A Long-Term Study of Elafibranor in Adult Participants With Primary Biliary Cholangitis

Official title

A Phase III Randomised, Parallel-Group, Double-Blind, Placebo-Controlled, Two-Arm Study to Evaluate the Efficacy and Safety of Elafibranor 80 mg on Long-Term Clinical Outcomes in Adult Participants With Primary Biliary Cholangitis (PBC)

Overview

The participants of this study will have confirmed Primary Biliary Cholangitis (PBC) and cirrhosis (scarring of the liver). PBC is a slowly progressive disease, characterised by damage to the bile ducts in the liver, leading to a build-up of bile acids which causes further damage. The liver damage in PBC may lead to 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 will compare a daily dose of elafibranor (the study drug) to a daily dose of placebo (a dummy treatment) and will last up to 3.5 years for each participant. The main aim of this study is to determine if elafibranor is better than placebo in preventing clinical outcome events showing disease worsening (including progression of disease leading to liver transplant or death). This study will also study the safety of long-term treatment with elafibranor, as well as the impact on symptoms such as itching and tiredness.

Interventions

• Drug Elafibranor
  Duration: up to an estimated 42-month (3.5-year) double-blind treatment period during which elafibranor 80 mg tablet will be administered once daily
• Other Matched 80 mg placebo
  Duration: up to an estimated 42-month (3.5-year) double-blind treatment period during which matching placebo tablet will be administered once daily

Primary outcome measures

• Event-free survival [Time frame: From baseline until 4 weeks after the last dose of study intervention (maximum duration of 3.5 years)]

Secondary outcome measures (12)

• 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 last dose of study intervention (maximum duration of 3.5 years)]
• Percentage of participants developing clinically significant changes in physical examination findings [Time frame: From baseline until 4 weeks after the last dose of study intervention (maximum duration of 3.5 years)]
• Percentage of participants developing clinically significant changes in vital signs [Time frame: From baseline until 4 weeks after the last dose of study intervention (maximum duration of 3.5 years)]
• Percentage of participants developing clinically significant changes in Electrocardiogram (ECG) readings. [Time frame: From baseline until 4 weeks after the last dose of study intervention (maximum duration of 3.5 years)]
• Percentage of participants with clinically significant changes in laboratory parameters (blood chemistry, hematology, coagulation and urinalysis) [Time frame: From baseline until 4 weeks after the last dose of study intervention (maximum duration of 3.5 years)]
• 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)]
• 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)]
• 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)]
• Percentage of participants with complete biochemical response [Time frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
• Percentage of participants with normalisation of TB and ALP [Time frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
• Percentage of participants with stabilisation in TB (i.e. no increase) [Time frame: At Month 6, Month 12, and every 12 months up to end of treatment (maximum duration of 3.5 years)]
• 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)]

Eligibility criteria

Inclusion criteria

• Male or female participants must be ≥18 years of age at the time of signing the informed consent.
• Participants with a definite or probable diagnosis of primary biliary cholangitis (PBC)
• Participants with cirrhosis at SV1. • Participants must be Child Pugh A or Child Pugh B.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• 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

• 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.
• 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.
• ii) Evidence of complications of cirrhosis, including hepatic decompensation or evidence of significant portal hypertension complications including presence of uncontrolled 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 ). • vi) Hospitalisation for liver-related complication within 12 weeks prior to SV1.
• Known history of human immunodeficiency virus (HIV) infection or having a positive confirmatory test for HIV type 1 or 2.
• Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget's disease).
• Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematologic, gastrointestinal, neurological, or psychiatric disease as evaluated by the investigator; other clinically significant conditions that are not well controlled.
• Non-hepatic medical conditions that may diminish life expectancy to <2 years, including known cancers.
• History of hepatocellular carcinoma.
• Alpha-fetoprotein (AFP) >20 ng/mL with 4-phase liver computerised tomography (CT) or magnetic resonance imaging (MRI) imaging suggesting presence of hepatocellular carcinoma.
• Known malignancy or history of malignancy within the last 5 years. Participants with non-melanoma skin cancer, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• 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 baseline: 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).
• 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.

• 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.
• Total bilirubin (TB) >5x ULN
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >5x ULN at SV1
• Creatinine phosphokinase (CPK) >2x ULN.
• Platelet count <50,000/μL
• International normalised ratio (INR) >1.8 in the absence of anticoagulant therapy.
• Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2 per the Modification of Diet in Renal Disease (MDRD)-6 Study formula at SV1.
• Significant renal disease, including nephritic syndrome, chronic kidney disease (CKD) (defined as participants with evidence of significantly impaired kidney function or underlying kidney injury).
• For female participants: known current pregnancy, or has a positive serum pregnancy test, or is breastfeeding.
• Participants unwilling or unable to be abstinent from alcohol during the study.
• History of alcohol abuse, or other substance abuse within 1 year prior to SV1.
• Known hypersensitivity to elafibranor or to any of the excipients of the investigational product(s).
• Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.
• 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.
• Alkaline phosphatase (ALP) ≥10x ULN.
• Albumin <2.8 g/dL due to impaired hepatic function.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 42 centers

• Arizona Liver Health — Tucson
• Arkansas Diagnostic Center, PA — Little Rock
• Southern California Research Center — Coronado
• Cedars-Sinai Medical Center — Los Angeles
• GastroIntestinal BioSciences — Los Angeles
• University of California Los Angeles — Los Angeles
• University of California Davis Medical Center — Sacramento
• University of Colorado — Aurora
• … and 34 more centers

South Korea · 19 centers

Center list to be confirmed — check the primary protocol.

Poland · 13 centers

Center list to be confirmed — check the primary protocol.

Spain · 13 centers

Center list to be confirmed — check the primary protocol.

France · 9 centers

Center list to be confirmed — check the primary protocol.

Argentina · 8 centers

• DIM Centro Medico — Buenos Aires
• Fundacion Respirar (Centro Medico Dra. De Salvo) - Instituto Argentino de Investigaciones — Buenos Aires
• Hospital Britanico de Buenos Aires — Buenos Aires
• Hospital Italiano de Buenos Aires — Buenos Aires
• Centro Medico Colon — Córdoba
• Hospital Espanol de Mendoza — Mendoza
• Hospital Universitario Austral — Pilar
• Hospital El Cruce — San Juan Bautista

Italy · 8 centers

Center list to be confirmed — check the primary protocol.

Brazil · 7 centers

• NUPEC Cardio — Belo Horizonte
• Universidade Federal de Goias — Goiânia
• Hospital de Clinicas de Porto Alegre (HCPA) — Porto Alegre
• Instituto D'Or de Pesquisa e Ensino - Hospital Aliança — Salvador
• Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo — São Paulo
• Hospital de Base - Centro Integrado de Pesquisa ( CIP ) — São Paulo
• Universidade Estadual Paulista Julio De Mesquita Filho (UNESP) Hospital das Clinicas Facul — São Paulo

Israel · 7 centers

Center list to be confirmed — check the primary protocol.

Australia · 6 centers

• Sunshine Coast University Hospital — Birtinya
• Footscray Hospital, Western Health — Footscray
• Nepean Clinical School — Kingswood
• Monash University - Monash Health -Monash Medical Centre — Melbourne
• St George Hospital — Sydney
• Westmead Hospital — Westmead

Chile · 6 centers

• Universidad De Los Andes — Las Condes
• Centro de Estudios Clinicos e Investigaciones Medicas (CECIM) — Santiago
• Enroll SpA — Santiago
• Hospital Clinico de la Pontificia Universidad Catolica de Chile — Santiago
• University of Chile Clinical Hospital (Hospital Clinico de la Universidad de Chile) — Santiago
• Centro Medico Cedid - Centro de Diagnostico Digestivo — Viña del Mar

Czechia · 5 centers

• Hepato-Gastroenterologie HK, s.r.o. — Hradec Králové
• Krajska Nemocnice Liberec — Liberec
• … and 3 more centers

Mexico · 5 centers

Center list to be confirmed — check the primary protocol.

Romania · 5 centers

Center list to be confirmed — check the primary protocol.

Belgium · 4 centers

• Universitair Ziekenhuis Antwerpen — Edegem
• Ziekenhuis Oost-Limburg — Genk
• Gent University Hospital — Ghent
• Algemeen Ziekenhuis Delta — Roeselare

Greece · 4 centers

Center list to be confirmed — check the primary protocol.

Bulgaria · 3 centers

• Diagnostic-Consultative Center Aleksandrovska EOOD — Sofia
• Tokuda Hospital, Dept. of Internal Medicine — Sofia
• University Hospital City Clinic Cancer Center — Sofia

Hungary · 3 centers

Center list to be confirmed — check the primary protocol.

Malaysia · 3 centers

Center list to be confirmed — check the primary protocol.

Portugal · 3 centers

Center list to be confirmed — check the primary protocol.

Slovakia · 3 centers

Center list to be confirmed — check the primary protocol.

Thailand · 3 centers

Center list to be confirmed — check the primary protocol.

Canada · 2 centers

• University of Alberta - Faculty of Medicine & Dentistry - The Centre of Excellence for Gas — Edmonton
• University Health Network (UHN) - Toronto General Hospital (TGH) - Toronto General Researc — Toronto

Lithuania · 2 centers

Center list to be confirmed — check the primary protocol.

New Zealand · 2 centers

Center list to be confirmed — check the primary protocol.

Denmark · 1 center

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06016842 · CLIN-60190-454 · 2023-505251-43-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗