A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and Safety of Elafibranor in Patients With Nonalcoholic Steatohepatitis (NASH) and Fibrosis
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- Genfit
- 入组人数
- 2,157
- 试验地点
- 319
- 主要终点
- Number of Elafibranor-treated Participants Relative to Placebo Achieving Resolution of Nonalcoholic Steatohepatitis Without Worsening of Fibrosis
研究概览
简要总结
The primary objectives of this study are to evaluate the effect of Elafibranor treatment compared to placebo on 1) histological improvement and 2) all-cause mortality and liver-related outcomes in patients with nonalcoholic steatohepatitis (NASH) and fibrosis.
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 aged from 18 to 75 years inclusive at first screening visit.
- •Must provide signed written informed consent and agree to comply with the study protocol.
- •Females participating in this study must be of nonchildbearing potential or using highly efficient contraception for the full duration of the study and for 1 month after the end of treatment, as described below:
- •Cessation of menses for at least 12 months due to ovarian failure,
- •Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian failure
- •If requested by local IRB regulations and/or National laws, sexual abstinence may be considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
- •Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, vasectomized partner, or intra-uterine device)
- •Double contraception with barrier AND highly effective hormonal method of contraception (oral, intravaginal, or transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation; oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation; or intrauterine hormone-releasing system). The hormonal contraception must be started at least 1 month prior to Randomization.
- •Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides (biopsy obtained within 6 months prior to randomization or during the screening period) with at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3).
- •NAS score ≥
- •Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.
- •Stable dose of vitamin E, polyunsaturated fatty acids, or ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy
- •For participants with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic drugs, change in anti-diabetic therapy must follow these requirements:
- •No qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., implementation of a new anti-diabetic therapy) for participants treated with metformin, gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose in the 6 months prior to diagnostic liver biopsy.
- •No implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment (Visit 7).
- •Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians' judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the end of treatment.
排除标准
- •Known heart failure (Grade I to IV of New York Heart Association classification).
- •History of efficient bariatric surgery within 5 years prior to screening.
- •Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy
- •Type 1 diabetes participants .
- •Participants with decompensated diabetes (HbA1c>9%).
- •Participants with a history of clinically significant acute cardiac event within 6 months prior to screening
- •Weight loss of more than 5% within 6 months prior to randomization
- •Compensated and decompensated cirrhosis
- •Current or recent history (<5 years) of significant alcohol consumption
- •Pregnant or lactating females or females planning to become pregnant during the study period.
- •Other well documented causes of chronic liver disease according to standard diagnostic procedures
- •Participants with previous exposure to Elafibranor
- •Prohibited concomitant medication
- •Any medical conditions that may diminish life expectancy to less than 2 years including known cancers.
- •Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric disease.
- •Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.
- •Participants with biological criteria exclusion as per effective protocol
研究组 & 干预措施
120 mg Elafibranor
Coated tablets dosed at 120mg Elafibranor; oral administration; one tablet per day before breakfast with a glass of water
干预措施: Elafibranor (Drug)
Placebo
Coated placebo tablets; oral administration; one tablet per day before breakfast with a glass of water
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Elafibranor-treated Participants Relative to Placebo Achieving Resolution of Nonalcoholic Steatohepatitis Without Worsening of Fibrosis
时间窗: Measurement at 72 weeks
To evaluate the effect of Elafibranor compared to placebo on liver histology in nonalcoholic steatohepatitis (NASH) participants with fibrosis by assessing the following endpoint: The number of Elafibranor-treated participants relative to placebo achieving NASH resolution without worsening of fibrosis. This outcome measure is for the surrogate endpoint analysis.
Time to Long-term Outcome Composed of All-cause Mortality, Cirrhosis, and Liver-related Clinical Outcomes
时间窗: From first randomization up to early termination of the study corresponding to 54 months (54 months being the longest duration for any given participant)
Composite long-term outcome measured by the number of participants with the onset of any of the adjudicated events, composed of death due to any cause, histological liver cirrhosis, and the full list of portal hypertension/cirrhosis related events as follows: liver transplantation; model for end stage liver disease (MELD) score greater than or equal to 15 for participants with baseline score less than or equal to 12, and onset of variceal bleeding requiring hospitalization, hepatic encephalopathy with West Haven/Conn score greater than or equal to 2 and requiring hospitalization, spontaneous bacterial peritonitis, and ascites requiring treatment. The MELD scale ranges from 6 to 40, showing how much a participant needs a liver transplant: higher number is more urgent. The West Haven/Conn scale is 5-point (0 to 4) grading severity of hepatic encephalopathy: higher score means worse hepatic encephalopathy. This outcome measure is for the long-term endpoint analysis.
次要结局
- Change From Baseline of High-density Lipoprotein (HDL) Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo(Measurements after 72 weeks of treatment and up to study termination)
- Number of Elafibranor-treated Participants Relative to Placebo Achieving Improvement of Fibrosis of at Least 1 Stage(Measurements at 72 weeks)
- Change From Baseline of Hemoglobin A1c (HbA1c) in Diabetic Participants After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo(Measurements after 72 weeks of treatment and up to study termination)
- Change From Baseline of Low-density Lipoprotein (LDL) Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo(Measurements after 72 weeks of treatment and up to study termination)
- Change From Baseline of Homeostatic Model Assessment-IR (HOMA-IR) After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo in Non-diabetic Participants(Measurements after 72 weeks of treatment and up to study termination)
- Change From Baseline of Non-high Density Lipoprotein Cholesterol After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo(Measurements after 72 weeks of treatment and up to study termination)
- Change From Baseline of Triglycerides After 72 Weeks of Treatment in Elafibranor-treated Participants Relative to Placebo(Measurements after 72 weeks of treatment and up to study termination)