A Long-Term Study of Elafibranor in Adult Participants with Primary Biliary Cholangitis (ELFIDENCE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ipsen Bioscience Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

28 Feb 2024 → ongoing

Decision date (initial)

2024-02-07

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ipsen Bioscience, Inc.

External identifiers

EU CT number

2023-505251-43-00

ClinicalTrials.gov

NCT06016842

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To evaluate the efficacy of daily oral administration of elafibranor 80 mg compared to placebo based on time to the occurrence of clinical outcome events in adult participants with PBC and cirrhosis.

Secondary objectives 3

1. To assess the safety and tolerability of daily long-term oral administration of elafibranor 80 mg compared to placebo in adult participants with PBC and cirrhosis.
2. To evaluate the efficacy of daily oral administration of elafibranor 80 mg compared to placebo in adult participants with PBC and cirrhosis on efficacy measures, including: − Biochemical and clinical markers of response − Disease-related symptoms − PROs including other disease related symptoms, and QOL − Individual components of the composite primary endpoint and liver-related mortality
3. To evaluate the PK of elafibranor and its metabolite GFT1007 in adult participants with PBC and cirrhosis using a Population PK approach, including identification of covariates impacting PK variability.

Conditions and MedDRA coding

Primary Biliary Cholangitis

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Male or female participants must be ≥18 years of age at the time of signing the informed consent.
2. Participants with a definite or probable diagnosis of primary biliary cholangitis (PBC)
3. Participants with cirrhosis at SV1. • Participants must be Child Pugh A or Child Pugh B.
4. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
5. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion criteria 28

1. History or presence of other concomitant liver disease including but not limited to: i) Primary sclerosing cholangitis (PSC).ii) Autoimmune hepatitis (AIH) by simplified Diagnostic Criteria of the International Autoimmune Hepatitis Group (IAIHG) ≥6, or if treated for an overlap of PBC with AIH, or if there is clinical suspicion and evidence of overlap AIH features, that cannot be explained alone by insufficient response to UDCA. iii) Positive hepatitis B surface antigen (HBsAg). Participants with negative HBsAg and positive hepatitis B core antibody (HBcAb) may be eligible if hepatitis B virus deoxyribonucleic acid (HBV DNA) is negative. iv) Hepatitis C virus (HCV) infection defined by positive anti-HCV antibody and positive HCV ribonucleic acid (RNA) (Note: Participants with positive anti-HCV antibody due to previously treated HCV infection, may be enrolled if a confirmatory HCV RNA is undetectable and sustained viral response has been documented). v) Alcohol-associated liver disease (ALD). vi) Nonalcoholic steatohepatitis (NASH). vii) Other chronic liver diseases, such as alpha-1 antitrypsin deficiency.
2. International normalised ratio (INR) >1.8 in the absence of anticoagulant therapy.
3. Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2 per the Modification of Diet in Renal Disease (MDRD)-6 Study formula at SV1.
4. History or presence of clinically significant hepatic decompensation, including: i)History of liver transplantation, current placement on a liver transplant list, current model for end-stage liver disease including (MELD)-3.0 score >12 due to hepatic impairment. Evidence of complications of cirrhosis, including hepatic decompensation or evidence of significant portal hypertension complications including presence of uncontrolled of ascites; history of variceal bleeding or related interventions (e.g. variceal banding, or transjugular intrahepatic portosystemic shunt placement); presence of hepatic encephalopathy Grade 2 or higher per West-Haven criteria; history or presence of spontaneous bacterial peritonitis. Note: participants with low-risk varices (Grade I) without history of bleeding or other treatment may be eligible to enrol. iii) Hepatorenal syndrome (HRS) (type I or II). iv) Hospitalisation for liver-related complication within 12 weeks prior to SV1.
5. Significant renal disease, including nephritic syndrome, chronic kidney disease (CKD) (defined as participants with evidence of significantly impaired kidney function or underlying kidney injury).
6. For female participants: known current pregnancy, or has a positive serum pregnancy test, or is breastfeeding.
7. Participants unwilling or unable to be abstinent from alcohol during the study.
8. History of alcohol abuse, or other substance abuse within 1 year prior to SV1.
9. Known hypersensitivity to elafibranor or to any of the excipients of the investigational product(s).
10. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.
11. Any other condition that, in the opinion of the investigator, would interfere with study participation or completion, or would put the participant at risk, including a potential participant assessed as being at high risk of noncompliance with the study.
12. Administration of the following medications is prohibited during the study, and prior to the study as per the timelines specified below: i) 3 months prior to screening period: fibrates, seladelpar, glitazones, obeticholic acid, 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).
13. Known history of human immunodeficiency virus (HIV) infection or having a positive confirmatory test for HIV type 1 or 2.
14. Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget’s disease).
15. Evidence of any other unstable or untreated clinically significant immunological, endocrine, haematologic, gastrointestinal, neurological, or psychiatric disease as evaluated by the investigator; other clinically significant conditions that are not well controlled.
16. Non-hepatic medical conditions that may diminish life expectancy to <2 years, including known cancers.
17. History of hepatocellular carcinoma.
18. Alpha-fetoprotein (AFP) >20 ng/mL with 4-phase liver computerised tomography (CT) or magnetic resonance imaging (MRI) imaging suggesting presence of hepatocellular carcinoma.
19. Known malignancy or history of malignancy within the last 5 years, with the exception of local, successfully treated basal cell carcinoma or in-situ carcinoma of the uterine cervix.
20. Participants with previous exposure to elafibranor.
21. Participants 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 5 half-lives, whichever is longer, prior to the screening period. i) If the previous study was for an experimental therapy being studied for potential benefit in PBC, and the potential therapeutic agent was proven to have no beneficial effect in PBC and there are no safety concerns, the participant may enrol after 30 days or 5 half-lives from the last dose of the therapeutic agent, whichever is longer. ii) For therapeutic agents being studied for potential benefit in PBC for which it is still unclear if there may be a potential benefit, participants may enrol after 6 months from the last dose of the therapeutic agent.
22. Electrocardiogram (ECG) with QT interval corrected by Fridericia’s formula (QTcF) >450 msec in males or QTcF >470 msec in females for participants without bundle branch block. For participants with bundle branch block or other intraventricular conduction delay, a longer QTcF >480 msec would be exclusionary.
23. Total bilirubin (TB) >5x ULN.
24. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >5x ULN at SV1.
25. Creatinine phosphokinase (CPK) >2x ULN.
26. Platelet count <50,000/μL
27. Alkaline phosphatase (ALP) ≥10x ULN.
28. Albumin <2.8 g/dL due to impaired hepatic function.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event-free survival. Event-free survival is defined as the time from randomization to either adjudicated disease progression or death, whichever occurs first. [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 3.5 years)]

Secondary endpoints 57

1. Percentage of participants experiencing Treatment Emergent Adverse Events (TEAEs), treatment-related TEAEs, Serious Adverse Events (SAEs), and Adverse Events of Special Interests (AESIs). [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 3.5 years)]
2. Percentage of participants developing clinically significant changes in physical examination findings Complete physical examination at screening and targeted examination at all other clinical visit timepoints. [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 3.5 years)]
3. Percentage of participants developing clinically significant changes in vital signs Percentage of participants with clinically significant changes in Vital Signs will be reported. The clinical significance will be graded by the investigator. [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 3.5 years)]
4. Percentage of participants developing clinically significant changes in Electrocardiogram (ECG) readings. Percentage of participants with clinically significant changes in ECG readings will be reported. The clinical significance will be graded by the investigator. [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 3.5 years)]
5. Percentage of participants with clinically significant changes in laboratory parameters (blood chemistry, haematology, coagulation and urinalysis) Percentage of participants with clinically significant change in laboratory parameters (blood chemistry, haematology and coagulation) will be reported. The clinical significance will be graded by the investigator. [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 3.5 years)]
6. Change from baseline in Alkaline phosphatase (ALP) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
7. Change from baseline in Total Bilirubin (TB) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
8. Percentage of participants with ALP≤ 1.67x ULN and TB≤ ULN [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
9. Percentage of participants with complete biochemical response Defined as normal levels of TB, ALP, transaminases, albumin, and International normalised ratio (INR) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
10. Percentage of participants with normalisation of TB and ALP Defined as TB< Upper Limit Normal (ULN) and ALP< ULN [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
11. Percentage of participants with stabilisation in TB (i.e. no increase) Defined as TB< 1x ULN or increase from baseline <0.1x ULN [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
12. Percentage of participants with a response based on albumin normalisation [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
13. Change from baseline in liver stiffness measurement (LSM) Assessed by vibration-controlled transient elastography (VCTE) using Fibroscan® on the day of the visit. [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
14. Change from baseline in PBC risk scores based in GLOBE score. GLOBE scoring system, which calculation is based on serum values of bilirubin, ALP, albumin and platelet count after 1 year of treatment and age at baseline. A high number is indicative of a worse score. [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
15. Change from baseline in UK-PBC score based on laboratory test measurements and upper limits of normal (ULN) for total BIL12; TA12 and ALP12 after at least 12 months of UDCA, and the laboratory test measurements and lower limits of normal (LLN) for the serum albumin and platelet count in the same timeframe. [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
16. Percentage of participants with LSM ≥15 kPa Assessed by VCTE using Fibroscan® [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
17. Change from baseline in hepatic function: Aspartate aminotransferase (AST) [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
18. Change from baseline in hepatic function: ALT [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
19. Change from baseline in hepatic function: Gamma-glutamyl transferase (GGT) [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
20. Change from baseline in hepatic function: Conjugated bilirubin [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
21. Change from baseline in hepatic function: Albumin [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
22. Change from baseline in hepatic function: international normalised ratio (INR) [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
23. Change from baseline in hepatic function: fractionated ALP [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
24. Percentage of participants with no worsening of LSM Assessed by VCTE using Fibroscan® defined as no increase >2kPa from baseline [Time Frame: At Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
25. Percentage of participants with ALP reduction of 40% [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
26. Percentage of participants with ALP <1.5x ULN, ALP decrease ≥15% and TB ≤ULN [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
27. Percentage of participants with ALP <1.5x ULN, ALP decrease ≥40% and TB ≤ULN [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
28. Percentage of participants with ALP <1.67x ULN, ALP decrease ≥15% and TB ≤ULN [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
29. Percentage of participants with ALP <3x ULN, AST <2x ULN and TB ≤1 mg/dL (Paris I) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
30. Percentage of participants with ALP ≤1.5x ULN, AST ≤1.5x ULN and TB ≤1 mg/dL (Paris II criteria) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
31. Percentage of participants with normalisation of abnormal TB [Time Frame: Assessed at Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
32. Percentage of participants with normalisation of abnormal TB and albumin (Rotterdam criteria) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
33. Percentage of participants with reduction in TB to ≤0.6x ULN in participants with TB >0.6x ULN at baseline [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
34. Change from baseline in lipid parameters: total cholesterol (TC) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
35. Change from baseline in lipid parameters: high density lipoprotein cholesterol (HDL-C) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
36. Change from baseline in lipid parameters: calculated very low density lipoprotein cholesterol (VLDL-C) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
37. Change from baseline in lipid parameters: low density lipoprotein cholesterol (LDL-C) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
38. Change from baseline in lipid parameters: triglycerides (TG) [Time Frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
39. Percentage of participants with a response in PBC Worst Itch NRS score Defined as ≥2-point reduction from baseline NRS in participants with a baseline NRS ≥4. [Time Frame: Through 6 months up to end of treatment (maximum duration of 3.5 years)]
40. Percentage of participants with a response in PBC Worst Itch NRS Defined as ≥3-point reduction from baseline NRS in participants with a baseline NRS ≥4 [Time Frame: Assessed through 6 months up to end of treatment (maximum duration of 3.5 years)]
41. Change from baseline in 5D-Itch scale Questionnaire that assesses symptoms in terms of 5 domains: degree, duration, direction, disability and distribution. Participants rate their symptoms over the preceding 2-week period on a 1 to 5 scale, with 5 being the most affected. [Time Frame: Assessed at every 6 months up to end of treatment (maximum duration of 3.5 years)]
42. Change from baseline in Patient Global Impression of Severity (PGI-S) A 1-item, 5-point scale designed to assess the participant’s impression of disease severity [Time Frame: Assessed at every 6 months up to end of treatment (maximum duration of 3.5 years)]
43. Patient Global Impression of Change (PGI-C) A 1-item, 5-point scale designed to assess the participant’s impression of change in disease severity since the baseline visit [Time Frame: Assessed at every 6 months up to end of treatment (maximum duration of 3.5 years)]
44. Change from baseline in Patient Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 7a Consists of 7 items that measure both the experience of fatigue and the interference of fatigue on daily activities over the past week. [Time Frame: Assessed at every 6 months up to end of treatment (maximum duration of 3.5 years)]
45. Change from baseline in the Epworth Sleepiness Scale (ESS). Self-administered questionnaire that consists of 8 questions asking to rate how likely it is to fall asleep in different situations commonly encountered in daily life (each question can be scored from 0 to 3 points; ‘0’ indicates no sleepiness, ‘3’ indicates significant sleepiness). Assessed at every 6 months up to end of treatment (maximum duration of 3.5 years)
46. Change from baseline in PBC-40 score. 40-item questionnaire that assesses symptoms across 6 domains: fatigue, emotional and social, cognitive function, general symptoms and itch. Participants respond 0 to 5 with 5 being the most affected. The PBC-40 has a 4-week recall period. Assessed at every 6 months up to end of treatment (maximum duration of 3.5 years)
47. Change from baseline in PBC Worst Itch Numeric Rating Scale (NRS) score. Assessed at every 6 months up to end of treatment (maximum duration of 3.5 years)
48. Change from baseline in EuroQol 5-dimensional 5-level questionnaire (EQ-5D-5L) Self-administered standardised questionnaire that assesses the 5-dimensions of mobility, self-care, usual activities, pain/discomfort, anxiety/depression descriptively (each dimension has 5 levels) and the overall health state via an EQ Visual Analogue Scale (VAS). [Time Frame: Assessed at every 6 months up to end of treatment (maximum duration of 3.5 years)
49. Change from baseline in Work Productivity and Activity Impairment General Health (WPAI-GH) Questionnaire (6 questions) that measures absenteeism, presenteeism as well as the impairments in unpaid activity because of health problem during the past seven days. Assessed at every 6 months up to end of treatment (maximum duration of 3.5 years)
50. Time to the first occurrence of each of individual adjudicated clinical outcome events. Among: • All-cause mortality •Liver-related mortality •Liver transplant •MELD-3.0 score ≥ 15 in participants with baseline MELD score ≤ 12 • Liver decompensation[Time Frame: From baseline until 4 weeks after the end of treatment]
51. Area under the plasma concentration-time curve from time 0 to 24 hours: AUC0-24 [Time Frame: At Day 1/Baseline, Month 6 and Month 12 (during a dosing period of 24 hours)]
52. Maximum (peak) plasma drug concentration: Cmax [Time Frame: At Day 1/Baseline, Month 6 and Month 12 (during a dosing period of 24 hours)]
53. Time to reach maximum (peak) plasma concentration following drug administration): Tmax [Time Frame: At Day 1/Baseline, Month 6 and Month 12 (during a dosing period of 24 hours)]
54. Apparent clearance of drug from plasma (CL) [Time Frame: At Day 1/Baseline, Month 6 and Month 12 (during a dosing period of 24 hours)]
55. Apparent volume of distribution (VZ) [Time Frame: At Day 1/Baseline, Month 6 and Month 12 (during a dosing period of 24 hours)]
56. Change from baseline in model for end-stage liver disease (MELD) 3.0 score. The MELD 3.0 score is calculated from parameters (sex, creatinine, bilirubin, INR, sodium and albumin) where a high score indicates a greater risk of needing a liver transplant. [Time Frame: From screening until end of treatment (maximum duration of 3.5 years)]
57. Change from baseline in Child Pugh grade Child Pugh grade is calculated using bilirubin, albumin, INR, ascites and encephalopathy. A high grade is indicative of worse liver disease. [Time Frame: From screening until end of treatment (maximum duration of 3.5 years)]

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ipsen Bioscience Inc.

Sponsor organisation

Ipsen Bioscience Inc.

Address

One Main Street, 7th Floor 7th Floor

City

Cambridge

Postcode

02142

Country

United States

Scientific contact point

Organisation

Ipsen Bioscience Inc.

Contact name

Ipsen Clinical Study Enquiries

Public contact point

Organisation

Ipsen Bioscience Inc.

Contact name

Ipsen Clinical Study Enquiries

Third parties 10

Locations

14 EU/EEA countries · 71 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 523 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

30 submissions — initial application plus substantial / non-substantial modifications