Clinical trial NCT06383403: A Study of Elafibranor in Adults With Primary Biliary Cholangitis and Inadequate Response or Intolerance to Ursodeoxycholic Acid.
Official title: A Phase IIIb Randomised, Parallel-Group, Double-Blind, Placebo-Controlled, Two-Arm Study to Evaluate the Effect of Elafibranor 80 mg on Normalisation of Alkaline Phosphatase in Adult Participants With Primary Biliary Cholangitis (PBC) and Inadequate Response or Intolerance to Ursodeoxycholic Acid.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Primary Biliary Cholangitis
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2024-04-25
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The participants in this study will have confirmed PBC with inadequate response or intolerance to Ursodeoxycholic acid (UDCA), which is a medication used in the management and treatment of cholestatic liver disease.

Primary biliary cholangitis is a slowly progressive disease characterised by damage of 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 scarring (cirrhosis). PBC may also be associated with multiple symptoms.

Many patients with PBC may require a 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).

The main aim of this study is to determine if elafibranor is better than placebo in reducing ALP levels to a normal value. High ALP levels in the blood can indicate liver disease.

There will be three periods in this study: A screening period (up to 8 weeks) to assess whether the participant can take part; a treatment period (up to 52 weeks) where eligible participants will be grouped as per their blood ALP levels and randomly assigned to either receive elafibranor or placebo, and a follow-up period (4 weeks) where participants' health will be monitored.

Participants will be twice as likely to receive elafibranor than placebo (2:1 ratio).

Participants will undergo blood sampling, urine collections, physical examinations, clinical evaluations, electrocardiograms (ECG: recording of the electrical activity of heart), ultrasound examinations (a noninvasive test that passes a probe over skin to look at the bladder, urinary tract, and liver), and Fibroscan® examinations (a noninvasive test that passes a probe on skin to measure stiffness of the liver).

They will also be asked to fill in questionnaires. Each participant will be in this study for up to 64 weeks (15 months).


Eligibility criteria: Inclusion Criteria

* Male or female participants age ≥18 years of age.
* Participants with a historical diagnosis of PBC as demonstrated by the presence of ≥2 of the following three historical diagnostic criteria:

  * i. History of elevated ALP levels for ≥6 months prior to the first screening visit (SV1).
  * ii. Positive Antimitochondrial antibody (AMA) titres (≥1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay) or positive PBC-specific antinuclear antibodies.
  * iii. Liver biopsy consistent with PBC.
* ALP \>1 × ULN and \<1.67 × ULN.
* Participants taking UDCA should have been on this medication for at least 6 months and at a stable dose for ≥3 months. Participants who are intolerant to UDCA should have taken the last dose of UDCA ≥3 months prior.
* Participants taking medications for management of pruritus must be on a stable dose for ≥3 months.
* Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

  \* (a) Male participants must agree that, if their partner is at risk of becoming pregnant, they will use an effective method of contraception. The participant must agree to use contraception during the whole period of the study and for 30 days after the last dose of study intervention.
* Capable of giving signed informed consent

Exclusion Criteria

* History or presence of other concomitant liver diseases.
* Participants with known cirrhosis who have a Child-Pugh B or C score. Participants with cirrhosis with Child-Pugh A score are allowed.
* History of liver transplantation.
* History or presence of clinically significant hepatic decompensation.
* Known history of human immunodeficiency virus (HIV) infection.
* Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget's disease).
* Evidence of any other unstable or untreated clinically significant conditions that are not well controlled.
* Medical condition with a life expectancy \<2 years.
* 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.
* History of hepatocellular carcinoma.
* Alpha-foetoprotein (AFP) \>20 ng/mL with 4-phase liver computed tomography (CT) or magnetic resonance imaging (MRI) scans suggesting presence of liver cancer.
* Administration 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)
* Participants with previous exposure to elafibranor.
* 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.
* 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.
* Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>5 × ULN.
* Creatine phosphokinase (CPK) \>2 × ULN.
* Platelet count \<75,000/µL.
* International normalised ratio \>1.3 in the absence of anticoagulant therapy.
* Estimated glomerular filtration rate (eGFR) \<45 mL/min/1.73m2.
* Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as participants with evidence of significantly impaired kidney function or underlying kidney injury).

Other exclusions

* For female participants: known pregnancy, or has a positive serum pregnancy test, or is breastfeeding.
* 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.
* History of alcohol abuse, or other substance abuse within 1 year prior.
* Known hypersensitivity to the investigational product or to any of the excipients of elafibranor.
* 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.

Primary outcomes:
measure: Percentage of participants with normalisation of Alkaline Phosphate (ALP) Levels
timeFrame: At Week 52
Secondary outcomes:
measure: Percentage of participants with normalisation of ALP Levels
timeFrame: From baseline to Week 4, Week 12, Week 24 and Week 36
measure: Change from baseline in ALP levels
timeFrame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52
measure: Percentage of participants with normalisation of ALP Levels and ≥15% decrease from Baseline
timeFrame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52
measure: Percentage of participants with ≥40% decrease from Baseline in ALP Levels
timeFrame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52
measure: Percentage of participants with ALP <0.5 × Upper Limit of Normal (ULN)
timeFrame: At Week 4, Week 12, Week 24, Week 36 and Week 52
measure: Changes from baseline in Total Bilirubin (TB) Levels
timeFrame: From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52
measure: Percentage of participants with TB <0.7 × ULN
timeFrame: At Week 4, Week 12, Week 24, Week 36 and Week 52
measure: Percentage of participants with normalisation of ALP and TB <0.7 × ULN
timeFrame: At Week 4, Week 12, Week 24, Week 36 and Week 52
measure: Percentage of participants with normalisation of TB and ALP Levels
timeFrame: At Week 4, Week 12, Week 24, Week 36 and Week 52
measure: Percentage of participants with complete biochemical response
timeFrame: At Week 4, Week 12, Week 24, Week 36 and Week 52
measure: Change from baseline in PBC Worst Itch Numeric Rating Scale (NRS) score
timeFrame: From baseline through Week 52
measure: Percentage of participants with moderate to severe pruritus at baseline (i.e. score ≥4) with a clinically meaningful response in PBC Worst Itch NRS
timeFrame: From baseline through Week 52
measure: Change from baseline in 5-D itch score
timeFrame: From baseline to Week 4, Week 24, and Week 52
measure: Change from baseline in Patient Global Impression of Severity (PGI-S) scores
timeFrame: From baseline to Week 4, Week 24, and Week 52
measure: Patient Global Impression of Change (PGI-C) scores
timeFrame: At Week 4, Week 24, and Week 52
measure: Change from baseline in PBC-40 Quality of Life (QoL) scores
timeFrame: From baseline to Week 4, Week 24, and Week 52
measure: Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a scores
timeFrame: From baseline to Week 4, Week 24, and Week 52
measure: Percentage of participants experiencing Treatment- Emergent Adverse Events (TEAEs), treatment- related TEAEs, Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs).
timeFrame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)
measure: Percentage of participants developing clinically significant changes in physical examination
timeFrame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)
measure: Percentage of participants developing clinically significant changes in vital signs
timeFrame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)
measure: Percentage of participants developing clinically significant changes in Electrocardiogram (ECG) Readings
timeFrame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)
measure: Percentage of participants developing clinically significant changes in laboratory parameters
timeFrame: From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks)
Other outcomes:
Locations:
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Los Angeles
country: United States
facility: Topgraphy Health, Inc.
state: California
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Colorado Springs
country: United States
facility: Peak Gastroenterology Associates
state: Colorado
city: Littleton
country: United States
facility: Rocky Mountain Gastroenterology
state: Colorado
city: Tampa
country: United States
facility: International Center for Research
state: Florida
city: West Monroe
country: United States
facility: Delta Research Partners, LLC
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Ypsilanti
country: United States
facility: Huron Gastroenterology Associates - Center for Digestive Care
state: Michigan
city: Englewood
country: United States
facility: South Denver Gastroenterology,P.C.
state: New Jersey
city: Albuquerque
country: United States
facility: Southwest Gastroenterology Associates, PC (SWGA)
state: New Mexico
city: Manhasset
country: United States
facility: Northwell Health Center for Liver Disease and Transplantation
state: New York
city: Charlotte
country: United States
facility: Charlotte Gastroenterology & Hepatology, PLLC
state: North Carolina
city: Fayetteville
country: United States
facility: Coastal Research Institute
state: North Carolina
city: Cordova
country: United States
facility: Gastroenterology Center of the Midsouth
state: Tennessee
city: Dallas
country: United States
facility: Methodist Transplant Physicians
state: Texas
city: San Antonio
country: United States
facility: American Research Corporation at The Texas Liver Institute
state: Texas
city: San Antonio
country: United States
facility: American Research Corporation
state: Texas
city: Seattle
country: United States
facility: Velocity Liver Institute NW
state: Washington
city: Hradec Králové
country: Czechia
facility: Hepato-Gastroenterologie HK, s.r.o.
city: Ostrava
country: Czechia
facility: Artroscan
city: Plzen
country: Czechia
facility: Research Site s.r.o.
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine - IKEM
city: Toulouse
country: France
facility: Clinique Pasteur
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Hemer
country: Germany
facility: Gastroenterologsiche Studiengesellschaft Herne
city: Leipzig
country: Germany
facility: EUGASTRO GmbH
city: Münster
country: Germany
facility: Universitaetsklinikum Muenster
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino - IRCCS
city: Palermo
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Rozzano
country: Italy
facility: IRCCS Istituto clinico humanitas - Humanitas Mirasole spa
city: Ansan si
country: Korea, Republic of
facility: Korea University Ansan Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital (KNUH)
city: Pusan
country: Korea, Republic of
facility: Pusan National University Hospital (PNUH)
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital (SNUBH)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Eunpyeong St. Mary's Hospital
city: Kraków
country: Poland
facility: Krakowskie Centrum Medyczne Sp.z.o.o - FutureMeds
city: Warsaw
country: Poland
facility: FutureMeds Warszawa Centrum
city: Cluj-Napoca
country: Romania
facility: Cluj County Clinical Emergency Hospital
city: Iaşi
country: Romania
facility: Gastromedica Srl
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro de Majadahonda
city: Sabadell
country: Spain
facility: Institut d Investigacio i Innovacio Parc Tauli, Hospital Universitari Parc Tauli
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary NHS Grampian Grampian Health Board
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary - Bradford Teaching Hospitals NHS Foundation
city: Frimley
country: United Kingdom
facility: Frimley Park Hospital - Frimley Health NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital - Greater Glasgow Health Board
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary - Hull University Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: Ambrose King Centre-Royal London Hospital-Barts Health NHS Trust
city: London
country: United Kingdom
facility: King's College Hospital
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References: