Clinical trial NCT03883607: Elafibranor, PK and Safety in Children and Adolescents 8 to 17 Years of Age With Non Alcoholic Steatohepatitis (NASH)
Official title: An Open Label, Randomized, Multicenter Study to Assess the Pharmacokinetic and Pharmacodynamic Profile and the Safety and Tolerability of Two Dose Levels of Elafibranor (80 mg and 120 mg) in Children and Adolescents, 8 to 17 Years of Age, With Nonalcoholic Steatohepatitis (NASH)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non Alcoholic Steatohepatitis
Keywords: Pediatric
Pharmacokinetics
Lead sponsor: Genfit
Sponsor class: INDUSTRY
First posted: 2019-03-21
Enrollment: 10
Sex: ALL
Minimum age (years): 8
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study was being conducted in order to assess the pharmacokinetics and the safety of elafibranor following once daily administration of two dose levels of elafibranor (80 milligrams \[mg\] and 120mg) during 3 months in children and adolescent population (8 to 17 years of age) with non alcoholic steatohepatitis (NASH).


Eligibility criteria: Inclusion Criteria:

* Was male or female between 8 and 17 years of age (inclusive) at the time of Screening Visit (when consent for study participation is given) and at the time of Randomization;
* Diagnosis of NASH confirmed by histological evaluation (with or without fibrosis) from a liver biopsy obtained within 24 months prior to Randomization;
* Had an alanine aminotransferase (ALT) level greater than (\>) 50 international units per liter (IU/L), at Screening;
* Had a Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) greater than or equal to (\>=) 5, at Screening;
* Had a Body Mass Index z-score (BMI z-score) (also referred to as BMI-for-age percentile) \>=85th percentile for age and gender at Screening;
* Had a Hemoglobin A1C (HbA1c) less than or equal (\<=) to 8.5%. If the participants had Type 2 diabetes and is taking anti-diabetic therapy (e.g., metformin or insulin), treatment must had been started at least 3 months prior to Screening and the dose must had been stable for at least 3 months prior to Screening and should remain stable through Randomization;
* Sexually active female participants of childbearing potential must had agree to utilize a highly effective method of contraception per the Clinical Trial Facilitation Group Guidelines from Screening through 30 days after the last dose of study drug (1 month after the end of treatment), and agree to monthly pregnancy testing during the study up to and including end of study.

Other inclusion criteria may apply

Exclusion Criteria:

* Had history of bariatric surgery or planned surgery during the study period;
* Had known history of heart disease;
* Had uncontrolled hypertension evidenced by sustained elevation in systolic blood pressure greater than140 mmHg or diastolic blood pressure greater than 90 mmHg despite treatment with antihypertensive therapy, prior to Randomization;
* Had a known history of Type 1 diabetes;
* Had a known history of acquired immunodeficiency syndrome or positive screening for human immunodeficiency virus antibodies at Screening Visit;
* Had a documented weight loss of more than 5% during the 6-month period prior to Randomization;
* Had a history of renal disease defined as an estimated glomerular filtration rate (eGFR) less than 90 mL/min/1.73 m\^2 using the Schwartz Bedside GFR Calculator for Children or present at Screening Visit;
* History of, significant alcohol consumption or inability to reliably quantify alcohol intake, and/or use of illicit drugs.
* Had clinical and/or historical evidence of cirrhosis, included by not limited to:

  1. Abnormal hemoglobin (with the exception of females with a documented history of a low hemoglobin during menstruation);
  2. White blood cell count less than 3,500 cells/mm\^3 of blood;
  3. Platelet count less than150,000 cells/mm\^3 of blood;
  4. Direct bilirubin greater than 0.3 mg/dL;
  5. Total bilirubin greater than 1.3 mg/dL unless the patient has a diagnosis of Gilbert disease in which case direct bilirubin, reticulocyte count and haemoglobin must be normal;
  6. Serum albumin less than 3.5 g/dL;
  7. International normalized ratio (INR) greater than 1.4;
* Has evidence of chronic liver disease other than NASH, defined by any one of the following:

  1. Biopsy consistent with histological evidence of autoimmune hepatitis;
  2. Serum hepatitis A antibody positive;
  3. Serum hepatitis B surface antigen positive;
  4. Serum hepatitis C antibody positive;
  5. Serum hepatitis E antibody positive;
  6. History of or current positive Anti-Mitochondrial Antibody Test;
  7. Known or current Iron/total iron binding capacity ratio (transferrin saturation) greater than 45% with histological evidence of iron overload;
  8. Known or current Alpha-1-antitrypsin phenotype/genotype ZZ or SZ;
  9. Diagnosis of Wilson's disease;
* Had AST and/or ALT greater than 8 fold the upper limit of normal;
* Was pregnant, lactating or is planning to become pregnant during the study;

Other exclusion criteria may apply

Primary outcomes:
measure: Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Elafibranor and Its Active Metabolite (GFT1007)
timeFrame: Day 1: at pre-dose; Day 29: at pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours post dose; Day 30 and 85: at 24 hours after previous day dose administration
measure: Pharmacokinetics: Time to Maximum Observed Plasma Concentration (Tmax) of Elafibranor and Active Metabolite (GFT1007)
timeFrame: Day 1: at pre-dose; Day 29: at pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours post dose; Day 30 and 85: at 24 hours after previous day dose administration
measure: Pharmacokinetics: Area Under The Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Elafibranor and Active Metabolite (GFT1007)
timeFrame: Day 1: at pre-dose; Day 29: at pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours post dose; Day 30 and 85: at 24 hours after previous day dose administration
measure: Pharmacokinetics: Terminal Elimination Half-life ( t½) of Elafibranor and Active Metabolite (GFT1007)
timeFrame: Day 1: at pre-dose; Day 29: at pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours post dose; Day 30 and 85: at 24 hours after previous day dose administration
measure: Pharmacokinetics: Plasma Trough Concentrations (Ctrough) of Elafibranor and Active Metabolite (GFT1007)
timeFrame: Pre-dose on Day 1 and 29
Secondary outcomes:
measure: Pharmacodynamics (PD) - Liver Markers: Change From Baseline in Serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma-glutamyl Transferase (GGT), and Alkaline Phosphatase (ALP) at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Other Liver Markers: Change From Baseline in Adiponectin at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Other Liver Markers: Change From Baseline in Cytokeratin 18 (CK-18)/M65 and CK-18/M30 at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Other Liver Markers: Change From Baseline in Ferritin at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Other Liver Markers: Change From Baseline in Fibroblast Growth Factor 19 and Fibroblast Growth Factor 21 at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Other Liver Markers: Change From Baseline in Hyaluronic Acid, Procollagen 3 N-Terminal Propeptide (PIIINP) and Tissue Inhibitor of Metalloproteinase 1 (TIMP1) at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Other Liver Markers: Change From Baseline in Alpha-2 Macroglobulin at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Glucose Homeostasis Markers: Change From Baseline in Fasting Plasma Glucose (FPG) at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Glucose Homeostasis Markers: Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Glucose Homeostasis Markers: Change From Baseline in Fasting Insulin at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Total Cholesterol (TC) at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Non High-density Lipoprotein Cholesterol (Non-HDL-C) at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum High-density Lipoprotein Cholesterol (HDL-C) at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Low-density Lipoprotein (LDL-C) at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Triglycerides at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Calculated Very Low-density Lipoprotein Cholesterol (VLDL-C) at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Apolipoprotein A-1 at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Apolipoprotein B at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Change From Baseline in Body Weight at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Change From Baseline in Body Mass Index (BMI) Z-Score at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Change From Baseline in Waist Circumference at Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
measure: Pharmacodynamics - Inflammatory Marker: Change From Baseline in Fibrinogen at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Inflammatory Marker: Change From Baseline in Haptoglobin at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Inflammatory Marker: Change From Baseline in Interleukin-6 at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Inflammatory Marker: Change From Baseline in Tumor Necrosis Factor Alpha at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 29, 57, 85, and 113
measure: Pharmacodynamics - Inflammatory Marker: Change From Baseline in Plasminogen Activator Inhibitor-1 at Days 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Day 29, 57, 85, and 113
measure: Pharmacodynamics - Change From Baseline in Pediatric Quality of Life (PedsQL™) (Version 4.0) Generic Core Scales at Day 85
timeFrame: Baseline (Day 1), Day 85
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: From Screening visit (signature of informed consent) up to last dose of study drug + 30 days (i.e., up to Day 113)
measure: Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Measurement
timeFrame: Baseline (Day 1), Day 85
measure: Number of Participants With Abnormal Clinical Chemistry Parameters
timeFrame: At Day 85 (i.e., end of treatment)
measure: Number of Participants With Abnormal Hematology and Coagulation Parameters
timeFrame: At Day 85 (i.e., end of treatment)
measure: Number of Participants With Abnormal Urinalysis Parameters
timeFrame: At Day 85 (i.e., end of treatment)
measure: Number of Participants With Abnormal Vital Signs
timeFrame: At Day 85 (i.e., end of treatment)
measure: Number of Participants With Clinically Significant Abnormalities in Physical Examination at Baseline, Days 15, 29, 57, 85, and 113
timeFrame: Baseline (Day 1), Days 15, 29, 57, 85, and 113
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California
state: California
city: New York
country: United States
facility: Columbia University
state: New York
Study officials:
affiliation: Genfit
name: Carol Addy, MD MMSc
role: STUDY_DIRECTOR
References: