Title

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.
  • Phase

    Phase 2
  • Study Type

    Interventional
  • Intervention/Treatment

    ds102 ...
  • Study Participants

    96
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)
Study Started
Dec 20
2016
Primary Completion
Jan 02
2019
Study Completion
Mar 04
2019
Results Posted
Apr 21
2022
Last Update
Oct 12
2022

Other Placebo capsules

Drug Epeleuton

Placebo Placebo Comparator

2 x placebo 500 mg capsules orally administered twice a day (4 capsules daily) for 16 weeks

1000 mg Epeleuton Experimental

1 x Epeleuton 500 mg capsule and 1 x placebo 500 mg capsule orally administered twice a day (4 capsules daily) for 16 weeks

2000 mg Epeleuton Experimental

2 x Epeleuton 500 mg capsules orally administered twice a day (4 capsules daily) for 16 weeks

Criteria

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.

Summary

Placebo

1000 mg Epeleuton

2000 mg Epeleuton

All Events

Event Type Organ System Event Term Placebo 1000 mg Epeleuton 2000 mg Epeleuton

Change in Serum ALT (Alanine Aminotransferase) From Baseline to Week 16

Change in serum ALT from baseline to Week 16 using ANCOVA.

Placebo

-16.3
U/L (Least Squares Mean)
95% Confidence Interval: -44.2 to 11.7

1000 mg Epeleuton

-6.9
U/L (Least Squares Mean)
95% Confidence Interval: -34.5 to 20.7

2000 mg Epeleuton

-10.1
U/L (Least Squares Mean)
95% Confidence Interval: -36.9 to 16.8

Change in Liver Stiffness Measurements by Transient Elastography From Baseline to Week 16

To evaluate change in liver stiffness measurements using Transient Elastography from baseline to Week 16 using FibroScan® 502 Touch model or equivalent.

Placebo

-2.226
kPa (Least Squares Mean)
95% Confidence Interval: -3.07 to -1.38

1000 mg Epeleuton

-1.308
kPa (Least Squares Mean)
95% Confidence Interval: -2.11 to -0.51

2000 mg Epeleuton

-0.727
kPa (Least Squares Mean)
95% Confidence Interval: -1.55 to 0.1

Number of Treatment Emergent Adverse Events (TEAEs) in Each Treatment Group Leading to Treatment Discontinuation

Subjects with at least 1 TEAE leading to treatment discontinuation

Placebo

1.0
TEAEs

1000 mg Epeleuton

2000 mg Epeleuton

Change in Serum ALT (Alanine Aminotransferase) From Baseline to Weeks 2, 4, 8 and 12

Change in serum ALT from baseline to weeks 2, 4, 8 and 12.

Placebo

Change from Baseline to Week 12

-18.3
U/L (Least Squares Mean)
95% Confidence Interval: -45.3 to 8.8

Change from Baseline to Week 2

-0.4
U/L (Least Squares Mean)
95% Confidence Interval: -13.3 to 12.4

Change from Baseline to Week 4

-3.4
U/L (Least Squares Mean)
95% Confidence Interval: -14.9 to 8.2

Change from Baseline to Week 8

-8.7
U/L (Least Squares Mean)
95% Confidence Interval: -23.1 to 5.7

1000 mg Epeleuton

Change from Baseline to Week 12

-19.2
U/L (Least Squares Mean)
95% Confidence Interval: -45.3 to 6.9

Change from Baseline to Week 2

-0.1
U/L (Least Squares Mean)
95% Confidence Interval: -13.0 to 12.8

Change from Baseline to Week 4

4.0
U/L (Least Squares Mean)
95% Confidence Interval: -7.6 to 15.7

Change from Baseline to Week 8

-12.7
U/L (Least Squares Mean)
95% Confidence Interval: -27.1 to 1.6

2000 mg Epeleuton

Change from Baseline to Week 12

-3.8
U/L (Least Squares Mean)
95% Confidence Interval: -28.7 to 21.0

Change from Baseline to Week 2

-5.8
U/L (Least Squares Mean)
95% Confidence Interval: -18.2 to 6.6

Change from Baseline to Week 4

-1.9
U/L (Least Squares Mean)
95% Confidence Interval: -13.0 to 9.3

Change from Baseline to Week 8

-3.8
U/L (Least Squares Mean)
95% Confidence Interval: -17.4 to 9.9

Change in AST (Aspartate Aminotransferase) From Baseline to Weeks 2, 4, 8, 12 and 16

Change in serum AST from baseline to weeks 2, 4, 8, 12 and 16.

Placebo

Change from Baseline to Week 12

-13.7
U/L (Least Squares Mean)
95% Confidence Interval: -28.3 to 0.9

Change from Baseline to Week 16

-8.9
U/L (Least Squares Mean)
95% Confidence Interval: -35.4 to 17.6

Change from Baseline to Week 2

-5.6
U/L (Least Squares Mean)
95% Confidence Interval: -22.1 to 10.8

Change from Baseline to Week 4

-4.0
U/L (Least Squares Mean)
95% Confidence Interval: -12.5 to 4.6

Change from Baseline to Week 8

-4.6
U/L (Least Squares Mean)
95% Confidence Interval: -13.1 to 3.8

1000 mg Epeleuton

Change from Baseline to Week 12

-11.2
U/L (Least Squares Mean)
95% Confidence Interval: -25.3 to 2.8

Change from Baseline to Week 16

7.7
U/L (Least Squares Mean)
95% Confidence Interval: -18.3 to 33.7

Change from Baseline to Week 2

-4.9
U/L (Least Squares Mean)
95% Confidence Interval: -21.3 to 11.5

Change from Baseline to Week 4

-1.1
U/L (Least Squares Mean)
95% Confidence Interval: -9.7 to 7.5

Change from Baseline to Week 8

-9.9
U/L (Least Squares Mean)
95% Confidence Interval: -18.2 to -1.6

2000 mg Epeleuton

Change from Baseline to Week 12

-3.2
U/L (Least Squares Mean)
95% Confidence Interval: -17.0 to 10.5

Change from Baseline to Week 16

-4.6
U/L (Least Squares Mean)
95% Confidence Interval: -32.5 to 23.4

Change from Baseline to Week 2

4.9
U/L (Least Squares Mean)
95% Confidence Interval: -11.3 to 21.1

Change from Baseline to Week 4

2.0
U/L (Least Squares Mean)
95% Confidence Interval: -6.4 to 10.5

Change from Baseline to Week 8

-0.9
U/L (Least Squares Mean)
95% Confidence Interval: -9.0 to 7.2

Change in AST:ALT Ratio 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.

Placebo

Change from Baseline to Week 12

0.02
Ratio (Least Squares Mean)
95% Confidence Interval: -0.07 to 0.11

Change from Baseline to Week 16

0.03
Ratio (Least Squares Mean)
95% Confidence Interval: -0.07 to 0.14

Change from Baseline to Week 2

Change from Baseline to Week 4

0.02
Ratio (Least Squares Mean)
95% Confidence Interval: -0.06 to 0.09

Change from Baseline to Week 8

0.01
Ratio (Least Squares Mean)
95% Confidence Interval: -0.06 to 0.08

1000 mg Epeleuton

Change from Baseline to Week 12

0.03
Ratio (Least Squares Mean)
95% Confidence Interval: -0.05 to 0.11

Change from Baseline to Week 16

0.1
Ratio (Least Squares Mean)
95% Confidence Interval: 0.01 to 0.19

Change from Baseline to Week 2

-0.04
Ratio (Least Squares Mean)
95% Confidence Interval: -0.15 to 0.07

Change from Baseline to Week 4

-0.03
Ratio (Least Squares Mean)
95% Confidence Interval: -0.1 to 0.05

Change from Baseline to Week 8

2000 mg Epeleuton

Change from Baseline to Week 12

0.01
Ratio (Least Squares Mean)
95% Confidence Interval: -0.07 to 0.09

Change from Baseline to Week 16

0.02
Ratio (Least Squares Mean)
95% Confidence Interval: -0.08 to 0.13

Change from Baseline to Week 2

0.05
Ratio (Least Squares Mean)
95% Confidence Interval: -0.06 to 0.16

Change from Baseline to Week 4

0.06
Ratio (Least Squares Mean)
95% Confidence Interval: -0.02 to 0.13

Change from Baseline to Week 8

0.03
Ratio (Least Squares Mean)
95% Confidence Interval: -0.04 to 0.09

Change in FIB-4 Index From Baseline to Week 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.

Placebo

-0.109
Scores on a scale (Least Squares Mean)
95% Confidence Interval: -0.398 to 0.181

1000 mg Epeleuton

0.114
Scores on a scale (Least Squares Mean)
95% Confidence Interval: -0.196 to 0.424

2000 mg Epeleuton

-0.068
Scores on a scale (Least Squares Mean)
95% Confidence Interval: -0.384 to 0.248

Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score (NFS) From Baseline to Week 16

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.

Placebo

-0.0073
Scores on a scale (Least Squares Mean)
95% Confidence Interval: -0.2653 to 0.2507

1000 mg Epeleuton

0.225
Scores on a scale (Least Squares Mean)
95% Confidence Interval: -0.0529 to 0.5028

2000 mg Epeleuton

-0.034
Scores on a scale (Least Squares Mean)
95% Confidence Interval: -0.3149 to 0.2469

Change in ELF (Enhanced Liver Fibrosis Score) From Baseline to Week 16

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.

Placebo

0.24
Scores on a scale (Least Squares Mean)
95% Confidence Interval: -0.09 to 0.56

1000 mg Epeleuton

0.1
Scores on a scale (Least Squares Mean)
95% Confidence Interval: -0.19 to 0.39

2000 mg Epeleuton

0.01
Scores on a scale (Least Squares Mean)
95% Confidence Interval: -0.29 to 0.31

Change in HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) From Baseline to Weeks 2, 4, 8, 12 and 16

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.

Placebo

Change from Baseline to Week 12

-0.045
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -1.769 to 1.68

Change from Baseline to Week 16

-0.393
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -1.31 to 0.524

Change from Baseline to Week 2

1.208
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -1.102 to 3.518

Change from Baseline to Week 4

2.175
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -1.393 to 5.743

Change from Baseline to Week 8

6.606
HOMA-IR (Least Squares Mean)
95% Confidence Interval: 0.563 to 12.649

1000 mg Epeleuton

Change from Baseline to Week 12

Change from Baseline to Week 16

-0.326
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -1.234 to 0.582

Change from Baseline to Week 2

1.25
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -1.024 to 3.525

Change from Baseline to Week 4

-0.54
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -4.154 to 3.075

Change from Baseline to Week 8

1.817
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -4.28 to 7.913

2000 mg Epeleuton

Change from Baseline to Week 12

-0.258
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -1.858 to 1.343

Change from Baseline to Week 16

-2.037
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -2.912 to -1.162

Change from Baseline to Week 2

-0.569
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -2.762 to 1.623

Change from Baseline to Week 4

2.347
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -1.166 to 5.86

Change from Baseline to Week 8

4.283
HOMA-IR (Least Squares Mean)
95% Confidence Interval: -1.707 to 10.273

Change in Adipo-IR (Adipose Tissue Insulin Resistance) From Baseline to Weeks 2, 4, 8, 12 and 16.

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.

Placebo

Change from Baseline to Week 12

4.2
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -12.46 to 20.86

Change from Baseline to Week 16

3.66
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -12.54 to 19.86

Change from Baseline to Week 2

9.69
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -6.05 to 25.42

Change from Baseline to Week 4

24.88
Adipo-IR (Least Squares Mean)
95% Confidence Interval: 1.94 to 47.82

Change from Baseline to Week 8

25.52
Adipo-IR (Least Squares Mean)
95% Confidence Interval: 5.86 to 45.18

1000 mg Epeleuton

Change from Baseline to Week 12

-6.28
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -22.88 to 10.32

Change from Baseline to Week 16

-10.68
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -26.8 to 5.43

Change from Baseline to Week 2

-5.55
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -21.08 to 9.97

Change from Baseline to Week 4

3.45
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -19.86 to 26.75

Change from Baseline to Week 8

10.4
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -9.28 to 30.07

2000 mg Epeleuton

Change from Baseline to Week 12

-20.66
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -36.35 to -4.97

Change from Baseline to Week 16

-21.07
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -36.44 to -5.69

Change from Baseline to Week 2

-10.8
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -25.66 to 4.06

Change from Baseline to Week 4

4.19
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -18.09 to 26.47

Change from Baseline to Week 8

6.63
Adipo-IR (Least Squares Mean)
95% Confidence Interval: -11.79 to 25.05

Change in Hepatic Fat Measured by CAP (Controlled Attenuation Parameter) From Baseline to Week 16.

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.

Placebo

-12.3
dB/m (Least Squares Mean)
95% Confidence Interval: -34.4 to 9.9

1000 mg Epeleuton

-16.3
dB/m (Least Squares Mean)
95% Confidence Interval: -36.8 to 4.1

2000 mg Epeleuton

-22.4
dB/m (Least Squares Mean)
95% Confidence Interval: -43.0 to -1.8

Total

96
Participants

Age, Continuous

48.4
years (Mean)
Standard Deviation: 12.44

Race (NIH/OMB)

Sex: Female, Male

Overall Study

Placebo

1000 mg Epeleuton

2000mg Epeleuton

Drop/Withdrawal Reasons

Placebo

1000 mg Epeleuton

2000mg Epeleuton