ELAFIBRANOR for Primary biliary cholangitis (PBC)

Stratification factors

• Baseline ALP level (participants grouped by blood ALP levels prior to randomisation)

Inclusion criteria

• {"criterion_text":"- Male or female participants age ≥18 years of age.\n- Participants with a historical diagnosis of PBC as demonstrated by the presence of ≥2 of the following three historical diagnostic criteria: i.\tHistory of elevated ALP levels for ≥6 months prior to SV1. ii.\tPositive (Antimitochondrial antibody ) AMA titres (≥1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay) or positive PBC-specific antinuclear antibodies. iii.\tLiver biopsy consistent with PBC.\n- ALP >1 × ULN and <1.67 × ULN.\n- (a) Participants taking UDCA should have been on this medication for at least 12 months and at a stable dose for ≥ 6 months prior to SV1. Participants who are intolerant to UDCA may participate and should have taken the last dose of UDCA ≥3 months prior.\n- (a) Participants taking medications for management of pruritus (e.g cholestyramine, naltrexone, sertraline or colchicine) must be on a stable dose for ≥3 months prior to screening.\n- (b) Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies (Appendix 10.4). Male participants: •\tMale participants are eligible to participate if they agree to the following during the study intervention period and for at least 30 days after the last dose of study intervention: •\tRefrain from donating sperm. PLUS either: -\tBe abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent. OR -\tMust agree to use contraception / barrier as detailed below: \tAgree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak as there remains when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Female participants •\tFemale participants are eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: •\tIs a woman of nonchildbearing potential (WONCBP) as defined in Appendix 10.4. OR •\tIs a WOCBP abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) or using a systemic hormonal contraceptive method that is highly effective (with a failure of <1% per year) along with a barrier method (e.g. condom) or using a non-hormonal contraceptive method that is highly effective (with a failure rate of <1% per year) preferably with low user dependency, as described in Appendix 10.4 during the study intervention period and for at least 30 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (e.g. noncompliance, recently initiated) in relationship to the first dose of study intervention. •\tA WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours before the first dose of study intervention (see Section 8.4.6). •\tIf a urine test cannot be confirmed as negative (e.g. an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. •\tAdditional requirements for pregnancy testing during and after study intervention are specified within the protocol. •\tThe investigator is responsible for review of medical history, menstrual history and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.\n- Capable of giving signed informed consent as described in Appendix 10.1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol."}

Exclusion criteria

• {"criterion_text":"- History or presence of other concomitant liver diseases\n- (18)\tPlatelet count <75,000/µL\n- International normalised ratio >1.3 in the absence of anticoagulant therapy\n- Participants with known cirrhosis who have a Child-Pugh B or C score. Participants with cirrhosis with Child-Pugh A score are allowed.\n- 20 (a) Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 per the Modification of Diet in Renal Disease (MDRD)-6 formula or on dialysis at SV1.\n- Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as participants with evidence of significantly impaired kidney function or underlying kidney injury).\n- For female participants: known pregnancy, or has a positive serum pregnancy test, or is breastfeeding\n- Regular alcohol intake in excess of the recommended limit of 2 standard drinks per day for men or 1 standard drink per day for women\n- History of alcohol abuse, or other substance abuse within 1 year prior\n- Known hypersensitivity to the investigational product or to any of the excipients of elafibranor\n- Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain\n- History of hepatocellular carcinoma\n- 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\n- History of liver transplantation\n- History or presence of clinically significant hepatic decompensation\n- Known history of human immunodeficiency virus (HIV) infection\n- Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget’s disease)\n- Evidence of any other unstable or untreated clinically significant conditions that are not well controlled\n- Medical condition with a life expectancy <2 years\n- Known malignancy or history of malignancy within the last 2 years, except for successfully treated localised basal cell carcinoma or squamous cell carcinoma of the skin; or in-situ carcinoma of the uterine cervix\n- Participants who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities\n- Alpha-foetoprotein (AFP) >20 ng/mL with 4-phase liver computed tomography (CT) or magnetic resonance imaging (MRI) scans suggesting presence of liver cancer\n- (12)\tAdministration of the following medications is prohibited during the study, and prior to the study as per the timelines specified below: i.Systemic (oral or parenteral) use within 3 months prior to SV1 of: fibrates, seladelpar, glitazones, obeticholic acid, azathioprine, cyclosporine, methotrexate, mycophenolate, or long-term systemic corticosteroids (parenteral and oral chronic administration only); potentially hepatotoxic drugs (including α-methyl-dopa, valproic acid, isoniazid or nitrofurantoin) ii) Breat Cancer Resistance Protein (BRCP) inhibitors within 1 month prior to SV 1\n- Participants with previous exposure to elafibranor\n- 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\n- Total bilirubin (TB) >2 × ULN. Participants with Gilbert’s syndrome are eligible with a TB above 2 × ULN if direct bilirubin is <30% of TB\n- (Alanine aminotransferase) ALT and/or (aspartate aminotransferase) AST >5 × ULN\n- (Creatine phosphokinase) CPK >2 × ULN"}

Primary endpoints

• {"endpoint_text":"- Percentage of participants with normalisation of ALP at Week 52","definition_or_measurement_approach":"Measured as the proportion of participants achieving normalisation of alkaline phosphatase (ALP) at Week 52, assessed by laboratory ALP measurement at Week 52."}

Secondary endpoints

• {"endpoint_text":"- Percentage of participants with normalisation of ALP Levels [Time Frame: From baseline to Week 4, Week 12, Week 24 and Week 36]","definition_or_measurement_approach":"Time Frame: From baseline to Week 4, Week 12, Week 24 and Week 36; measured by laboratory ALP levels at specified time points."}
• {"endpoint_text":"- Change from baseline in ALP levels [Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52]","definition_or_measurement_approach":"Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52; measured as change in laboratory ALP values from baseline at each specified time point."}
• {"endpoint_text":"- Percentage of participants with normalisation of ALP Levels and ≥15% decrease from Baseline [Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52]","definition_or_measurement_approach":"Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52; measured as proportion achieving both ALP normalisation and ≥15% decrease from baseline."}
• {"endpoint_text":"- Percentage of participants with ≥40% decrease from Baseline in ALP Levels [Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52]","definition_or_measurement_approach":"Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52; measured as proportion with ≥40% ALP decrease vs baseline."}
• {"endpoint_text":"- Percentage of participants with ALP <0.5 × Upper Limit of Normal (ULN) [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]","definition_or_measurement_approach":"Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52; measured by ALP laboratory results relative to ULN at each time point."}
• {"endpoint_text":"- Changes from baseline in Total Bilirubin (TB) Levels [Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52]","definition_or_measurement_approach":"Time Frame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52; measured as change in total bilirubin laboratory values from baseline."}
• {"endpoint_text":"- Percentage of participants with TB <0.7 × ULN [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]","definition_or_measurement_approach":"Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52; measured by total bilirubin lab results relative to ULN."}
• {"endpoint_text":"- Percentage of participants with normalisation of ALP and TB <0.7 × ULN [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]","definition_or_measurement_approach":"Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52; combined endpoint assessed by ALP and TB laboratory values."}
• {"endpoint_text":"- Percentage of participants with normalisation of TB and ALP Levels [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]","definition_or_measurement_approach":"Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52; measured by laboratory TB and ALP normalisation status."}
• {"endpoint_text":"- Percentage of participants with complete biochemical response [Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52]","definition_or_measurement_approach":"Time Frame: At Week 4, Week 12, Week 24, Week 36 and Week 52; defined by protocol-specified biochemical criteria (as per protocol documents)."}
• {"endpoint_text":"- Change from baseline in PBC Worst Itch Numeric Rating Scale (NRS) score [Time Frame: From baseline through Week 52]","definition_or_measurement_approach":"Time Frame: From baseline through Week 52; measured using the PBC Worst Itch NRS patient-reported tool per schedule."}
• {"endpoint_text":"- Percentage of participants with moderate to severe pruritus at baseline (i.e. score ≥4) with a clinically meaningful response in PBC Worst Itch NRS [Time Frame: From baseline through Week 52]","definition_or_measurement_approach":"Time Frame: From baseline through Week 52; assessed among participants with baseline Worst Itch NRS ≥4 using the PBC Worst Itch NRS tool."}
• {"endpoint_text":"- Change from baseline in 5-D itch score [Time Frame: From baseline to Week 4, Week 24, and Week 52]","definition_or_measurement_approach":"Time Frame: From baseline to Week 4, Week 24, and Week 52; measured using the 5-D itch instrument."}
• {"endpoint_text":"- Change from baseline in Patient Global Impression of Severity (PGI-S) scores [Time Frame: From baseline to Week 4, Week 24, and Week 52]","definition_or_measurement_approach":"Time Frame: From baseline to Week 4, Week 24, and Week 52; measured using PGI-S questionnaire."}
• {"endpoint_text":"- Patient Global Impression of Change (PGI-C) scores [Time Frame: At Week 4, Week 24, and Week 52]","definition_or_measurement_approach":"Time Frame: At Week 4, Week 24, and Week 52; measured using PGI-C questionnaire."}
• {"endpoint_text":"- Change from baseline in PBC-40 Quality of Life (QoL) scores [Time Frame: From baseline to Week 4, Week 24, and Week 52]","definition_or_measurement_approach":"Time Frame: From baseline to Week 4, Week 24, and Week 52; measured using the PBC-40 QoL instrument."}
• {"endpoint_text":"- Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a scores [Time Frame: From baseline to Week 4, Week 24, and Week 52]","definition_or_measurement_approach":"Time Frame: From baseline to Week 4, Week 24, and Week 52; measured using PROMIS Fatigue Short Form 7a."}
• {"endpoint_text":"- Percentage of participants experiencing Treatment- Emergent Adverse Events (TEAEs), treatment- related TEAEs, Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs). [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]","definition_or_measurement_approach":"Time Frame: From baseline until 4 weeks after end of treatment (up to 52 weeks); safety events recorded per standard adverse event reporting."}
• {"endpoint_text":"- Percentage of participants developing clinically significant changes in physical examination [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]","definition_or_measurement_approach":"Time Frame: From baseline until 4 weeks after end of treatment; clinical exam findings compared to baseline."}
• {"endpoint_text":"- Percentage of participants developing clinically significant changes in vital signs [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]","definition_or_measurement_approach":"Time Frame: From baseline until 4 weeks after end of treatment; vital signs monitored and assessed for clinically significant changes."}
• {"endpoint_text":"- Percentage of participants developing clinically significant changes in Electrocardiogram (ECG) Readings [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]","definition_or_measurement_approach":"Time Frame: From baseline until 4 weeks after end of treatment; ECGs assessed for clinically significant changes."}
• {"endpoint_text":"- Percentage of participants developing clinically significant changes in laboratory parameters [Time Frame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)]","definition_or_measurement_approach":"Time Frame: From baseline until 4 weeks after end of treatment; laboratory tests compared to baseline to identify clinically significant changes."}

Methods

• Recruitment materials including study flyers, brochures, posters, patient letters and study visit guides (documents titled K2_Flyer, K2_Brochure, K2_Poster, K2_Patient Letter, K2_Study Visit Guide) targeted at adults with Primary Biliary Cholangitis and distributed via participating hepatology/gastroenterology clinics and hospital sites in each country.
• Advocacy factsheets (K2_Advocacy_Factsheet) prepared for patient/advocacy engagement and awareness.
• Patient-facing materials including informed consent documents, IMP patient leaflet, patient emergency card, daily drug diary and ePRO/eDiary guidance (D4_Patient Reference Guide_iPhone_BYOD and ePRO screenshots) to support remote reporting and study participation.

Czechia

Earliest CTIS Part Ii Submission Date

06-09-2024

Latest Decision Or Authorization Date

01-10-2024

Processing Time Days

25

Number Of Sites

5

Number Of Participants

3

France

Earliest CTIS Part Ii Submission Date

23-08-2024

Latest Decision Or Authorization Date

30-09-2024

Processing Time Days

38

Number Of Sites

4

Number Of Participants

4

Italy

Earliest CTIS Part Ii Submission Date

23-08-2024

Latest Decision Or Authorization Date

30-09-2024

Processing Time Days

38

Number Of Sites

7

Number Of Participants

5

Spain

Earliest CTIS Part Ii Submission Date

01-07-2024

Latest Decision Or Authorization Date

30-09-2024

Processing Time Days

91

Number Of Sites

8

Number Of Participants

6

Romania

Earliest CTIS Part Ii Submission Date

06-12-2024

Latest Decision Or Authorization Date

21-01-2025

Processing Time Days

46

Number Of Sites

4

Number Of Participants

8

Germany

Earliest CTIS Part Ii Submission Date

26-08-2024

Latest Decision Or Authorization Date

30-09-2024

Processing Time Days

35

Number Of Sites

4

Number Of Participants

5

Poland

Earliest CTIS Part Ii Submission Date

30-08-2024

Latest Decision Or Authorization Date

30-09-2024

Processing Time Days

31

Number Of Sites

2

Number Of Participants

4

Primary sponsor

Full Name

Ipsen Bioscience Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Multiple operational roles including Clinical Supplies Management (sponsorDuties codes include 1,2,4,5,6,8,10,12,13,15; value provided: Clinical Supplies MAnagement)

Name

Parexel International (IRL) Limited

Responsibilities

Pharmacovigilance vendor (sponsorDuties code 15; value: Pharmacovigilance vendor)

Third parties

• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"sponsorDuties codes: 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Rules Based Medicine Inc.","duties_or_roles":"sponsorDuties: code 15; value: IL-6, IL-31, TNF-alpha and Autotaxin testing analysis","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"sponsorDuties codes: 1,10,12,13,15 (Clinical Supplies MAnagement),2,4,5,6,8","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"S-Clinica","duties_or_roles":"sponsorDuties code: 3","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"sponsorDuties: code 15; value: Drug Distribution","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Eurofins Adme Bioanalyses","duties_or_roles":"sponsorDuties: code 15; value: pk analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Labcorp Early Development Laboratories Limited","duties_or_roles":"sponsorDuties: code 15; value: LPA Testing","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"sponsorDuties: code 15; value: Pharmacovigilance vendor","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Gray Consulting Inc.","duties_or_roles":"sponsorDuties: code 15; value: Patient Reimbursement, Payments Patient Travel","organisation_type":"Pharmaceutical company"}