Study to Evaluate the Efficacy and Safety of Elafibranor in Patients With Primary Biliary Cholangitis (PBC) and Inadequate Response to Ursodeoxycholic Acid

Study Overview
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Brief Summary
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The primary objective of the study is to compare the effect of daily oral administration of elafibranor 80mg and 120 mg on change in serum alkaline phosphatase (ALP) to that of placebo in patients with PBC and inadequate response to Ursodeoxycholic acid (UDCA).

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy and Safety of Elafibranor at Doses of 80 mg and 120mg After 12 Weeks of Treatment in Patients With Primary Biliary Cholangitis and Inadequate Response to Ursodeoxycholic Acid

Conditions
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Primary Biliary Cholangitis (PBC)

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have provided written informed consent Definite or probable PBC diagnosis as demonstrated by the presence of at least 2 of the following 3 diagnostic factors: History of elevated ALP levels for at least 6 months prior to Day 0 (randomization visit) Positive Anti-Mitochondrial Antibodies (AMA) titers (> 1/40 on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay (ELISA) or positive PBC-specific antinuclear antibodies Liver biopsy consistent with PBC ALP >= 1.67x upper limit of normal (ULN) Taking UDCA for at least 12 months (stable dose for ≥ 6 months) prior to screening visit Contraception: Females participating in this study must be of non-childbearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the end of treatment. Exclusion Criteria: History or presence of other concomitant liver diseases Screening creatine phosphokinase (CPK) > upper limits of normal (ULN) Screening alanine transaminase (ALT) or aspartate aminotransferase (AST) > 5 ULN Screening total bilirubin > 2 ULN Screening serum creatinine > 1.5 mg/dl Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 60 mL/min/1.73 m^2). Patients with moderate or severe hepatic impairment (defined as Child-Pugh B/C) Platelet count <150 X 10^3/microliter Albumin <3.5 g/dL Presence of clinical complications of PBC or clinically significant hepatic decompensation If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating Known history of human immunodeficiency virus (HIV) infection Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Study subjects will take two tablets per day orally before breakfast with a glass of water each morning | Drug: Placebo<br>* Two coated tablets daily for 12 weeks<br>|
| Active Comparator: Elafibranor 80 mg<br>Study subjects will take two tablets per day orally before breakfast with a glass of water each morning | Drug: Elafibranor 80 mg<br>* Two coated tablets daily for 12 weeks<br>* Other names: GFT505;|
| Active Comparator: Elafibranor 120 mg<br>Study subjects will take two tablets per day orally before breakfast with a glass of water each morning | Drug: Elafibranor 120 mg<br>* Two coated tablets daily for 12 weeks<br>* Other names: GFT505;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change From Baseline in Serum Alkaline Phosphatase (ALP) Levels at Week 12 (Endpoint) | Relative change from baseline is in serum ALP levels at Week 12 (endpoint) were reported. Relative change from baseline is defined as percentage (%) change from baseline to endpoint. | Baseline, Week 12 (Endpoint) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Response Defined by Composite Risk Scores (ALP< 1.67 * Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] Within Normal Limits at Endpoint, and Greater Than [>] 15% ALP Reduction From Baseline to Endpoint) | Percentage of participants with response defined by Composite Risk Scores (ALP Less than [<] 1.67 * ULN at endpoint, Total BIL within normal limits at endpoint, and > 15% ALP reduction from baseline to Endpoint) was reported. | Up to Week 12 (Endpoint) | 
| Percentage of Participants With Response Defined by Composite Risk Scores (ALP < 2 * Upper Limit of Normal at Endpoint, Total Bilirubin Within Normal Limits at Endpoint, and > 40% ALP Reduction From Baseline to Endpoint) | Percentage of participants with response defined by composite risk scores (ALP < 2 * ULN at endpoint, Total BIL within normal limits at endpoint, and > 40% ALP reduction from baseline to endpoint) was reported. | Up to Week 12 (Endpoint) | 
| Percentage of Participants With Response Based on PARIS I Risk Score at Endpoint | Percentage of participants with response based on Paris I risk score was defined as ALP less than or equal to (<=) 3 * ULN and aspartate aminotransferase (AST) <= 2 * ULN and bilirubin within normal limits. | At Week 12 (Endpoint) | 
| Percentage of Participants With Response Based on PARIS II Risk Score at Endpoint | Percentage of participants with response based on Paris II risk score was defined as ALP <= 1.5 * ULN and AST <= 1.5 * ULN and bilirubin within normal limits. | At Week 12 (Endpoint) | 
| Percentage of Participants With Response Based on Toronto I Risk Score at Endpoint | Percentage of participants with response based on Toronto I risk score was defined as ALP <= 1.67 *ULN. | At Week 12 (Endpoint) | 
| Percentage of Participants With Response Based on Toronto II Risk Score at Endpoint | Percentage of participants with response based on Toronto II risk scores was defined as ALP <= 1.75 * ULN. | At Week 12 (Endpoint) | 
| Median Percentage Risk as Assessed by United Kingdom-Primary Biliary Cholangitis (UK-PBC) Risk Total Score at Endpoint | UK-PBC risk score at endpoint estimated that the median percentage risk that a participant treated with ursodeoxycholic acid (UDCA) will develop liver failure requiring liver transplant in 5, 10 and 15 years. UK-PBC score was calculated at each of the 3 survivor functions 1-baseline survival function^exp(0.0287854*[alpEPxuln-1.722136304] - 0.0422873*[{(altastEPxuln/10)^-1} - 8.675729006] + 1.4199 * [ln{bilEPxuln /10}+2.709607778] -1.960303*[albxlln -1.17673001]-0.4161954*[ pltxlln -1.873564875]). Where: Baseline survivor function=0. 982 (at 5 years); 0. 941 (at 10 years); 0.893 (at 15 years). alpEPxuln = ALP at endpoint/upper level normal ALP; altastEPxuln=(ALT, AST) at endpoint/upper level normal of the value; bilEPxuln=bilirubin at endpoint/upper level normal bilirubin; albxlln=albumin at baseline/albumin lower level normal; pltxlln=platelet count at baseline/ platelet count lower level normal. | At Week 12 (Endpoint) | 
| Percentage of Participants With Response Defined by 10, 20 and 40 Percent Reduction in Alkaline Phosphatase | Percentage of participants with response (defined by at least 10%, 20%, and 40% decrease in ALP from baseline to Endpoint) reported. | At Week 12 (Endpoint) | 
| Percentage of Participants With Response Defined by Normalized Alkaline Phosphatase Levels at Endpoint | The response was defined by normalized ALP levels (ALP ULN 105 units per liter [U/L] for females, 129 U/L for males) at endpoint. | At Week 12 (Endpoint) | 
| Percentage of Participants With Response Defined by Normalized Bilirubin (BIL) at Endpoint | The response was defined by normalized BIL levels (BIL ULN <1.20 milligram per deciliter [mg/dL]) at endpoint. | At Week 12 (Endpoint) | 
| Percentage of Participants With Response Defined by Normalized Albumin (ALB) Levels at Endpoint | The response was defined by normalized ALB levels (3.5-5.2 gram per deciliter [g/dL] for ages 18-60 years; 3.2-4.6 g/dL for ages 61-91 years) at endpoint. | At Week 12 (Endpoint) | 
| Change From Baseline in Alanine Aminotransferase (ALT) Levels at Endpoint | Change from baseline in ALT levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Aspartate Aminotransferase (AST) Levels at Endpoint | Change from baseline in AST levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Gamma-glutamyl Transferase (GGT) Levels at Endpoint | Change from baseline in GGT levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in 5 Prime (') Nucleotidase Levels at Endpoint | Change from baseline in 5' nucleotidase levels at endpoint was reported. 5' nucleotidase is an enzyme used as a biomarker of hepatobiliary cholestasis and is less sensitive but more specific than GGT and ALP. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Total Bilirubin (BIL) Levels at Endpoint | Change from baseline in total BIL levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Conjugated Bilirubin Levels at Endpoint | Change from baseline in conjugated bilirubin levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Albumin Levels at Endpoint | Change from baseline in albumin levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Cholesterol Levels at Endpoint | Change from baseline in cholesterol levels at endpoints was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Low-density Lipoprotein (LDL) Cholesterol Levels at Endpoint | Change from baseline in LDL-cholesterol at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in High-density Lipoprotein (HDL) Cholesterol Levels at Endpoint | Change from baseline in HDL-cholesterol levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Triglycerides Levels at Endpoint | Change from baseline in triglycerides levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Total Free Bile Acid Levels at Endpoint | Change from baseline in total free bile acid levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Total Conjugated Bile Acid Levels at Endpoint | Change from baseline in total conjugated bile acid levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Total Bile Acid Levels at Endpoint | Change from baseline in total bile acid levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in 7 Alpha-hydroxy-4-cholesten-3-one Levels at Endpoint | Change from baseline in 7 alpha-hydroxy-4-cholesten-3-one levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Fibroblast Growth Factor-19 Levels at Endpoint | Change from baseline in fibroblast growth factor-19 levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Immunoglobulin M (IgM) Levels at Endpoint | Change from baseline in IgM levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Tumor Necrosis Factor Levels at Endpoint | Change from baseline in tumor necrosis factor levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Transforming Growth Factor Beta Levels at Endpoint | Change from baseline in transforming growth factor beta levels at endpoint was reported, | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Interleukin 6 Levels at Endpoint | Change from baseline in interleukin 6 levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Plasminogen Activator Inhibitor-1 Antigen (AG) Levels at Endpoint | Change from baseline in plasminogen activator inhibitor-1 AG levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Cytokeratin-18 Levels at Endpoint | Change from baseline in cytokeratin-18 (M30 and M65) levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Autotaxin Levels at Endpoint | Change from baseline in autotaxin levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| C-reactive Protein Level at Endpoint | C-reactive protein level at endpoint was reported. | Week 12 (Endpoint) | 
| Change From Baseline in Haptoglobin Levels at Endpoint | Change from baseline in haptoglobin levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Fibrinogen Levels at Endpoint | Change from baseline in fibrinogen levels at endpoint was reported. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in 5D-Itch Scale Total Score | 5 dimensional (5D)-Itch Scale is a reliable, multidimensional measure of itching that has been validated in participants with chronic pruritus to detect changes over time. It consists of 5 domains: duration, degree, direction, disability, and distribution. The duration, degree and direction domains each include one item, while the disability domain has four items (sleep, leisure/social, housework/errands, work/school). All items of the first four domains were measured on a 5-point Likert scale. The distribution domain included 16 potential locations of itch, including 15 body part items (head/scalp, soles, face, palms, chest, abdomen, back, buttocks, thighs, lower legs, tops of feet/toes, tops of hands/fingers, upper arms, groin, forearms) and one point of contact with clothing or bandages. Scores of each of five domains are achieved separately and then summed together to obtain a total 5-D score. 5-D scores can potentially range between 5 (no pruritus) and 25 (most severe pruritus). | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Pruritus as Assessed by Visual Analogue Scale (VAS) Total Score | The VAS is a reliable and validated method of pruritus assessment. The VAS is adequate in assessing the severity of the symptom; it does not take into account other aspects of pruritus, such as the relative impact of pruritus on quality of life. The VAS, for pruritus assessment, requires the participant to use abstract thought processes to convert their itch severity to a mark on a continuum. A participant draws a line anywhere on the scale ranging from 0 to 10 (where 0 represents 'no itching' and 10 represents 'worst possible itching') that best represents the severity of participant's itching and the scoring involves manual measuring of the mark with a ruler on range of 0 to 100 millimeter (mm). Higher scores indicate worse itching. | Baseline, Week 12 (Endpoint) | 
| Change From Baseline in Primary Biliary Cholangitis -40 (PBC-40) Quality of Life (QoL) Questionnaire Scores | PBC-40 QoL Questionnaire is a patient-derived, disease-specific QoL measure developed and validated for use in PBC. It consists of 9 domains with total 40 questions as: 1) digestion and diet (questions 1-3, total score range: 3-15); 2) experiences (questions 4-7, total score range: 4-20); 3) itching (questions 8-10, total score range: 3-15); 4) fatigue (questions 11-18, total score range: 8-40); 5) effort and planning (questions 19-21, total score range: 3-15); 6) memory and concentration (questions 22-27, total score range: 6-30); 7) affects you as a person (questions 28-33, total score range: 6-30); 8) affects your social life (questions 34-37, total score range: 4-20); 9) overall impact on your life (questions 38-40, total score range: 3-15). PBC-40 QoL Questionnaire has 40 questions, each scored on scale of 1-5 (1 = least impact, 5 = greatest impact). For each domain, scoring involved summing individual question response scores. Higher scores indicate poorer quality of life. | Baseline, Week 12 (Endpoint) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Treatment Emergent Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a patient 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) is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization/prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is another medically important condition. TEAEs is defined as (1) it is not present when active phase of study (time of first dose) begins and is not a chronic condition that is part of patient's medical history, or it is present at start of active phase or as part of patient's medical history, but severity/frequency increases during active phase. | Up to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Elafibranor, Primary Biliary Cholangitis, Alkaline phosphatase