Elafibranor, PK and Safety in Children and Adolescents 8 to 17 Years of Age With Non Alcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Non Alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Elafibranor 80mg
* Drug: Elafibranor 120mg


Participation Criteria
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Eligibility Criteria
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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: Abnormal hemoglobin (with the exception of females with a documented history of a low hemoglobin during menstruation); White blood cell count less than 3,500 cells/mm^3 of blood; Platelet count less than150,000 cells/mm^3 of blood; Direct bilirubin greater than 0.3 mg/dL; 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; Serum albumin less than 3.5 g/dL; International normalized ratio (INR) greater than 1.4; Has evidence of chronic liver disease other than NASH, defined by any one of the following: Biopsy consistent with histological evidence of autoimmune hepatitis; Serum hepatitis A antibody positive; Serum hepatitis B surface antigen positive; Serum hepatitis C antibody positive; Serum hepatitis E antibody positive; History of or current positive Anti-Mitochondrial Antibody Test; Known or current Iron/total iron binding capacity ratio (transferrin saturation) greater than 45% with histological evidence of iron overload; Known or current Alpha-1-antitrypsin phenotype/genotype ZZ or SZ; 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

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Elafibranor 80 mg<br>Participants received Elafibranor 80 mg tablet orally once daily for 12 weeks. | Drug: Elafibranor 80mg<br>* Once daily oral intake of elafibranor 80 mg during 3 months<br>* Other names: GFT505;|
| Experimental: Elafibranor 120 mg<br>Participants received Elafibranor 120 mg tablet orally once daily for 12 weeks. | Drug: Elafibranor 120mg<br>* Once daily oral intake of elafibranor 120 mg during 3 months<br>* Other names: GFT505;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Elafibranor and Its Active Metabolite (GFT1007) | Cmax was defined as maximum observed plasma concentration. | 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 | 
| Pharmacokinetics: Time to Maximum Observed Plasma Concentration (Tmax) of Elafibranor and Active Metabolite (GFT1007) | Tmax was defined as time to reach maximum observed plasma concentration. | 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 | 
| Pharmacokinetics: Area Under The Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Elafibranor and Active Metabolite (GFT1007) | AUC0-24 defined as the area under the plasma concentration versus time curve of the study drug from time 0 to 24 hours. | 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 | 
| Pharmacokinetics: Terminal Elimination Half-life ( t½) of Elafibranor and Active Metabolite (GFT1007) | Plasma t1/2 was defined as the time taken by drug to reduce to half of its initial plasma concentration. | 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 | 
| Pharmacokinetics: Plasma Trough Concentrations (Ctrough) of Elafibranor and Active Metabolite (GFT1007) | Ctrough was defined as the plasma concentration of study drug observed just before treatment administration during repeated dosing. | Pre-dose on Day 1 and 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. Missing data were not imputed for the analysis. Normal range at screening: AST: 0 - 39 international units per liter (IU/L), ALT: 5 - 30 IU/L, GGT: 2 - 24 IU/L, and ALP: 74 - 390 IU/L. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Other Liver Markers: Change From Baseline in Adiponectin at Days 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. Missing data were not imputed for the analysis. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| Pharmacodynamics - Other Liver Markers: Change From Baseline in Cytokeratin 18 (CK-18)/M65 and CK-18/M30 at Days 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. Missing data were not imputed for the analysis. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| Pharmacodynamics - Other Liver Markers: Change From Baseline in Ferritin at Days 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. Missing data were not imputed for the analysis. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| Pharmacodynamics - Other Liver Markers: Change From Baseline in Fibroblast Growth Factor 19 and Fibroblast Growth Factor 21 at Days 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. Missing data were not imputed for the analysis. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| 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 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. Missing data were not imputed for the analysis. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| Pharmacodynamics - Other Liver Markers: Change From Baseline in Alpha-2 Macroglobulin at Days 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. Missing data were not imputed for the analysis. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| Pharmacodynamics - Glucose Homeostasis Markers: Change From Baseline in Fasting Plasma Glucose (FPG) at Days 15, 29, 57, 85, and 113 | Blood samples were taken after minimum 10 hours of fasting. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Glucose Homeostasis Markers: Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at Days 15, 29, 57, 85, and 113 | HOMA IR measures insulin resistance based on fasting glucose and insulin measurements: HOMA IR = fasting plasma insulin (micro international units per milliliter [mcIU/mL]) * fasting plasma glucose (mmol/L) / 22.5. A higher value indicates a greater insulin resistance. Blood samples were taken after minimum 10 hours of fasting. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Glucose Homeostasis Markers: Change From Baseline in Fasting Insulin at Days 15, 29, 57, 85, and 113 | Blood samples were taken after minimum 10 hours of fasting. Baseline was defined as the last measurement before first intake of study treatment on Day 1. Here, mIU/L was abbreviated as milli-international unit per liter. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Total Cholesterol (TC) at Days 15, 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| 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 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum High-density Lipoprotein Cholesterol (HDL-C) at Days 15, 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Low-density Lipoprotein (LDL-C) at Days 15, 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Triglycerides at Days 15, 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| 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 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Apolipoprotein A-1 at Days 15, 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Serum Lipid Parameters: Change From Baseline in Serum Apolipoprotein B at Days 15, 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Change From Baseline in Body Weight at Days 15, 29, 57, 85, and 113 | Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Change From Baseline in Body Mass Index (BMI) Z-Score at Days 15, 29, 57, 85, and 113 | The BMI for a given age (in years) and gender (male) was converted to an exact z-score. Given a participant's age, sex, BMI, and an appropriate reference standard, a BMI Z-score was determined. BMI Z-score >=85th percentile was considered as overweight. Z-score was a statistical measure to describe whether a mean was above or below the standard. A Z-score of 0 was equal to the mean and is considered normal. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. Negative values are indicative of decrease in BMI (weight loss) and positive values are indicative of increase in BMI. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Change From Baseline in Waist Circumference at Days 15, 29, 57, 85, and 113 | Waist circumference (in centimeters [cm]) was measured at the midpoint between the lower margin of the least palpable rib and the top of the iliac crest. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 
| Pharmacodynamics - Inflammatory Marker: Change From Baseline in Fibrinogen at Days 29, 57, 85, and 113 | Blood samples to assess fibrinogen levels were taken after minimum 10 hours of fasting. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| Pharmacodynamics - Inflammatory Marker: Change From Baseline in Haptoglobin at Days 29, 57, 85, and 113 | Blood samples to assess Haptoglobin level were taken after minimum 10 hours of fasting. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| Pharmacodynamics - Inflammatory Marker: Change From Baseline in Interleukin-6 at Days 29, 57, 85, and 113 | Blood samples to assess Interleukin-6 level were taken after minimum 10 hours of fasting. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| Pharmacodynamics - Inflammatory Marker: Change From Baseline in Tumor Necrosis Factor Alpha at Days 29, 57, 85, and 113 | Blood samples to assess Necrosis Factor Alpha level were taken after minimum 10 hours of fasting. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 29, 57, 85, and 113 | 
| Pharmacodynamics - Inflammatory Marker: Change From Baseline in Plasminogen Activator Inhibitor-1 at Days 29, 57, 85, and 113 | Blood samples to assess plasminogen activator inhibitor-1 level were taken after minimum 10 hours of fasting. Baseline was defined as the last measurement before first intake of study treatment on Day 1. Here, IU/mL was abbreviated as International units per milliliter. | Baseline (Day 1), Day 29, 57, 85, and 113 | 
| Pharmacodynamics - Change From Baseline in Pediatric Quality of Life (PedsQL™) (Version 4.0) Generic Core Scales at Day 85 | The child, adolescent and parent/legal guardian PedsQL™ (Version 4.0) generic core scales was used to measure health-related quality of life (HRQOL). The response information was completed by the participant and by a parent/legal guardian individually. It consisted of 23 item questionnaire encompassing 4 core scale domains: Physical Functioning (8 items); Emotional Functioning (5 items); Social Functioning (5 items); and School Functioning (5 items). Items were scored on a 5 point Likert-type response scale: 0=never a problem to 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Once scored, items were reverse scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), where higher scores indicated better HRQOL. Total Scale Score was the sum of all the items over the number of items answered on all the Scales. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Day 85 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event (AE) was any untoward medical in a participant or clinical investigation patient administered a pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship with this treatment. A Serious adverse event (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was another medically important condition. TEAEs were defined as AEs that started prior to first study drug dose and that worsened after, and the AEs that started on or after first study drug dose. TEAEs: Serious and non-serious AEs. | From Screening visit (signature of informed consent) up to last dose of study drug + 30 days (i.e., up to Day 113) | 
| Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Measurement | ECG measurements were taken with the participants in resting position for at least 10 minutes. The investigator determined whether abnormal assessment results were clinically significant or not. The number of participants with abnormal clinically significant ECG findings were reported. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Day 85 | 
| Number of Participants With Abnormal Clinical Chemistry Parameters | Fasting blood samples (collected after 10 hours fasting) were used to assess the following clinical chemistry parameters: creatinine, glomerular filtration rate, creatinine clearance, total proteins, albumin, electrolytes (sodium, potassium, chloride, calcium), uric acid, urea nitrogen, urea, creatine phosphokinase (CPK), AST, ALT, GGT, ALP, total and conjugated bilirubin, high sensitivity C-reactive protein, fasting plasma glucose, fasting insulin, HOMA-IR, fructosamine, C-peptide, free fatty acids, glycated hemoglobin A1c, cystatin C. Abnormal clinical chemistry values were classified based on reference range: lower limit of normality (LLN); normal (>= LLN and <= upper limit of normality [ULN]); > ULN and <3 ULN; >=3 ULN and <5 ULN and >=5 ULN. Only the parameters for which at least one value of abnormality were reported and presented in this outcome measure. | At Day 85 (i.e., end of treatment) | 
| Number of Participants With Abnormal Hematology and Coagulation Parameters | Fasting blood samples (collected after 10 hours fasting) were used to assess the following hematology and coagulation parameters: hemoglobin, hematocrit, red blood cells (RBC), white blood cells (WBC), neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelets, prothrombin time (PT) and international normalized ratio (INR). Hematology and coagulation values were classified based on the reference range: LLN; normal (>= LLN and <= ULN); > ULN and <3 ULN; >=3 ULN and <5 ULN and >=5 ULN. | At Day 85 (i.e., end of treatment) | 
| Number of Participants With Abnormal Urinalysis Parameters | Blood samples were collected to assess the following urinalysis parameters: alpha-1 macroglobulin, N-acetyl glucosamide, neutrophil gelatinase-associated lipocalin, albumin, and creatinine. Abnormal urinalysis values were classified based on the reference range: LLN; normal (>= LLN and <= ULN); > ULN and <3 ULN; >=3 ULN and <5 ULN and >=5 ULN. | At Day 85 (i.e., end of treatment) | 
| Number of Participants With Abnormal Vital Signs | Vital signs were taken before any invasive procedures. Following vital signs were assessed: systolic blood pressure, diastolic blood pressure, heart rate. Abnormal vita signs was defined as any abnormal findings in the vital sign parameters and were categorized as 'abnormal, not clinically significant (NCS)' and 'abnormal, clinically significant (CS)'. | At Day 85 (i.e., end of treatment) | 
| Number of Participants With Clinically Significant Abnormalities in Physical Examination at Baseline, Days 15, 29, 57, 85, and 113 | Physical examination findings were collected according to pre-defined body systems: general appearance; skin; eyes; ears; nose; throat; neck and thyroid; lungs; heart; upper/lower extremities; lymph nodes; abdomen; musculoskeletal system; basic neurological assessment. Additional systems were evaluated as needed. Clinical significance was defined as any variation in assessment results that had medical relevance resulting in an alteration in medical care. Participants with at least one clinically significant abnormality in physical examination were reported and presented in this outcome measure. Baseline was defined as the last measurement before first intake of study treatment on Day 1. | Baseline (Day 1), Days 15, 29, 57, 85, and 113 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric, Pharmacokinetics