 × IFG/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio - 0.013 × platelet (×10^9/l) - 0.66 × albumin (g/dl). A decrease in NFS score represents a positive outcome. An NFS score of <-1.455 indicates no advanced fibrosis and a score of >0.676 indicates liver fibrosis.
Change in ELF from baseline to week 16. Enhanced Liver Fibrosis score is an extracellular matrix marker set consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA). A decrease in ELF score represents a positive outcome. The ELF score was calculated for the instrument based on the following equation: ELF score = 2.494 + 0.846 In (CHA) + 0.735 In (CPIIINP) + 0.391 In (CTIMP-1). An ELF score of less than 7.7 indicates no fibrosis. An ELF score greater than or equal to 9.8 indicates severe fibrosis. An ELF score of 11.3 or greater indicates cirrhosis.
Change in HOMA-IR from baseline to weeks 2,4,8,12,16. Homeostatic model assessment for insulin resistance (HOMA-IR) was assessed as a measure of insulin resistance. HOMA-IR is calculated by multiplying fasting plasma insulin by fasting plasma glucose, then dividing by the constant 405. A decrease in HOMA-IR indicates a positive outcome. HOMA-IR values of greater than 1.9 indicates early insulin resistance and levels above 2.9 indicate significant insulin resistance.
Change in Adipo-IR from baseline to weeks 2, 4, 8, 12 and 16. Adipose tissue insulin resistance (Adipo-IR) was assessed as a measure of insulin resistance. Adipo- IR is calculated by multiplying fasting non-esterified fatty acids by fasting insulin. A decrease in Adipo-IR indicates a positive outcome.
Change in hepatic fat measured by CAP (controlled attenuation parameter) from baseline to week 16 using FibroScan® 502 Touch model or equivalent. CAP score is measured in decibels per meter (dB/m). A reduction in hepatic fat measured non-invasively by CAP indicates an improvement in hepatic steatosis. CAP scores range from 100 to 400dB/m. 0 to 237 dB/M indicates no hepatic steatosis, 238 to 260 dB/m indicates mild hepatic steatosis, 260 to 290 dB/m indicates moderate steatosis and a CAP score greater than 290 dB/m indicates severe steatosis.