Primary Objective * To evaluate the effect of a 6-week treatment with elafibranor versus placebo on hepatic lipid composition in subjects with a fatty liver.Secondary objectives * To evaluate the between treatment difference (elafibranor 120 mg/d vs…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Metabolism disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
* Relative amount of saturated fatty acids in the liver (%SFA) measured by
1H-MRS at the end of 6 weeks treatment periods.
Secondary outcome
Secondary Endpoints:
* Hepatic insulin sensitivity measured by HGP (Hepatic Glucose Production) at
the end of 6 weeks treatment periods.
* Changes from baseline achieved after 6-week treatment in:
o Glycaemic markers (Fasting glycaemia, HbA1C, Fasting insulinemia, c-peptide
and HOMA-IR index, Fructosamine levels)
o Lipid markers (Fasting TG, Total cholesterol, HDL-C, LDL-C and non-HDL-C
levels, FFA)
o Inflammatory markers (hs-CRP, fibrinogen, haptoglobin)
o Liver function (ALT, AST, GGT, ALP, total and conjugated bilirubin)
o Renal Function (creatinine, eGFR, urea (BUN), albumin, uric acid, total
proteins)
o Body weight, BMI, waist circumference determined at the end of the 6 weeks
treatment period.
Safety endpoints:
* The tolerability and safety will be assessed using the following endpoints:
o AEs and SAEs,
o Vital signs and other observations related to safety
o Hematological parameters,
o Liver markers,
o Renal biomarkers,
o Metabolic parameters,
o Other biochemical safety markers
Exploratory Endpoint
* Correlation between the difference in SFA and difference in hepatic insulin
sensitivity at the end of 6 weeks treatment periods.
* Whole-body insulin sensitivity measured at the end of 6 weeks treatment
periods by:
o Glucose Infusion Rate
o Rate of disappearance
o Metabolic flexibility as difference in (Respiratory exchange ratio) RER
between non-insulin stimulated state and insulin stimulated state
o Non-oxidative glucose disposal
o Insulin-stimulated glucose oxidation
o Insulin-suppressed fat oxidation
* Whole body energy expenditure and substrate utilization during the night at
the end of 6 weeks treatment periods:
o Sleeping metabolic rate
o Substrate oxidation
* Adipose tissue distribution and liver volume (by MRI) measured at the end of
6 weeks treatment periods.
Background summary
Previous results have shown that the dual PPAR*/* agonist elafibranor (GFT505)
specifically targets the liver and that this drug improves both peripheral as
well as hepatic insulin sensitivity. As such, this drug is a promising drug
for the treatment of individuals with a fatty liver (non-alcholic fatty liver,
NAFL) and type 2 diabetes, although the exact mechanisms underlying the
observed improvements in insulin sensitivity are not fully elucidated.
Strikingly, the beneficial effects of the drug does not seem to be related to
reduced hepatic steatosis per se. To get more mechanistic information about the
mode of action of elafibranor on the (lipid) metabolism in the human fatty
liver, state-of-the art Magnetic Resonance Spectroscopy (MRS) techniques can be
used. These non-invasive techniques will allow to not only study the total
amount of hepatic fat, but can also give qualitative information about the
hepatic fat pool (i.e. degree of saturated, mono-unsaturated and
poly-unsaturated fatty acids, SFA/MUFA and PUFA respectively).
Study objective
Primary Objective
* To evaluate the effect of a 6-week treatment with elafibranor versus placebo
on hepatic lipid composition in subjects with a fatty liver.
Secondary objectives
* To evaluate the between treatment difference (elafibranor 120 mg/d vs.
placebo) in HGP (Hepatic Glucose Production) measured at the end of 6 weeks
treatment periods.
* To compare the changes from baseline, achieved after 6-week treatment with
elafibranor 120mg/d versus placebo in:
* Glucose homeostasis,
* Lipid metabolism,
* Inflammatory markers,
* Liver function.
* Renal function
* Antropometry
Safety
* To assess the safety and tolerability profile of 6-week elafibranor
administration orally (120 mg/d) in NAFL subjects:
* serious adverse events, adverse events, vital signs
* hematological parameters,
* liver markers,
* renal biomarkers,
* metabolic parameters,
* other biochemical safety markers.
Exploratory Objectives
* To explore whether there is an association between the difference in
saturated fatty acids (SFA) and difference of
hepatic insulin sensitivity after treatment with elafibranor vs.
placebo.
* To evaluate the between treatment difference (elafibranor 120 mg/d vs.
placebo) in whole body insulin sensitivity
measured at the end of 6 weeks treatment periods.
* To study whole body energy expenditure and substrate utilization during the
night upon treatment with elafibranor vs. placebo.
* To study adipose tissue distribution and liver volume (by MRI) upon treatment
with elafibranor vs. placebo.
Study design
Randomized, double-blind, cross-over (placebo or elafibranor [GFT505])
placebo-controlled study, evaluating the effect on hepatic lipid composition
and safety of elafibranor 120 mg QD versus placebo in an adult NAFL population
after 6 weeks of treatment with a 4-6 week wash-out period. This study will
achieve mechanistic information about the mode of action of Elafibranor on the
(lipid) metabolism in the human fatty liver.
Intervention
In this study we will investigate the effect of six weeks of elafibranor
treatment on hepatic lipid composition in a randomized placebo-controlled
cross-over trial.
Study burden and risks
Results of this study will provide insight into the mechanism of elafibranor as
treatment to improve metabolic health in subjects with a fatty liver. Previous
studies have highlighted the good safety profile of elafibranor and no major
safety concerns have been raised.
The risks of the performed measurements are low and low physical discomfort is
to be expected. The measurements itself are regarded safe due to the use of
sophisticated measurement tools and the research group itself has ample
experience in using these tools. There is a risk of hypoglycaemia during the
hyperinsulinemic euglycemic clamp. Measurements performed during the time
course of the study can potentially lead to unexpected medical findings.
Subjects will be informed about such a finding and their treating physician
will also be informed. It is not expected that subjects will directly benefit
from participation in the study.
Avenue Eugène Avinée 885
Loos 59120
FR
Avenue Eugène Avinée 885
Loos 59120
FR
Listed location countries
Age
Inclusion criteria
1. Males or post-menopausal females aged from 40-75 years inclusive at first
Screening Visit. (Post-menopausal defined as: subject should be surgically
sterilized at least 6 months or no spontaneous menses for at least 1 year prior
to screening)
2. Must provide signed written informed consent (ICF) and agrees to comply with
the study protocol.
3. Liver fat percentage IHL * 5% (as measured with 1H-MRS)
4. 25.0 * BMI * 38.0 kg/m2
5. Stable dietary habits and physical activity pattern (over 3 months prior to
Screening Visit)
6. Subject agrees not to change dietary habits and physical activity pattern,
to follow diet and lifestyle recommendations and not to consume or use illicit
drugs during the study up to end of treatment.
Exclusion criteria
Medical history:
1. Documented weight loss of more than 5% during the 6-month period prior to
Screening Visit
2. Contra-indications for MRI/MRS
3. Known history of Type 1 and 2 diabetes
4. Known chronic heart failure (Grade I to IV of New York Heart Association
classification)
5. History of clinically significant acute cardiac event within 6 months prior
to Screening Visit such as: stroke, transient ischemic attack, or coronary
heart disease (angina pectoris, myocardial infarction, revascularization
procedures)
6. Uncontrolled hypertension despite optimal antihypertensive therapy
7. Other well documented causes of chronic liver disease according to standard
diagnostic procedures.
8. Symptoms of clinical depression
9. Other concurrent medical (e.g., immunological, neoplastic, endocrine,
hematological, gastrointestinal or neurological) or psychiatric condition,
which, in the opinion of the Investigator, would place the subject at increased
risk, preclude obtaining voluntary consent/assent or compliance with required
study procedures, or would confound the objectives of study
10. Known hypersensitivity to the investigation product or any of its
formulation excipients, Concomitant medications and lifestyle:
11. Fibrates are not permitted from 8 weeks before Screening up to end of
treatment. Subjects taking statins or ezetimibe prior to Screening Visit 1 may
participate if the dose has been stable for 3 months prior to Screening Visit 1
and no dose adjustments are anticipated
12. Currently taking drugs that can induce steatosis/steatohepatitis including,
but not restricted to: corticosteroids (parenteral & oral chronic
administration only), amiodarone (Cordarone), tamoxifen (Nolvadex), and
methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to
Screening and up to end of treatment
13. Subjects receiving thiazoledinediones (glitazones [pioglitazone,
rosiglitazone])
14. Currently taking any medication that could interfere with study medication
absorption, distribution, metabolism, or excretion or could lead to induction
or inhibition of microsomal enzymes, e.g., indomethacin, which are not
permitted from Randomization until end of treatment
15. Any medication use known to interfere with glucose homeostasis/metabolism
16. Smoking
17. Current or recent history (<5years) of significant alcohol consumption. For
men, significant consumption is typically defined as higher than 30 g pure
alcohol per day. For women, it is typically defined as higher than 20 g pure
alcohol per day
18. Subjects who have donated blood or blood products within the previous month
prior to screening or who plan to donate blood or blood products at any time
during the trial and in the month following the end of the study
19. Is participating in any other study and have received any other
investigational drug or device within 30 days prior to Screening or are taking
part in a non-medication study which, in the opinion of the Investigator, would
interfere with study compliance or outcome assessments
20. Subjects who cannot be contacted in case of emergency, In addition to the
above criteria, subject should not present any of the following biological
exclusion criteria:
21. Positive anti-human immunodeficiency virus (HIV) antibody
22. Positive hepatitis B surface antigen
23. Positive hepatitis C Virus (HCV) antibody
24. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >5 x
upper limit of normal (ULN)
25. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note:
Gilbert Disease subjects are allowed into the study
26. International normalized ratio >1.40 due to altered hepatic function
27. Platelet count <100,000/mm3 due to portal hypertension
28. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females
29. Significant renal disease, including nephritic syndrome, chronic kidney
disease (defined as subjects with markers of kidney damage or estimated
glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2)
30. Unexplained serum creatine phosphokinase (CPK) >2 x ULN. In case of
explained elevated CPK >2 x ULN, the measurement can be repeated prior to
Randomization. In this case, retest should be performed within 1 to 2 weeks
after initial test. A CPK retest >2 x ULN leads to exclusion
31. Hemoglobin A1c (HbA1C) > 6.4% and/or fasting plasma glucose (FGP) > 126
mg/dl
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-000645-12-NL |
| ClinicalTrials.gov | NCT03953456 |
| CCMO | NL69148.068.19 |