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Study of Elafibranor in Patients With Primary Biliary Cholangitis (PBC) (ELATIVE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04526665
Recruitment Status : Active, not recruiting
First Posted : August 26, 2020
Last Update Posted : May 10, 2024
Sponsor:
Information provided by (Responsible Party):
Ipsen

Study Description
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Brief Summary:

The participants of this study will have confirmed Primary Biliary Cholangitis (PBC) with inadequate response or intolerance to ursodeoxycholic acid (which is a medication used in the management and treatment of cholestatic liver disease).

PBC is a slowly progressive disease characterized by damage of the bile ducts in the liver, leading to a buildup of bile acids which causes further damage. The liver damage in PBC may lead to scarring (cirrhosis).

PBC may also be associated with multiple symptoms. Many patients with PBC may require liver transplant or may die if the disease progresses and a liver transplant is not done.

This study has two main parts; the first part will compare a daily dose of elafibranor (the study drug) to a daily dose of placebo (a dummy treatment), and will last between a minimum of one year and a maximum of two years. In the second part, all participants will receive elafibranor, for a period between 4-5 years.

The main aim of this study is to determine if elafibranor is better than placebo at decreasing the levels of a specific blood test (alkaline phosphatase) that provides information about participant's disease. This study will also study the safety of long-term treatment with elafibranor, as well as the impact on symptoms such as pruritus and fatigue.


Condition or disease Intervention/treatment Phase
Primary Biliary Cirrhosis Drug: Elafibranor 80mg Drug: Placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 161 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a double-blind (DB), randomized, placebo-controlled study followed by an open-label long term extension (LTE)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients With Primary Biliary Cholangitis With Inadequate Response or Intolerance to Ursodeoxycholic Acid
Actual Study Start Date : September 24, 2020
Actual Primary Completion Date : June 1, 2023
Estimated Study Completion Date : December 1, 2028

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Elafibranor 80mg
Study subjects will take 1 tablet per day orally before breakfast with a glass of water each morning
 Drug: Elafibranor 80mg
Elafibranor 80mg daily
Placebo Comparator: Placebo
Study subjects will take 1 tablet per day orally before breakfast with a glass of water each morning
 Drug: Placebo
Placebo daily for double blind period and elafibranor 80 mg daily fo the open label period.


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of participants with response to treatment measured by the combination levels of Alkaline Phosphate Levels (ALP) and Total Bilirubin (TB) [ Time Frame: At Week 52 ]

Secondary Outcome Measures :
  1. Percentage of participants who normalised ALP levels [ Time Frame: At Week 52 ]
  2. Change in pruritus from baseline in participants with baseline PBC Worst Itch NRS Score ≥ 4 [ Time Frame: Through 52 weeks of treatment ]
  3. Change in pruritus from baseline in participants with baseline PBC Worst Itch NRS Score ≥ 4 [ Time Frame: Through 24 weeks of treatment ]
  4. Change from baseline in ALP levels [ Time Frame: At Week 4, 13, 26, 39 and Week 52 and up to a maximum of 6 years ]
  5. Percentage of participants with ≥10%, ≥20%, and ≥40% decrease from Baseline in ALP Levels [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  6. Percentage of Participants with response to treatment [ Time Frame: At Week 52 and up to a maximum of 6 years ]
    Based on different biochemical response criteria

  7. Change from baseline in PBC risk scores based on United Kingdom (UK)-PBC score. [ Time Frame: At Week 52 and up to a maximum of 6 years ]
    the UK-PBC risk score estimates the risk that a patient with PBC will require liver transplantation within 5, 10 or 15 years. A high number is indicative of a worse prognosis.

  8. Change from baseline in Global PBC Study Group (GLOBE) score [ Time Frame: At Week 52 and up to a maximum of 6 years ]
    The GLOBE score is a prognostic tool used to identify patients with PBC who are at higher/lower risk of liver transplant or death. A high number is indicative of a worse prognosis.

  9. Percentage of participants who normalised bilirubin levels [ Time Frame: At Week 52 and up to a maximum of 6 years ]
  10. Percentage of participants who normalised albumin levels [ Time Frame: At Week 52 and up to a maximum of 6 years ]
  11. Change from baseline in levels of aspartate aminotransferase (AST) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  12. Change from baseline in levels of alanine aminotransferase (ALT ) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  13. Change from baseline in levels of gamma-glutamyl transferase (GGT) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  14. Change from baseline in levels of 5'-nucleotidase (5' NT) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  15. Change from baseline in levels of total and conjugated bilirubin [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  16. Change from baseline in levels of albumin [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  17. Change from baseline in international normalised ratio (INR) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  18. Change from baseline in fractionated alkaline phosphatase (ALP) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  19. Change from baseline in levels of high sensitivity C-reactive protein (hsCRP) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  20. Change from baseline in levels of fibrinogen [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  21. Change from baseline in levels of haptoglobin [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  22. Change from baseline in levels of tumor necrosis factor-alpha (TNF-α) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  23. Change from baseline in levels of immunoglobulin G (IgG) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  24. Change from baseline in levels of immunoglobulin M (IgM) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  25. Change from baseline in enhanced liver fibrosis (ELF) score [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  26. Change from baseline in levels of plasminogen activator inhibitor-1 (PAI-1) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  27. Change from baseline in levels of transforming growth factor beta (TGF-β) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  28. Change from baseline in levels of cytokeratin-18 (CK-18) (M65 and M30) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  29. Change from baseline in levels of Pro-C3 [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  30. Change from baseline in liver stiffness as measured by Transient Elastography (TE) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  31. Change from baseline in levels of total cholesterol (TC) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  32. Change from baseline in levels of low density lipoprotein cholesterol (LDL-C) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  33. Change from baseline in levels of high density lipoprotein cholesterol (HDL-C) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  34. Change from baseline in calculated very low density lipoprotein cholesterol (VLDL-C) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  35. Change from baseline in levels of triglycerides (TG) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  36. Change from baseline in Fasting Plasma Glucose (FPG) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  37. Change from baseline in levels of individual bile acids [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  38. Change from baseline in levels of 7-α-hydroxy-4-cholesten-3-one (C4) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  39. Change from baseline in levels of fibroblast growth factor 19 (FGF19) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  40. Percentage of participants with no worsening of pruritus [ Time Frame: From baseline to week 52 and up to a maximum of 6 years ]
    Measured by the PBC Worst Itch Numeric Rating Scale (NRS)

  41. Percentage of responders in PBC Worst Itch NRS [ Time Frame: Baseline through 52 weeks and up to a maximum of 6 years ]
    Defined as at least 30% reduction from baseline of NRS at week 52 in patients with a baseline NRS ≥ 4

  42. Change from baseline in 5D-Itch [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]

    Change from baseline in symptoms in terms of 5 domains: degree, duration, direction, disability and distribution.

    Patients rate their symptoms over the preceding 2-week period on a 1 to 5 scale, with 5 being the most affected


  43. Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
    Change from baseline in assessing seven items that measure both the experience of fatigue and the interference of fatigue on daily activities over the past week

  44. Change from baseline in Epworth Sleepiness Scale (ESS) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
    Change from baseline in ESS that assesses eight questions asking to rate how likely it is to fall asleep in everyday situations (each question can be scored from 0 to 3 points; '0' indicates no sleepiness, '3' indicates significant sleepiness).It provides a total score which has been shown to relate to the patient's level of daytime sleepiness (total score range 0-24 points).

  45. Change from baseline in PBC-40 [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]

    Assesses symptoms across six domains: fatigue, emotional and social, cognitive function, general symptoms and itch. Patients respond on a verbal response scale, depending on the section options range from 'never' / 'not at all' / 'strongly disagree' to 'always' / 'very much'/ 'strongly agree'.

    Five items (3/3 in the itch domain and 2/10 in the social domain) also include a 'does not apply' option. A score for each domain is provided (but a total score is not calculated), with each verbal response scale correlating to a score of 1-5 per item (0-5 on items with a 'does not apply' option) with 5 being the most affected. The PBC-40 has a 4-week recall period.


  46. Change from baseline in health utility [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
    Measured by Euro quality of life (EQ-5D-5L), a 6-item, standardized questionnaire that assesses mobility, self-care, usual activities, pain / discomfort, anxiety / depression, and overall health state

  47. Change from baseline in levels of type I collagen N-telopeptides (CTXI) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  48. Change from baseline in levels of procollagen 1 N-terminal propeptide (P1NP) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  49. Change from baseline in bone mineral density (hip and lumbar) as assessed by DEXA scanning [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  50. Percentage of patients with onset of clinical outcomes [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  51. Number of participants experiencing Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs). [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
    An Adverse event (AE) is any untoward medical occurrence, temporally associated with the use of study intervention, whether or not related to the study intervention. AESIs are AEs that may not be serious but are of special importance to a particular drug or class of drugs.

  52. Number of participants with clinically significant changes in physical examination [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
    Percentage of participants with clinically significant changes in physical examination will be reported. The clinical significance will be graded by the investigator.

  53. Number of participants with clinically significant Changes in vital signs [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
    Percentage of participants with clinically significant changes in Vital Signs will be reported. The clinical significance will be graded by the investigator.

  54. Number of participants with clinically significant changes in electrocardiogram (ECG) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
    Percentage of participants with clinically significant changes in ECG readings will be reported. The clinical significance will be graded by the investigator.

  55. Number of participants with clinically significant changes in laboratory parameters (blood chemistry and hematology) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
    Percentage of participants with clinically significant change in laboratory parameters (blood chemistry, hematology and coagulation) will be reported. The clinical significance will be graded by the investigator.

  56. Number of Participants With Clinically Significant Changes in liver markers [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  57. Number of Participants With Clinically Significant Changes in Renal biomarkers (including urinalysis) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  58. Number of Participants With Clinically Significant Changes in other biochemical safety markers (e.g. urinary myoglobin) [ Time Frame: From baseline to Week 52 and up to a maximum of 6 years ]
  59. Area Under Curve steady state (AUCss) of study drug [ Time Frame: After 4 weeks of treatment during the double-blind period ]
  60. Pharmacokinetic (PK) Parameter: Clearance (CL) of study drug [ Time Frame: After 4 weeks of treatment during the double-blind period ]
    Clearance (CL) is defined as the systemic clearance of the drug following oral administration.

  61. Pharmacokinetic (PK) Parameter: Vz of study drug [ Time Frame: After 4 weeks of treatment during the double-blind period ]
    Vz is defined as the volume of distribution of the drug after oral administration.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Males or females age of 18 to 75 years (inclusive)
  • Definite or probable PBC diagnosis
  • ALP ≥ 1.67x upper limit of normal (ULN)
  • Total bilirubin (TB) ≤ 2x ULN
  • UDCA for at least 12 months (stable dose ≥ 3 months) prior to screening, or unable to tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to screening (per country standard-of-care dosing)
  • Must have PBC Worst Itch NRS collected prior to randomization
  • Females participating in this study must be of non-child bearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the last drug intake

Exclusion Criteria:

  • History or presence of other concomitant liver disease
  • Clinically significant hepatic decompensation, including patients with complications of cirrhosis/portal hypertension
  • Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease) or which may diminish life expectancy to < 2 years, including known cancers
  • Patient has a positive test for HIV Type 1 or 2 at screening, or patient is known to have tested positive for HIV
  • Evidence of any other unstable or untreated clinically significant disease
  • History of alcohol abuse
  • For female patients: known pregnancy or lactating
  • Use of fibrates and glitazones within 2 months prior to screening
  • Use of OCA, azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids (parenteral and oral chronic administration only); potentially hepatotoxic drugs
  • (including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin) within 3 months prior to screening
  • Use of antibodies or immunotherapy directed against interleukins (ILs) or other cytokines or chemokines within 12 months prior to screening
  • For patients with previous exposure to obeticholic acid (OCA), OCA should be discontinued 3 months prior to screening
  • Patients who are currently participating in, plan to participate in, or have participated in an investigational drug study or medical device study containing active substance within 30 days or five half-lives, whichever is longer, prior to screening; for patients with previous exposure to seladelpar, seladelpar should be discontinued 3 months prior to screening
  • ALT and/or AST values > 5 x ULN
  • For patients with AT or TB>ULN at SV1, variability of AT or TB > 40% (see section 3.5.1)
  • Albumin<3.0 g/dl
  • Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin <LLN)
  • INR > 1.3 due to altered hepatic function
  • CPK > 2 x ULN
  • Screening serum creatinine > 1.5 mg/dl
  • Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney failure damage or eGFR < 60 mL/min/1,73 m2) calculated by MDRD
  • Platelet count < 150 x 103/μL
  • AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting presence of liver cancer
  • Known hypersensitivity to the investigational product or to any of the formulation excipients of the elafibranor or placebo tablet Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04526665


Locations
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Sponsors and Collaborators
Ipsen
Investigators
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Study Director: Ipsen Medical Director Ipsen
More Information
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Responsible Party: Ipsen
ClinicalTrials.gov Identifier: NCT04526665    
Other Study ID Numbers: GFT505B-319-1
2019-004941-34 ( EudraCT Number )
First Posted: August 26, 2020    Key Record Dates
Last Update Posted: May 10, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants.

Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board.
Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later.
Access Criteria: Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available here (https://vivli.org/members/ourmembers/).
URL: https://vivli.org/members/ourmembers/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ipsen:
Primary Biliary Cholangitis
PBC
Elafibranor
Additional relevant MeSH terms:
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Cholangitis
Liver Cirrhosis, Biliary
Fibrosis
Pathologic Processes
Bile Duct Diseases
Biliary Tract Diseases
 Digestive System Diseases
Cholestasis, Intrahepatic
Cholestasis
Liver Diseases
Liver Cirrhosis