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.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Ipsen
- 入组人数
- 92
- 试验地点
- 104
- 主要终点
- Percentage of participants with normalisation of Alkaline Phosphate (ALP) Levels
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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/1.73m
- •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.
研究组 & 干预措施
Placebo
Participants will take 1 placebo tablet per day orally before breakfast with a glass of water at approximately the same time each morning.
干预措施: Placebo (Other)
Elafibranor 80 mg
Participants will take 1 tablet of elafibranor 80 mg per day orally before breakfast with a glass of water at approximately the same time each morning.
干预措施: Elafibranor (Drug)
结局指标
主要结局
Percentage of participants with normalisation of Alkaline Phosphate (ALP) Levels
时间窗: At Week 52
次要结局
- Change from baseline in ALP levels(From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52)
- Change from baseline in PBC Worst Itch Numeric Rating Scale (NRS) score(From baseline through Week 52)
- Percentage of participants with moderate to severe pruritus at baseline (i.e. score ≥4) with a clinically meaningful response in PBC Worst Itch NRS(From baseline through Week 52)
- Percentage of participants developing clinically significant changes in Electrocardiogram (ECG) Readings(From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks))
- Percentage of participants with normalisation of ALP and TB <0.7 × ULN(At Week 4, Week 12, Week 24, Week 36 and Week 52)
- Percentage of participants with normalisation of TB and ALP Levels(At Week 4, Week 12, Week 24, Week 36 and Week 52)
- Change from baseline in 5-D itch score(From baseline to Week 4, Week 24, and Week 52)
- Change from baseline in Patient Global Impression of Severity (PGI-S) scores(From baseline to Week 4, Week 24, and Week 52)
- Percentage of participants developing clinically significant changes in laboratory parameters(From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks))
- Percentage of participants with normalisation of ALP Levels(From baseline to Week 4, Week 12, Week 24 and Week 36)
- Percentage of participants with normalisation of ALP Levels and ≥15% decrease from Baseline(From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52)
- Percentage of participants with ≥40% decrease from Baseline in ALP Levels(From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52)
- Changes from baseline in Total Bilirubin (TB) Levels(From baseline to Week 4, Week 12, Week 24, Week 36 and Week 52)
- Percentage of participants with ALP <0.5 × Upper Limit of Normal (ULN)(At Week 4, Week 12, Week 24, Week 36 and Week 52)
- Percentage of participants with TB <0.7 × ULN(At Week 4, Week 12, Week 24, Week 36 and Week 52)
- Percentage of participants with complete biochemical response(At Week 4, Week 12, Week 24, Week 36 and Week 52)
- Change from baseline in PBC-40 Quality of Life (QoL) scores(From baseline to Week 4, Week 24, and Week 52)
- Percentage of participants experiencing Treatment- Emergent Adverse Events (TEAEs), treatment- related TEAEs, Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs).(From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks))
- Patient Global Impression of Change (PGI-C) scores(At Week 4, Week 24, and Week 52)
- Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a scores(From baseline to Week 4, Week 24, and Week 52)
- Percentage of participants developing clinically significant changes in physical examination(From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks))
- Percentage of participants developing clinically significant changes in vital signs(From baseline until 4 weeks after the end of treatment (maximum duration of 52 weeks))