NCT04526665进行中（未招募）3 期
A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients With Primary Biliary Cholangitis With Inadequate Response or Intolerance to Ursodeoxycholic Acid
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- Ipsen
- 入组人数
- 161
- 试验地点
- 221
- 主要终点
- Percentage of Participants With Response to Treatment Based on Cholestasis Response at Week 52
研究概览
简要总结
The participants of this study will have confirmed Primary Biliary Cholangitis (PBC) with inadequate response or intolerance to ursodeoxycholic acid (which is a medication used in the management and treatment of cholestatic liver disease).
PBC is a slowly progressive disease characterized by damage of the bile ducts in the liver, leading to a buildup 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 liver transplant or may die if the disease progresses and a liver transplant is not done.
The main aim of this study is to determine if elafibranor (the study drug) is better than placebo (a dummy treatment) at decreasing the levels of a specific blood test (alkaline phosphatase) that provides information about participant's disease. This study will also evaluate the safety of long-term treatment with elafibranor, as well as the impact on symptoms such as itchy skin (pruritus) and tiredness (fatigue).
This study has two main parts:
Part 1 will compare a daily dose of elafibranor to a daily dose of placebo and will last between a minimum of one year and a maximum of two years.
Part 2, all participants will receive elafibranor for a period of up to 5 years or until the total treatment duration (part 1 and part 2) reaches 6 years, whichever occurs first.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males or females age of 18 to 75 years (inclusive)
- •Definite or probable Primary biliary cholangitis (PBC) diagnosis
- •Alkaline phosphatase (ALP) ≥ 1.67x upper limit of normal (ULN)
- •Total bilirubin (TB) ≤ 2x ULN
- •Ursodeoxycholic acid (UDCA) for at least 12 months (stable dose ≥ 3 months) prior to screening, or unable to tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to screening (per country standard-of-care dosing)
- •Must have PBC Worst Itch Numeric rating scale (NRS) collected prior to randomization
- •Females participating in this study must be of non-child bearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the last drug intake
排除标准
- •History or presence of other concomitant liver disease
- •Clinically significant hepatic decompensation, including patients with complications of cirrhosis/portal hypertension
- •Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease) or which may diminish life expectancy to < 2 years, including known cancers
- •Patient has a positive test for HIV Type 1 or 2 at screening, or patient is known to have tested positive for HIV
- •Evidence of any other unstable or untreated clinically significant disease
- •History of alcohol abuse
- •For female patients: known pregnancy or lactating
- •Use of fibrates and glitazones within 2 months prior to screening
- •Use of Obeticholic acid (OCA), 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) within 3 months prior to screening
- •Use of antibodies or immunotherapy directed against interleukins (ILs) or other cytokines or chemokines within 12 months prior to screening
- •For patients with previous exposure to OCA, OCA should be discontinued 3 months prior to screening
- •Patients 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 five half-lives, whichever is longer, prior to screening; for patients with previous exposure to seladelpar, seladelpar should be discontinued 3 months prior to screening
- •Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) values > 5 x ULN
- •For patients with AT or TB>ULN at SV1, variability of AT or TB > 40% (see section 3.5.1)
- •Albumin<3.0 g/dl
- •Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin \ 1.3 due to altered hepatic function
- •CPK > 2 x ULN
- •Screening serum creatinine > 1.5 mg/dl
- •Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney failure damage or eGFR < 60 mL/min/1.73 m^2) calculated by Modification of diet in renal disease (MDRD)
- •Platelet count < 150 x 10^3/μL
- •AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting presence of liver cancer
- •Known hypersensitivity to the investigational product or to any of the formulation excipients of the elafibranor or placebo tablet Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
研究组 & 干预措施
Elafibranor 80mg open label
Experimental
Study participants will take 1 tablet per day orally before breakfast with a glass of water each morning
干预措施: Elafibranor 80mg (Drug)
Placebo
Placebo Comparator
Study participants will take 1 tablet per day orally before breakfast with a glass of water each morning
干预措施: Placebo (Drug)
Elafibranor 80mg double-blind
Experimental
Study participants will take 1 tablet per day orally before breakfast with a glass of water each morning
干预措施: Elafibranor 80mg (Drug)
结局指标
主要结局
Percentage of Participants With Response to Treatment Based on Cholestasis Response at Week 52
时间窗: At Week 52
Cholestasis response was defined as alkaline phosphatase (ALP) \< 1.67 x upper limit of normal (ULN) and total bilirubin (TB) \<= ULN and ALP decrease from baseline \>= 15% at Week 52 and based on the composite strategy imputing non-response for participants who experienced intercurrent events (ICEs) (study treatment discontinuation or use of rescue therapy for PBC) prior to Week 52.
次要结局
- Change From Baseline in ALP at Weeks 4, 13, 26, 39 and 52(Baseline (Day 1) and at Weeks 4, 13, 26, 39 and 52)
- Percentage of Participants With ALP Response From Baseline at Week 52(Baseline (Day 1) and at Week 52)
- Percentage of Participants With Response to Treatment According to ALP < 1.5x ULN, ALP Decrease From Baseline >= 40% and TB =<ULN at Week 52(At Week 52)
- Global PBC Study Group (GLOBE) Score at Week 52(At Week 52)
- Change From Baseline in Hepatobiliary Injury and Liver Function as Assessed by AST, ALT, Gamma-glutamyl Transferase (GGT), 5 Prime Nucleotidase (5'-NT), and Fractionated ALP (Hepatic) (H1 and H2) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Hepatobiliary Injury and Liver Function as Measured by Total and Conjugated Bilirubin at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Hepatobiliary Injury and Liver Function as Measured by Albumin at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Hepatobiliary Injury and Liver Function as Measured by INR at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Biomarkers of Inflammation as Measured by Fibrinogen and Haptoglobin at Week 52(Baseline (Day 1) and at Week 52)
- Key Secondary Endpoint: Percentage of Participants With Response to Treatment Based on ALP Normalization at Week 52(At Week 52)
- Key Secondary Endpoint: Change From Baseline in Pruritus Based on PBC Worst Itch Numeric Rating Scale (NRS) Score in Participants With Baseline PBC Worst Itch NRS Score ≥4 to Week 52(Baseline (up to 14 days pre-dose) and Week 52)
- Key Secondary Endpoint: Change From Baseline in Pruritus Based on PBC Worst Itch NRS Score in Participants With Baseline PBC Worst Itch NRS Score ≥4 to Week 24(Baseline (up to 14 days pre-dose) and Week 24)
- Percentage of Participants With Response to Treatment According to ALP < 3x ULN, Aspartate Aminotransferase (AST) < 2x ULN and TB =< 1 Milligrams Per Deciliter (mg/dL) (Paris I) at Week 52(At Week 52)
- Percentage of Participants With Response to Treatment According to ALP =< 1.5x ULN, AST =< 1.5x ULN and TB =< 1 mg/dL (Paris II) at Week 52(At Week 52)
- Percentage of Participants With Response to Treatment According to TB Decrease of 15% Change From Baseline at Week 52(At Week 52)
- Percentage of Participants With Response to Treatment According to Normalization of TB (TB =< ULN) and/or Albumin (ALB >= Lower Limit of Normal [LLN]) (Rotterdam) at Week 52(At Week 52)
- Percentage of Participants With Response to Treatment According to TB ≤0.6 x ULN at Week 52(At Week 52)
- Percentage of Participants With Response to Treatment According to ALP ≤1.67 x ULN and TB ≤1 mg/dL (Momah/ Lindor) at Week 52(At Week 52)
- Percentage of Participants With Response to Treatment According to no Worsening of TB at Week 52(At Week 52)
- Percentage of Participants With Response to Treatment According to Complete Biochemical Response at Week 52(At Week 52)
- PBC 5-, 10- and 15-year Risk Scores Based on United Kingdom (UK)-PBC Score at Week 52(At Week 52)
- Change From Baseline in Biomarkers of Inflammation as Measured by High-sensitivity C-reactive Protein (hsCRP) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Biomarkers of Inflammation as Measured by Tumor Necrosis Factor Alpha at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Immune Response as Measured by Immunoglobulin (Ig)G and IgM at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Biomarkers and Non-invasive Measures of Hepatic Fibrosis as Measured by Cytokeratin-18 (CK-18) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Biomarkers and Non-invasive Measures of Hepatic Fibrosis as Measured by Enhanced Liver Fibrosis (ELF) and Plasminogen Activator Inhibitor-1 (PAI-1) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Biomarkers and Non-invasive Measures of Hepatic Fibrosis as Measured by Transforming Growth Factor Beta (TGF-beta) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Liver Stiffness Measured by Transient Elastography (TE) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Lipid Parameters at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Fasting Plasma Glucose (FPG) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Bile Acids and Biomarkers of Bile Acid Synthesis at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline at Week 52 in Bile Acids and Biomarkers of Bile Acid Synthesis as Measured by 7 Alpha-hydroxy-4-cholesten-3-one (C4) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Bile Acids and Biomarkers of Bile Acid Synthesis as Measured Fibroblast Growth Factor 19 at Week 52(Baseline (Day 1) and at Week 52)
- Percentage of Participants With Response in PBC Worst Itch NRS Score at Weeks 24 and 52(Baseline (up to 14 days pre-dose) and at Week 24 and Week 52)
- Percentage of Participants With no Worsening of Pruritus as Measured by the PBC Worst Itch NRS Score at Weeks 24 and 52(Baseline (up to 14 days pre-dose) and at Week 24 and Week 54)
- Change From Baseline in 5-D Itch at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Epworth Sleepiness Scale (ESS) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in PBC-40 at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Health Utility as Measured by the European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in T-Scores for Bone Mineral Density Assessed by Dual-energy X-ray Absorptiometry (DEXA) Scanning at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Serum Markers of Bone Turnover Carboxy Terminal Crosslinked Telopeptides of Type 1 Collagen [CTX] at Week 52(Baseline (Day 1) and at Week 52)
- Change From Baseline in Serum Markers of Bone Turnover Type 1 Procollagen Peptide [P1NP]) at Week 52(Baseline (Day 1) and at Week 52)
- Percentage of Participants With Onset of Clinical Outcomes(From Day 1 up to Week 52)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs)(TEAEs were collected from the start of study treatment administration (Day 1) up to DCO date of 01 June 2023, approximately 980 days.)
- Plasma Concentrations of Elafibranor and GFT1007(Week 4: pre-dose, 0.5 hour, 1.5 hours, between 2-3 hours, 4 hours and 6 hours post-dose)
研究者
研究点 (221)
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