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

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ClinicalTrials.gov Identifier: NCT03124108
Recruitment Status : Completed
First Posted : April 21, 2017
Results First Posted : September 24, 2019
Last Update Posted : September 24, 2019
Sponsor:
Information provided by (Responsible Party):
Genfit

Tracking Information
First Submitted Date  ICMJE March 28, 2017
First Posted Date  ICMJE April 21, 2017
Results First Submitted Date  ICMJE August 16, 2019
Results First Posted Date  ICMJE September 24, 2019
Last Update Posted Date September 24, 2019
Actual Study Start Date  ICMJE April 5, 2017
Actual Primary Completion Date October 31, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 20, 2019)
Relative Change From Baseline in Serum Alkaline Phosphatase (ALP) Levels at Week 12 (Endpoint) [ Time Frame: Baseline, 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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 20, 2017)
Change in serum alkaline phosphatase (ALP) [ Time Frame: Measurements at Baseline and 12 weeks ]
To evaluate the efficacy of elafibranor 80 and 120 mg with respect to relative change from baseline in serum ALP levels compared to placebo
Change History Complete list of historical versions of study NCT03124108 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 20, 2019)
  • 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) [ Time Frame: Up to Week 12 (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.
  • 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) [ Time Frame: Up to Week 12 (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.
  • Percentage of Participants With Response Based on PARIS I Risk Score at Endpoint [ Time Frame: At Week 12 (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.
  • Percentage of Participants With Response Based on PARIS II Risk Score at Endpoint [ Time Frame: At Week 12 (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.
  • Percentage of Participants With Response Based on Toronto I Risk Score at Endpoint [ Time Frame: At Week 12 (Endpoint) ]
    Percentage of participants with response based on Toronto I risk score was defined as ALP <= 1.67 *ULN.
  • Percentage of Participants With Response Based on Toronto II Risk Score at Endpoint [ Time Frame: At Week 12 (Endpoint) ]
    Percentage of participants with response based on Toronto II risk scores was defined as ALP <= 1.75 * ULN.
  • Median Percentage Risk as Assessed by United Kingdom-Primary Biliary Cholangitis (UK-PBC) Risk Total Score at Endpoint [ Time Frame: At Week 12 (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.
  • Percentage of Participants With Response Defined by 10, 20 and 40 Percent Reduction in Alkaline Phosphatase [ Time Frame: At Week 12 (Endpoint) ]
    Percentage of participants with response (defined by at least 10%, 20%, and 40% decrease in ALP from baseline to Endpoint) reported.
  • Percentage of Participants With Response Defined by Normalized Alkaline Phosphatase Levels at Endpoint [ Time Frame: At Week 12 (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.
  • Percentage of Participants With Response Defined by Normalized Bilirubin (BIL) at Endpoint [ Time Frame: At Week 12 (Endpoint) ]
    The response was defined by normalized BIL levels (BIL ULN <1.20 milligram per deciliter [mg/dL]) at endpoint.
  • Percentage of Participants With Response Defined by Normalized Albumin (ALB) Levels at Endpoint [ Time Frame: At Week 12 (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.
  • Change From Baseline in Alanine Aminotransferase (ALT) Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in ALT levels at endpoint was reported.
  • Change From Baseline in Aspartate Aminotransferase (AST) Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in AST levels at endpoint was reported.
  • Change From Baseline in Gamma-glutamyl Transferase (GGT) Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in GGT levels at endpoint was reported.
  • Change From Baseline in 5 Prime (') Nucleotidase Levels at Endpoint [ Time Frame: Baseline, Week 12 (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.
  • Change From Baseline in Total Bilirubin (BIL) Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in total BIL levels at endpoint was reported.
  • Change From Baseline in Conjugated Bilirubin Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in conjugated bilirubin levels at endpoint was reported.
  • Change From Baseline in Albumin Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in albumin levels at endpoint was reported.
  • Change From Baseline in Cholesterol Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in cholesterol levels at endpoints was reported.
  • Change From Baseline in Low-density Lipoprotein (LDL) Cholesterol Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in LDL-cholesterol at endpoint was reported.
  • Change From Baseline in High-density Lipoprotein (HDL) Cholesterol Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in HDL-cholesterol levels at endpoint was reported.
  • Change From Baseline in Triglycerides Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in triglycerides levels at endpoint was reported.
  • Change From Baseline in Total Free Bile Acid Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in total free bile acid levels at endpoint was reported.
  • Change From Baseline in Total Conjugated Bile Acid Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in total conjugated bile acid levels at endpoint was reported.
  • Change From Baseline in Total Bile Acid Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in total bile acid levels at endpoint was reported.
  • Change From Baseline in 7 Alpha-hydroxy-4-cholesten-3-one Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in 7 alpha-hydroxy-4-cholesten-3-one levels at endpoint was reported.
  • Change From Baseline in Fibroblast Growth Factor-19 Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in fibroblast growth factor-19 levels at endpoint was reported.
  • Change From Baseline in Immunoglobulin M (IgM) Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in IgM levels at endpoint was reported.
  • Change From Baseline in Tumor Necrosis Factor Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in tumor necrosis factor levels at endpoint was reported.
  • Change From Baseline in Transforming Growth Factor Beta Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in transforming growth factor beta levels at endpoint was reported,
  • Change From Baseline in Interleukin 6 Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in interleukin 6 levels at endpoint was reported.
  • Change From Baseline in Plasminogen Activator Inhibitor-1 Antigen (AG) Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in plasminogen activator inhibitor-1 AG levels at endpoint was reported.
  • Change From Baseline in Cytokeratin-18 Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in cytokeratin-18 (M30 and M65) levels at endpoint was reported.
  • Change From Baseline in Autotaxin Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in autotaxin levels at endpoint was reported.
  • C-reactive Protein Level at Endpoint [ Time Frame: Week 12 (Endpoint) ]
    C-reactive protein level at endpoint was reported.
  • Change From Baseline in Haptoglobin Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in haptoglobin levels at endpoint was reported.
  • Change From Baseline in Fibrinogen Levels at Endpoint [ Time Frame: Baseline, Week 12 (Endpoint) ]
    Change from baseline in fibrinogen levels at endpoint was reported.
  • Change From Baseline in 5D-Itch Scale Total Score [ Time Frame: Baseline, Week 12 (Endpoint) ]
    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).
  • Change From Baseline in Pruritus as Assessed by Visual Analogue Scale (VAS) Total Score [ Time Frame: Baseline, Week 12 (Endpoint) ]
    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.
  • Change From Baseline in Primary Biliary Cholangitis -40 (PBC-40) Quality of Life (QoL) Questionnaire Scores [ Time Frame: Baseline, Week 12 (Endpoint) ]
    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.
  • Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Treatment Emergent Adverse Events [ Time Frame: Up to Week 12 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 20, 2017)
  • Composite endpoint composed of ALP and total bilirubin [ Time Frame: Measurements at 12 weeks ]
    To assess response rate in elafibranor 80 mg and 120 mg and placebo groups, with response defined as ALP less than 1.67 times ULN and total bilirubin within normal limits and ALP reduction > 15%
  • Composite endpoint composed of ALP and total bilirubin [ Time Frame: Measurements at 12 weeks ]
    To assess response rate in elafibranor 80 mg and 120 mg and placebo groups, with response defined as ALP less than 2 times ULN and total bilirubin within normal limits and ALP reduction > 40%
  • Paris I PBC risk score [ Time Frame: Measurements at 12 weeks ]
    To assess response rate in elafibranor 80 mg and 120 mg and placebo groups according to Paris I PBC risk score
  • Paris II PBC risk score [ Time Frame: Measurements at 12 weeks ]
    To assess response rate in elafibranor 80 mg and 120 mg and placebo groups according to Paris II PBC risk score
  • Toronto I PBC risk score [ Time Frame: Measurements at 12 weeks ]
    To assess response rate in elafibranor 80 mg and 120 mg and placebo groups according to Toronto I PBC risk score
  • Toronto II PBC risk score [ Time Frame: Measurements at 12 weeks ]
    To assess response rate in elafibranor 80 mg and 120 mg and placebo groups according to Toronto II PBC risk score
  • UK PBC risk score [ Time Frame: Measurements at 12 weeks ]
    To assess response rate in elafibranor 80 mg and 120 mg and placebo groups according to UK PBC risk score
  • Normalization of ALP levels [ Time Frame: Measurements at 12 weeks ]
    To assess the response to elafibranor 80 mg and 120 mg versus placebo treatment on normalization of ALP
  • Liver enzymes [ Time Frame: Measurements at Baseline and 12 weeks ]
    To assess the response to elafibranor 80 mg and 120 mg versus placebo treatment on liver enzymes and liver markers
  • Fibrosis markers [ Time Frame: Measurements at Baseline and 12 weeks ]
    To assess the response to elafibranor 80 mg and 120 mg versus placebo treatment on fibrosis markers
  • Lipid parameters [ Time Frame: Measurements at Baseline and 12 weeks ]
    To assess the response to elafibranor 80 mg and 120 mg versus placebo treatment on lipid parameters
  • Inflammatory markers [ Time Frame: Measurements at Baseline and 12 weeks ]
    To assess the response to elafibranor 80 mg and 120 mg versus placebo treatment on inflammatory markers
  • Pruritis score [ Time Frame: Measurements at Baseline and 12 weeks ]
    To assess the efficacy of elafibranor 80 and 120 mg versus placebo treatment with respect to the change from baseline in pruritus (through 5D-itch scale and visual analogue score VAS)
  • Quality of Life parameters [ Time Frame: Measurements at Baseline and 12 weeks ]
    To assess the efficacy of elafibranor 80 and 120 mg versus placebo treatment with respect to the change from baseline in Quality of Life (using PBC 40 questionnaire)
  • Assess the tolerability and safety of elafibranor 80 mg and 120 mg in patients with PBC [ Time Frame: 12 weeks ]
    To monitor adverse events
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate the Efficacy and Safety of Elafibranor in Patients With Primary Biliary Cholangitis (PBC) and Inadequate Response to Ursodeoxycholic Acid
Official Title  ICMJE 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
Brief Summary 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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Primary Biliary Cholangitis (PBC)
Intervention  ICMJE
  • Drug: Elafibranor 80 mg
    Two coated tablets daily for 12 weeks
    Other Name: GFT505
  • Drug: Elafibranor 120 mg
    Two coated tablets daily for 12 weeks
    Other Name: GFT505
  • Drug: Placebo
    Two coated tablets daily for 12 weeks
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Study subjects will take two tablets per day orally before breakfast with a glass of water each morning
    Intervention: Drug: Placebo
  • Active Comparator: Elafibranor 80 mg
    Study subjects will take two tablets per day orally before breakfast with a glass of water each morning
    Intervention: Drug: Elafibranor 80 mg
  • Active Comparator: Elafibranor 120 mg
    Study subjects will take two tablets per day orally before breakfast with a glass of water each morning
    Intervention: Drug: Elafibranor 120 mg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 20, 2017)
45
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 31, 2018
Actual Primary Completion Date October 31, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Must have provided written informed consent
  2. 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
  3. ALP >= 1.67x upper limit of normal (ULN)
  4. Taking UDCA for at least 12 months (stable dose for ≥ 6 months) prior to screening visit
  5. 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:

  1. History or presence of other concomitant liver diseases
  2. Screening creatine phosphokinase (CPK) > upper limits of normal (ULN)
  3. Screening alanine transaminase (ALT) or aspartate aminotransferase (AST) > 5 ULN
  4. Screening total bilirubin > 2 ULN
  5. Screening serum creatinine > 1.5 mg/dl
  6. 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).
  7. Patients with moderate or severe hepatic impairment (defined as Child-Pugh B/C)
  8. Platelet count <150 X 10^3/microliter
  9. Albumin <3.5 g/dL
  10. Presence of clinical complications of PBC or clinically significant hepatic decompensation
  11. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
  12. Known history of human immunodeficiency virus (HIV) infection
  13. Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Germany,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03124108
Other Study ID Numbers  ICMJE GFT505B-216-1
2016-003817-80 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Genfit
Study Sponsor  ICMJE Genfit
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Head Genfit
PRS Account Genfit
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP