Primary objectives * surrogate endpoint (at interim analysis)To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without worsening of fibrosis.* Resolution of NASH is defined as the disappearance of…
ID
Source
Brief title
Condition
- Hepatobiliary neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objectives * surrogate endpoint (at interim analysis)
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on
resolution of NASH without worsening of fibrosis.
* Resolution of NASH is defined as the disappearance of ballooning and
disappearance or persistence of minimal lobular inflammation (grade 0 or 1)
with an overall pattern of injury not qualifying for steatohepatitis.
* Worsening of fibrosis is evaluated using the NASH Clinical Research Network
(CRN) fibrosis staging system and defined as progression of at least one stage.
Primary objectives * long-term endpoints
To evaluate the efficacy of elafibranor on clinical outcomes described as a
composite endpoint composed of death to any cause, liver cirrhosis, and the
full list of portal hypertension/cirrhosis related events:
* Liver transplantation
* MELD score *15
* HCC
* Hospitalization (as defined by a stay of 24 hours or greater) for new onset
or recurrence of:
o variceal bleed,
o hepatic encephalopathy,
o spontaneous bacterial peritonitis,
o uncontrolled ascites,
o hepatorenal syndrome,
o hepatopulmonary syndrome,
o chronic gastrointestinal blood loss due to portal hypertensive gastropathy
(provided that these lead to hospitalization or transfusion).
Key secondary objective (at interim analysis)
To assess histological changes after 72 weeks of treatment on the following
endpoint parameter:
* Percentage of patients with improvement of fibrosis of at least 1 stage
according to NASH CRN scoring.
Other secondary objectives
* To assess histological changes after 72 weeks of treatment and follow-up
biopsy on the following parameters:
o percentage of patients with resolution of NASH without worsening of fibrosis
(follow-up biopsy)
o percentage of patients with improvement of fibrosis of at least 1 stage
according to NASH CRN scoring
o percentage of patients with at least 1 point improvement in histological
scores (NASH CRN scoring: total nonalcoholic fatty liver disease (NAFLD)
activity score (NAS), steatosis, hepatic ballooning, lobular inflammation),
fibrosis (NAFLD Ishak scoring system), or portal inflammation
o percentage of patients with improvement of NAS score of at least 2 points.
o percentage of patients with at least a 1 point improvement in
steatosis-activity-fibrosis (SAF) activity score
o mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular
inflammation, portal inflammation, SAF activity score
o changes in area of fibrosis by morphometry
o mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring.
* To assess the following endpoints in elafibranor treated patients relative to
placebo, at Week 72, and at the end of the Long-term Treatment Period:
o cardiovascular events
o liver-related death events
o changes in liver enzymes and liver markers
o changes in noninvasive markers of fibrosis and steatosis
o changes in lipid parameters
o variation in body weight
o changes in insulin resistance and glucose homeostasis markers
o changes in inflammatory markers
o changes in cardiovascular risk profile as assessed by Framingham scores
o changes in quality of life (36-Item Short-Form Health Survey [SF-36])
questionnaire)
* To assess Time to first occurrence of:
o liver cirrhosis
o death of any cause
o any portal hypertension or cirrhosis related events.
Exploratory objectives
* To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and
GFT1007 after 72 weeks of treatment for PK population analyses.
* To constitute a biobank for discovery and validation of biomarkers in NASH.
Exploratory objectives for F1 group
* To explore the following endpoints in elafibranor treated F1 patients in the
exploratory group relative to placebo at Week 72 and at the end of the
Long-term Treatment Period:
o resolution of NASH without worsening of fibrosis
o percentage of patients with at least 1 point reduction in NASH CRN fibrosis
score and NAFLD Ishak score
o percentage of patients with at least 1 point improvement in NAS, steatosis,
ballooning, lobular inflammation, or portal inflammation
o percentage of patients with improvement of NAS score of at least 2 points
o percentage of patients with at least a 1 point improvement in SAF activity
score
o mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring
system), steatosis, hepatic ballooning, lobular inflammation, portal
inflammation, SAF activity score
o changes in area of fibrosis by morphometry.
* To explore the following endpoints in F1 patients at Week 72 and after the
Long-term Treatment Period:
o composite long-term endpoints
o cardiovascular events
o changes in liver enzymes and liver markers
o changes in noninvasive markers of fibrosis and steatosis
o changes in lipid parameters
o variation in body weight
o changes in insulin resistance and glucose homeostasis markers
o changes in inflammatory markers
o changes in cardiovascular risk profile as assessed by Framingham scores
o changes in quality of life (SF-36 questionnaire).
* To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks
of treatment.
* To assess the tolerability and safety.
Safety secondary objectives
* To assess the tolerability and safety of once a day administration of oral
doses of elafibranor 120 mg description of:
o serious adverse events, adverse events, physical examination, vital signs,
medical history, electrocardiogram
o hematological parameters
o liver function parameters
o renal function parameters (including urinalysis)
o cardiac function parameters
o metabolic parameters
o other biochemical safety markers.
Secondary outcome
Other secondary objectives
* To assess histological changes after 72 weeks of treatment and follow-up
biopsy on the following parameters:
o percentage of patients with resolution of NASH without worsening of fibrosis
(follow-up biopsy)
o percentage of patients with improvement of fibrosis of at least 1 stage
according to NASH CRN scoring
o percentage of patients with at least 1 point improvement in histological
scores (NASH CRN scoring: total nonalcoholic fatty liver disease (NAFLD)
activity score (NAS), steatosis, hepatic ballooning, lobular inflammation),
fibrosis (NAFLD Ishak scoring system), or portal inflammation
o percentage of patients with improvement of NAS score of at least 2 points.
o percentage of patients with at least a 1 point improvement in
steatosis-activity-fibrosis (SAF) activity score
o mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular
inflammation, portal inflammation, SAF activity score
o changes in area of fibrosis by morphometry
o mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring.
* To assess the following endpoints in elafibranor treated patients relative to
placebo, at Week 72, and at the end of the Long-term Treatment Period:
o cardiovascular events
o liver-related death events
o changes in liver enzymes and liver markers
o changes in noninvasive markers of fibrosis and steatosis
o changes in lipid parameters
o variation in body weight
o changes in insulin resistance and glucose homeostasis markers
o changes in inflammatory markers
o changes in cardiovascular risk profile as assessed by Framingham scores
o changes in quality of life (36-Item Short-Form Health Survey [SF-36])
questionnaire)
* To assess Time to first occurrence of:
o liver cirrhosis
o death of any cause
o any portal hypertension or cirrhosis related events.
Exploratory objectives
* To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and
GFT1007 after 72 weeks of treatment for PK population analyses.
* To constitute a biobank for discovery and validation of biomarkers in NASH.
Exploratory objectives for F1 group
* To explore the following endpoints in elafibranor treated F1 patients in the
exploratory group relative to placebo at Week 72 and at the end of the
Long-term Treatment Period:
o resolution of NASH without worsening of fibrosis
o percentage of patients with at least 1 point reduction in NASH CRN fibrosis
score and NAFLD Ishak score
o percentage of patients with at least 1 point improvement in NAS, steatosis,
ballooning, lobular inflammation, or portal inflammation
o percentage of patients with improvement of NAS score of at least 2 points
o percentage of patients with at least a 1 point improvement in SAF activity
score
o mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring
system), steatosis, hepatic ballooning, lobular inflammation, portal
inflammation, SAF activity score
o changes in area of fibrosis by morphometry.
* To explore the following endpoints in F1 patients at Week 72 and after the
Long-term Treatment Period:
o composite long-term endpoints
o cardiovascular events
o changes in liver enzymes and liver markers
o changes in noninvasive markers of fibrosis and steatosis
o changes in lipid parameters
o variation in body weight
o changes in insulin resistance and glucose homeostasis markers
o changes in inflammatory markers
o changes in cardiovascular risk profile as assessed by Framingham scores
o changes in quality of life (SF-36 questionnaire).
* To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks
of treatment.
* To assess the tolerability and safety.
Safety secondary objectives
* To assess the tolerability and safety of once a day administration of oral
doses of elafibranor 120 mg description of:
o serious adverse events, adverse events, physical examination, vital signs,
medical history, electrocardiogram
o hematological parameters
o liver function parameters
o renal function parameters (including urinalysis)
o cardiac function parameters
o metabolic parameters
o other biochemical safety markers.
Background summary
The Sponsor, GENFIT, located at Parc Eurasanté, 885 Avenue Eugène Avinée, 59120
LOOS, FRANCE is developing a new drug, Elafibranor, for the treatment of NASH.
Elafibranor is an investigational drug and has not been approved by Centrale
Commissie Mensgebonden Onderzoek (CCMO)
The safety and the tolerability of Elafibranor has been studied in 811
individuals including healthy volunteers (447) and patients (364) suffering
from dyslipidemia, pre-diabetes, type 2 Diabetes and NASH.
The Sponsor, GENFIT, is doing this research study to learn more about the
efficacy and safety of 120 mg daily Elafibranor
Study objective
Primary objectives * surrogate endpoint (at interim analysis)
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on
resolution of NASH without worsening of fibrosis.
* Resolution of NASH is defined as the disappearance of ballooning and
disappearance or persistence of minimal lobular inflammation (grade 0 or 1)
with an overall pattern of injury not qualifying for steatohepatitis.
* Worsening of fibrosis is evaluated using the NASH Clinical Research Network
(CRN) fibrosis staging system and defined as progression of at least one stage.
Primary objectives * long-term endpoints
To evaluate the efficacy of elafibranor on clinical outcomes described as a
composite endpoint composed of death to any cause, liver cirrhosis, and the
full list of portal hypertension/cirrhosis related events:
* Liver transplantation
* MELD score *15
* HCC
* Hospitalization (as defined by a stay of 24 hours or greater) for new onset
or recurrence of:
o variceal bleed,
o hepatic encephalopathy,
o spontaneous bacterial peritonitis,
o uncontrolled ascites,
o hepatorenal syndrome,
o hepatopulmonary syndrome,
o chronic gastrointestinal blood loss due to portal hypertensive gastropathy
(provided that these lead to hospitalization or transfusion).
Key secondary objective (at interim analysis)
To assess histological changes after 72 weeks of treatment on the following
endpoint parameter:
* Percentage of patients with improvement of fibrosis of at least 1 stage
according to NASH CRN scoring.
Other secondary objectives
* To assess histological changes after 72 weeks of treatment and follow-up
biopsy on the following parameters:
o percentage of patients with resolution of NASH without worsening of fibrosis
(follow-up biopsy)
o percentage of patients with improvement of fibrosis of at least 1 stage
according to NASH CRN scoring
o percentage of patients with at least 1 point improvement in histological
scores (NASH CRN scoring: total nonalcoholic fatty liver disease (NAFLD)
activity score (NAS), steatosis, hepatic ballooning, lobular inflammation),
fibrosis (NAFLD Ishak scoring system), or portal inflammation
o percentage of patients with improvement of NAS score of at least 2 points.
o percentage of patients with at least a 1 point improvement in
steatosis-activity-fibrosis (SAF) activity score
o mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular
inflammation, portal inflammation, SAF activity score
o changes in area of fibrosis by morphometry
o mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring.
* To assess the following endpoints in elafibranor treated patients relative to
placebo, at Week 72, and at the end of the Long-term Treatment Period:
o cardiovascular events
o liver-related death events
o changes in liver enzymes and liver markers
o changes in noninvasive markers of fibrosis and steatosis
o changes in lipid parameters
o variation in body weight
o changes in insulin resistance and glucose homeostasis markers
o changes in inflammatory markers
o changes in cardiovascular risk profile as assessed by Framingham scores
o changes in quality of life (36-Item Short-Form Health Survey [SF-36])
questionnaire)
* To assess Time to first occurrence of:
o liver cirrhosis
o death of any cause
o any portal hypertension or cirrhosis related events.
Exploratory objectives
* To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and
GFT1007 after 72 weeks of treatment for PK population analyses.
* To constitute a biobank for discovery and validation of biomarkers in NASH.
Study design
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505])
placebo-controlled study, evaluating the efficacy and safety of elafibranor 120
mg QD versus placebo in an adult NASH population with fibrosis. The first
double-blind 72-week treatment period will assess the efficacy and safety of
elafibranor on the resolution of NASH without worsening of fibrosis at the
intermediate efficacy analysis, followed by a Long-term Treatment Period to
assess efficacy on all-cause mortality and liver-related clinical outcomes as
measured by the time to first occurrence of any of the listed adjudicated
events (all-cause mortality, progression to histological cirrhosis, and the
full list of portal hypertension/cirrhosis related events).
Dose level
120 mg
Route of administration:
Oral (1 tablet once daily [QD])
Intervention
Double-Blind Study to Evaluate the Efficacy and Safety of Elafibranor
Study burden and risks
In a study of mating male and female rats treated with high doses of
Elafibranor male rats showed very small changes in the internal structure of
sperm cells they produced and there was a slight decrease in the percentage of
pregnant female rats. However the human relevance of these minimal effects of a
high dose of Elafibranor is currently unknown.
During all previous clinical studies involving human beings with Elafibranor,
there were 9 serious adverse events in 6 patients believed to be related to the
study treatment. Only 5 of them were considered reasonably associated with the
study treatment. These were spontaneous abortion, acute pancreatitis (sudden
inflammation of the pancreas), ataxia (changes to co-ordination, balance and
speech), tremor and involuntary muscle contractions.
The known unwanted effects and symptoms include gastro-intestinal disorders
such as nausea, diarrhea, and vomiting, asthenia or fatigue (weakness), myalgia
(muscle pain), decrease of appetite, rash and hot flush. Certain markers in the
blood that may suggest liver, muscle or kidney problems may also be affected by
Elafibranor
As with any study drug, there may be a risk of allergic reaction. Symptoms can
include skin rashes, itching, respiratory problems, swelling in the face
Risks associated with the evaluation procedures specific to the study
Blood sampling will be performed at several visits. Sometimes the blood
sampling may be a little uncomfortable and may be painful, some redness or
swelling in the area where blood has been taken. Some people also experience
faintness.
Being fasted for 12 hours before each visit can induce dizziness, headaches,
abdominal pains and seldom fainting.
There is no known side effect related to ECG, except possible skin irritation
at the place where the electrode is applied.
The Ultrasound of the liver (Fibroscan), is not known to have any
inconveniences.
The most commonly used technique to collect the liver sample is a needle
puncture through the skin liver biopsy. For this method, a hollow needle is
inserted through the abdomen into the liver to remove a small piece of tissue.
Pain is the most frequent risk occurring in about 20% of patients. In some rare
cases, other inconveniences may occur such as hemorrhage, pneumothorax (air in
the pleural space) or vesicular perforation (hole in the gallbladder).
Liver biopsy is usually done under local anesthesia. Nevertheless, in case
general anesthesia is chosen, adverse events may occur, like nausea, vomiting,
sore throat, dizziness, headache, and pain at the injection area. More rarely,
urinary difficulty, pulmonary infection, mouth injury, nervous lesion, allergy
or even death can occur.
Although all precautions are taken not to divulge personal identity and to
protect medical information, there is a risk that someone could get access to
the personal information in medical records or other information researchers
have stored .
Adres Parc Eurasanté - avenue Eugène Avinée 885
Loos 59120
BE
Adres Parc Eurasanté - avenue Eugène Avinée 885
Loos 59120
BE
Listed location countries
Age
Inclusion criteria
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit.
2. Must provide signed written informed consent and agree to comply with the
study protocol.
3. Body Mass Index *45 kg/m².
4. Females participating in the study must either not be of childbearing
potential (hysterectomy, bilateral oophorectomy, medically documented ovarian
failure, or >50 years of age with cessation of menses for at least 12 months
due to ovarian failure) or using efficient double contraception: hormonal
contraception (including patch, contraceptive ring, etc), intra-uterine device,
or other mechanical contraception method + condom or diaphragm or spermicide
for the full duration of the study and for 1 month after the end of treatment.
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by
central reading of the slides (biopsy obtained within 6 months prior to
Randomization or during the Screening Period) with at least 1 in each component
of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and
lobular inflammation scored 0-3).
6. NAS score *4.
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN
fibrosis staging system.
For patients with fibrosis stage 1, only patients at high risk of progression
will be included meaning with a NAS score *5 and 2 of the following conditions:
persistent elevated ALT, obesity defined by a BMI *30, metabolic syndrome (NCEP
ATP III definition), type 2 diabetes, or HOMA IR >6.
8. Patients agree to have 1 liver biopsy during the Screening Period for
diagnostic purpose (if no historical biopsy within 6 months before
Randomization is available), 1 liver biopsy after 72-weeks of treatment for
assessment of the treatment effects on NASH, as well as another in case of
suspicion of cirrhosis (to have a histological confirmation), and a final liver
biopsy after approximately 4 years of treatment (visit V13), unless a biopsy
has already been performed within the year.
9. Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (>2
g/day), or ursodeoxycholic acid from at least 6 months prior to diagnostic
liver biopsy.
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia
is controlled by antidiabetic drugs, no change in anti-diabetic therapy is
allowed within 6 months prior to diagnostic liver biopsy, under the following
conditions:
o no change in dose for patients treated by glucagon-like peptide 1 agonist
o no qualitative change (i.e. implementation of a new anti-diabetic drug) for
patients treated by metformin, dipeptidyl-peptidase 4 inhibitors,
sodium/glucose cotransporter 2 inhibitors, sulfamides, or insulin.
Exclusion criteria
1. Known heart failure (Grade I to IV of New York Heart Association
classification).
2. History of efficient bariatric surgery within 5 years prior to Screening.
3. Uncontrolled hypertension during the Screening Period despite optimal
antihypertensive therapy.
4. Type 1 diabetes patients.
5. Patients with decompensated diabetes (hemoglobin A1c [HbA1c] >9.0%). If
abnormal at the first Screening Visit, the HbA1c measurement can be repeated at
the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c
>9.0%) leads to exclusion.
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless
the drug was discontinued at least 6 months before the diagnostic liver biopsy.
7. Patients with a history of clinically significant acute cardiac event within
6 months prior to Screening such as: acute cardiovascular episode, stroke,
transient ischemic attack, or coronary heart disease (angina pectoris,
myocardial infarction, revascularization procedures).
8. Weight loss of more than 5% within 6 months prior to Randomization.
9. Compensated and decompensated cirrhosis (clinical and/or histological
evidence of cirrhosis). Notably, NASH patients with fibrosis stage = 4
according to the NASH CRN fibrosis staging system are excluded.
10. Current or recent history (<5 years) 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.
11. Patients who have donated blood or blood products within 1 month prior to
Screening or who plan to donate blood or blood products at any time during the
trial and in the 2 months following the end of the study.
12. Pregnant or lactating females or females planning to become pregnant during
the study period.
13. Other well documented causes of chronic liver disease according to standard
diagnostic procedures including, but not restricted to:
o positive hepatitis B surface antigen
o positive hepatitis C Virus RNA)
o suspicion of drug-induced liver disease
o alcoholic liver disease
o autoimmune hepatitis
o Wilson*s disease hemochromatosis
o primary biliary cirrhosis, primary sclerosing cholangitis
o genetic hemochromatosis
o known or suspected HCC
o history or planned liver transplant, or current MELD score >12
14. Where applicable, patients not covered by Health Insurance System and/or
not in compliance with the recommendations of National Law in force.
15. Patients who cannot be contacted in case of emergency.
16. Known hypersensitivity to the investigation product or any of its
formulation excipients.
17. Patients with previous exposure to elafibranor.
18. Patients who are currently participating in, plan to participate in, or
have participated in an investigational drug or medical device trial within 30
days or five half-lives, whichever is longer, prior to Screening.
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 | EUCTR2015-005385-38-NL |
| ClinicalTrials.gov | NCT02704403 |
| CCMO | NL57358.056.16 |