CTRI/2024/11/076383招募中3 期
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Efruxifermin in Subjects with Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)/Metabolic Dysfunction-Associated Steatohepatitis (MASH).
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 1,150
- 试验地点
- 25
- 主要终点
- Proportion of subjects who achieve more than or equal to 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at Week 96 (Cohort 1 only).
研究概览
简要总结
Cohort 1: Biopsy-proven Cirrhosis due to NASH/MASH
This is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the clinical benefit and safety of EFX in subjects with compensated cirrhosis due to NASH/MASH. The study will enroll in 2 cohorts. Cohort 1 will enroll approximately 750 subjects with biopsy-proven compensated cirrhosis due to NASH/MASH. Cohort 2 will enroll approximately 400 subjects with a clinical diagnosis of compensated cirrhosis due to NASH/MASH.
Evaluation of the clinical outcomes primary endpoint will occur when a pre-specified number of adjudicated events has been accrued, which is anticipated to be approximately 156 weeks. This time frame may be extended until the prespecified number of events has accrued.
A histology primary endpoint analysis will occur after all subjects in Cohort 1 have completed the Histology Primary Endpoint Treatment Duration (i.e., completed 96 weeks of treatment or permanently discontinued from the study prior to Week 96). For evaluation of longer-term safety and efficacy, all subjects will continue to receive their assigned treatment until the pre-specified number of adjudicated events has been accrued.
Subjects meeting the study’s eligibility criteria will be randomly assigned in a 1:1 ratio into 1 of 2 treatment groups as shown in the figures below.
Cohort 2: Clinical Diagnosis of Cirrhosis due to NASH/MASH
Subjects will be enrolled into Cohort 2 only after enrollment for Cohort 1 is complete. With Sponsor approval, a subject may be considered for Cohort 2 enrollment prior to completion of Cohort 1 enrollment in scenarios such as those outlined below:
Biopsy confirms fibrosis stage 4 but minimum scores for steatosis, ballooning, and/or lobular inflammation are not met. Esophagogastroduodenoscopy (EGD) confirms either no varices or presence of low-risk varices
Biopsy confirms fibrosis stage 4 and minimum scores for steatosis, ballooning, and lobular inflammation are met. EGD confirms presence of low-risk varices
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- Participant and Investigator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 80.00 Year(s)（—）
- 性别
- All
入选标准
- •1.Males and non-pregnant, non-lactating females between 18–80 years of age, inclusive, on the day of signing informed consent.2.Previous history or presence of type 2 diabetes (T2D) (as determined by medical history or based on screening lab values if previously undiagnosed [i.e., HbA1c greater than or equal to 6.5%]) or 2 out of 4 components of metabolic syndrome (obesity, dyslipidemia, elevated blood pressure, elevated fasting glucose).
- •Body mass index (BMI) greater than or equal to 25.0 kg/m².4.Cohort 1 Subjects only: Subjects who do not have a historical liver biopsy specimen (meeting Inclusion Criteria 5 below) must meet either inclusion criterion 4a OR 4b: a.
- •FibroScan liver stiffness measurement (LSM) greater than or equal to 15 kilopascals (kPa) Note: All subjects must complete a FibroScan examination during the screening period, unless historical values for a FibroScan assessment performed within 12 weeks prior to baseline/Day 1 (or up to 14 weeks prior to baseline/Day 1 with an approved screening window extension) are available.b. ELF score greater than or equal to 9.8.5.Cohort 1 Subjects only: Biopsy-proven compensated cirrhosis (fibrosis stage 4) due to NASH/MASH based on a centrally read biopsy.
- •Must have had a liver biopsy obtained less than or equal to 365 days prior to screening with fibrosis stage 4 and a NAFLD activity score (NAS) of greater than or equal to 3 with at least 1 point in each of the following components: a.Steatosis (scored 0 to 3) b.Ballooning degeneration (scored 0 to 2), and c.
- •Lobular inflammation (scored 0 to 3) 6.Cohort 2 Subjects only: Subjects must meet either Inclusion Criterion 6a, 6b, OR 6c below:a.Biopsy-proven compensated cirrhosis (fibrosis stage 4) with no competing etiology for liver disease.
- •Must have had a liver biopsy specimen collected during screening or within 365 days prior to screening with confirmation of fibrosis stage 4 from a pathologist (centrally or locally read).Note: A subject cannot be considered for Cohort 2 based on Inclusion Criterion 6b or 6c if a biopsy previously submitted for central read failed to meet Inclusion Criterion 6a.
- •If there is reason to suspect progression to cirrhosis, a new biopsy may be obtained and submitted for evaluation (centrally or locally) OR b.FibroScan LSM greater than or equal to 20.0 kPa. Note: All subjects must complete a FibroScan examination during the screening period, unless historical values for a FibroScan assessment performed within 12 weeks prior to baseline/Day 1 (or up to 14 weeks prior to baseline/Day 1 with an approved screening window extension) are available OR c.ELF score greater than or equal to 10.5.7.Central laboratory tests that meet all of the following criteria at screening: a.Albumin greater than or equal to 3.5 g/dL.b.Estimated glomerular filtration rate (eGFR) greater than or equal to 15 mL/min, as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).c.Hemoglobin A1c (HbA1c) less than or equal to 9.5%.d.International Normalized Ratio (INR) less than or equal to 1.3, unless due to therapeutic anticoagulation.e.Direct bilirubin less than or equal to 0.5 mg/dL.f.Creatine kinase (CK) less than 3 × upper limit of normal (ULN).
- •g.Triglyceride (TG) level less than or equal to 500 mg/dL.h.25-Hydroxy Vitamin D greater than or equal to 13 ng/mL.Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion.
- •A subject who fails to meet Inclusion Criterion 7h will be allowed to retest 25-Hydroxy Vitamin D during the same screening period OR rescreen provided that they agree to take supplementation with Vitamin D.8.Central laboratory tests that meet all of the following criteria at screening and pre-baseline:a.Total bilirubin less than 1.3 mg/dL.
- •For subjects with Gilbert’s syndrome or hemolytic anemia, total bilirubin may be elevated if direct bilirubin less than or equal to ULN.b.Platelet count greater than or equal to 75,000/µL.c.Alanine aminotransferase (ALT) less than or equal to 5 × ULN.d.Aspartate aminotransferase (AST) less than or equal to 5 x ULN.e.Alkaline phosphatase (ALP) less than 1.5 × ULN.Note: Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion 9.Documented stability of ALT and AST levels, as evidenced by no significant worsening of ALT and AST values at pre-baseline relative to screening values and the following parameters: a.If the screening and pre-baseline ALT and AST values are both less than or equal to 1.5 × ULN, there is no limit to the difference between the values b.
- •If at least 1 of the screening or pre-baseline ALT or AST values is greater than 1.5 × ULN and shows worsening at pre-baseline, the percent increase must be less than or equal to 50%.Note: Subjects must have ALT and AST repeated during the screening period (Pre-baseline visit), with a minimum of 28 days between blood draws to confirm either criterion 9a or 9b above.Laboratory tests for eligibility assessment may be repeated one time at the Investigator’s discretion.10.Use of any conditionally allowed medications must follow the stable dose and adjustment criteria as outlined in protocol.11.Willing and able to give written informed consent prior to any study specific procedures being performed.12.Female subjects of childbearing potential (see definition in protocol) must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline/Day
- •13.Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in protocol.
排除标准
- •1.Weight loss at screening defined as: a.
- •Cohort 1: Weight loss greater than 10% within 90 days prior to the collection date of the liver biopsy specimen used to assess subject eligibility through randomization.b.Cohort 2: Weight loss greater than 10 % within 90 days prior to screening through randomization.
- •Type 1 diabetes.3.Unstable T2D defined as: a.Insulin dose adjustment greater than 35% within 30 days prior to screening through randomization.
- •Any prior history of diabetic ketoacidosis and/or hyperosmolar hyperglycemic state.4.Hypoglycemia unawareness, hospitalization due to hypoglycemia, or history of severe hypoglycemia (hypoglycemia requiring outside assistance to regain normal neurologic status) within 90 days prior to screening.5.Subjects with osteoporosis, defined as a T-score of less than or equal to minus 2.5 at the femoral neck, total hip, or lumbar spine based on a centrally read dual-energy X-ray absorptiometry (DXA) scan performed during screening.Note: A historical DXA scan performed within 90 days prior to screening may be accepted as the screening DXA scan.
- •The historical scan must have been performed on a scanner previously qualified by the central imaging vendor that is available for use at post-baseline visits.6.Poorly controlled hypertension (systolic blood pressure greater than 160 mm Hg, or diastolic blood pressure greater than 100 mm Hg) at the Screening visit or Pre-baseline visit.
- •Note: Vital signs for eligibility assessment may be repeated one time at the Investigator’s discretion.7.Presence of varices (Cohort 1) OR presence of high-risk varices (Cohort 2), based on a centrally read upper gastrointestinal (GI) EGD exam conducted at screening.8.Any current or prior history of decompensated liver disease including ascites, hepatic encephalopathy (HE), or variceal bleeding.9.Model for End-Stage Liver Disease (MELD) score greater than 12, unless due to hemolytic anemia, therapeutic anticoagulation, or Gilbert’s syndrome.10.Child-Pugh score greater than 6 (Class B or C), unless due to hemolytic anemia, therapeutic anticoagulation, or Gilbert’s syndrome.11.History of significant pancreatic disorders (acute pancreatitis, chronic pancreatitis, hereditary pancreatitis, and pancreatic cancer).
- •12.Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive) or acute hepatitis A infection (hepatitis A immunoglobulin M [IgM] antibody positive).
- •For subjects with positive hepatitis B core antibody (HBcAb), HBV DNA by quantitative polymerase chain reaction (PCR) will be required.13.Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV RNA positive).
- •Subjects cured of HCV infection less than 2 years prior to the Screening visit (based on date of RNA PCR negative confirmation following conclusion of treatment) are not eligible.Note: Subjects who were previously diagnosed with chronic HCV infection who achieved sustained viral response (SVR) following treatment, or subjects with spontaneous clearance of HCV infection (positive serology for HCV infection, negative for HCV RNA at screening, and no documented history of acute HCV infection within 2 years prior to screening) may be enrolled.
- •Prior (less than 2 years prior to screening) or planned (during the study period) bariatric surgery (e.g., gastroplasty, Roux-en-Y gastric bypass) or reversal or removal of intragastric balloon.
- •Surgery failure less than 2 years prior to screening is also exclusionary 15.Other causes of liver disease based on medical history and/or centralized review of liver histology and/or central laboratory results, including but not limited to: alcoholic liver disease, autoimmune disorders (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis [PSC], autoimmune hepatitis), drug induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitryspin deficiency.16.History of liver transplantation.
- •Current or prior history of hepatocellular carcinoma (HCC).18.Current diagnosis of Cushing’s syndrome.
- •History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening Note: Significant alcohol consumption is defined as an average exceeding 1 ethanol containing drink/day in female subjects and 2 ethanol-containing drinks/day in male subjects.20.Human immunodeficiency virus (HIV) infection.
- •Uncontrolled cardiac arrhythmia or confirmed QT interval corrected using Fridericia’s formula (QTcF) greater than 450 msec for males and greater than 470 msec for females at the screening ECG assessment.
- •Subjects with cardiac pacemakers and elevated QTcF (greater than 450 msec for males and greater than 470 msec for females) may be allowed to participate if, in the Investigator’s opinion, the subject’s cardiac function is stable Note: ECG for eligibility assessment may be repeated one time at the Investigator’s discretion.22.Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 90 days prior to screening and through randomization.23.Life expectancy of less than 2 years.24.Use of any investigational medication within 30 days or 5 halflives, whichever is longer, prior to screening or concurrent participation in another therapeutic clinical study.Note: Without written approval from the Sponsor, a historical biopsy cannot be used for screening eligibility if the biopsy was collected prior to or during treatment with an investigational drug.25.Use of any prohibited medication(s) as outlined in protocol, including any prior exposure to EFX Positive urine drug screen for amphetamines, cocaine, or opiates (e.g., heroin, morphine) at screening.
- •Subjects with a 26.positive urine drug screen due to prescription medication (e.g., opiates, methylphenidate) are eligible if the prescription and diagnosis are reviewed and approved by the Investigator.
- •Subjects on stable methadone or buprenorphine maintenance treatment for at least 180 days prior to screening may be included in the study.
- •Cohort 1 only: Unable to safely undergo a liver biopsy.28.Presence of any laboratory abnormality or significant systemic or major illnesses (other than liver disease) that, in the opinion of the Investigator, compromises the subject’s ability to safely participate in and complete the study including, but not limited to: a.
- •Pulmonary disease, heart failure, renal failure, organ transplantation, serious psychiatric disease, malignancy, history of substance abuse and/or a psychiatric condition requiring hospitalization and/or emergency room visit within 180 days of screening.
- •Unavailable for follow-up assessment or concern for subject’s compliance with the protocol procedures.30.Known hypersensitivity to the study drug, its metabolites, or formulation excipients.
结局指标
主要结局
Proportion of subjects who achieve more than or equal to 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at Week 96 (Cohort 1 only).
时间窗: Week 96
次要结局
- Proportion of subjects who achieve more than or equal to 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) & no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at End of Study(Cohort 1)(Proportion of subjects who achieve more than or equal to 1 stage improvement in fibrosis (based on NASH CRN fibrosis score) at Week 96 & End of Study(Cohort 1))
- Change from baseline in ELF score & components (TIMP-1, HA, PIIINP), Pro-C3, liver(stiffness assessed by FibroScan, & FAST score)
研究者
Dr Sawan Bopanna
KlinEra Global Services
研究点 (25)
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