A Phase 3, Randomized, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Denifanstat in Patients With Noncirrhotic Metabolic Dysfunction-associated Steatohepatitis (MASH) and F2/F3 Fibrosis (FASCINATE-3)
试验速览
- 阶段
- 3 期
- 状态
- 撤回
- 入组人数
- 1,260
- 主要终点
- Dual Primary Efficacy Endpoint 1: Interim Analysis: MASH Resolution (denifanstat 50 mg compared to placebo)
研究概览
简要总结
A randomized, double-blind, placebo-controlled Phase 3 study to determine if denifanstat 50 mg or 25 mg is effective, as compared to placebo, in resolving MASH without the worsening of fibrosis and/or in fibrosis regression without the worsening of steatohepatitis.
详细描述
Approximately 1260 patients (including at least 60% of F3 patients) will be enrolled to receive either denifanstat 50 mg (580 patients), placebo (580 patients), or denifanstat 25 mg (100 patients).
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
- •Willing and able to participate in the study and provide written informed consent.
- •Adults between 18 and 75 years of age.
- •Body mass index (BMI) ≥23 kg/m^2 for Asian patients and ≥25 kg/m^2 for patients of other races.
- •Presence of metabolic risk factor(s), as follows:
- •2 out of 4 of the following:
- •BMI ≥30 kg/m^
- •Hypertension, or on active antihypertensive treatment.
- •Elevated fasting serum TGs or on active treatment for hypertriglyceridemia.
- •Reduced fasting serum HDL-c or on active treatment for dyslipidemia.
- •For patients with T2DM:
- •HbA1c ≤9.5%.
- •Metformin, insulin, dipeptidyl peptidase-4 inhibitors (DPP4-Is), sodium-glucose transport protein-2 inhibitors (SGLT2-Is), and alpha-glucosidase inhibitors (α-GIs): stable dose for at least 12 weeks prior to qualifying liver biopsy and screening.
- •Sulfonylureas (SUs) and glinides: stable dose with no history of relevant hypoglycemia for at least 12 weeks prior to qualifying liver biopsy and screening.
- •GLP-1 RA: stable dose for at least 18 weeks prior to start of screening.
- •Noncirrhotic, biopsy-proven MASH with:
- •A fibrosis stage of F2 or F
- •NAS ≥4 with at least a score of 1 in each of the following NAS components:
- •Steatosis (scored 0 to 3).
- •Hepatocyte ballooning (scored 0 to 2).
- •Lobular inflammation (scored 0 to 3).
- •A qualifying historical liver biopsy within 6 months before the screening visit. Historical biopsy results will be confirmed by central reading.
- •If there is no available historical liver biopsy within this time period, a liver biopsy must be performed during the screening period. Patients should be deemed likely to have MASH F2/F3 fibrosis prior to proceeding to a liver biopsy, as indicated by the following:
- •Liver stiffness measurement (LSM) ≥8.5 kPa.
- •Controlled attenuation parameter (CAP) ≥280 dB/m.
- •Aspartate aminotransferase (AST) >20 U/L.
- •Stable ALT and AST levels.
排除标准
- •Previous intake of an approved MASH medication.
- •Exclusionary laboratory values:
- •ALT and/or AST >5 × ULN.
- •ALP ≥2 × ULN.
- •Total serum bilirubin concentration >1.3 mg/dL.
- •Serum albumin concentration <3.5 g/dL.
- •INR >1.3 except for patients receiving anticoagulant treatment.
- •Platelet count <140,000/μL.
- •Fasting TG level ≥500 mg/dL.
- •eGFR <45 mL/min/1.73 m^
- •History of excessive alcohol intake for a period of more than 3 consecutive months within 1 year prior to screening.
- •Presence of cirrhosis on liver histology according to the assessment of the central reader.
- •Current or historical clinically evident hepatic decompensation.
- •Evidence of another form of active liver disease.
- •Positive serologic evidence of current infectious liver disease.
- •MELD score ≥
- •Planned or history of liver transplantation.
- •Prior or planned bariatric surgery.
- •Gain or loss of >5% of body weight in the 3 months or >10% of body weight in the 6 months prior to screening, qualifying liver biopsy, and the baseline visit (V1).
- •Any of the following within 6 months prior to the baseline visit (V1):
- •Myocardial infarction.
- •Unstable angina.
- •Transient ischemic attack, stroke, or cerebrovascular disease.
- •Unstable or undiagnosed arrhythmias.
- •Uncontrolled high BP.
- •Malignancy with a complete remission date within 5 years prior to the baseline visit (V1).
- •Any current or history of hepatocellular carcinoma.
- •Diabetes other than T2DM.
- •Uncontrolled hypothyroidism.
- •Any other known serious disease or other disease which in the Investigator's opinion would exclude the patient from participating in the study.
- •Previous intake of an approved MASH medication, unless there is at least a 6-month wash-out period between the last date of intake of the approved MASH medication and date of screening.
- •Use of a nonpermitted concomitant medication within 30 days or 5 half-lives prior to the qualifying liver biopsy and screening.
研究组 & 干预措施
Denifanstat 50 mg
Denifanstat tablet, orally, once daily
干预措施: Denifanstat (Drug)
Denifanstat 25 mg
Denifanstat tablet, orally, once daily
干预措施: Denifanstat (Drug)
Placebo
Placebo tablet, orally, once daily
干预措施: Placebo (Drug)
结局指标
主要结局
Dual Primary Efficacy Endpoint 1: Interim Analysis: MASH Resolution (denifanstat 50 mg compared to placebo)
时间窗: 52 weeks
Proportion of patients who achieve MASH resolution (defined as NAS\* of 0 for ballooning, and 0 or 1 for inflammation) without worsening of fibrosis stage at Week 52. \*NAS: nonalcoholic fatty liver disease activity score
Dual Primary Efficacy Endpoint 2: Interim Analysis: Improvement in Fibrosis (denifanstat 50 mg compared to placebo)
时间窗: 52 weeks
Proportion of patients who achieve at least a 1-point improvement in fibrosis stage and without worsening of steatohepatitis (defined as no increase in NAS\* for ballooning, inflammation, or steatosis) at Week 52.
Primary Endpoint: End of Study Analysis: Liver-related Composite Clinical Outcome (denifanstat 50 mg compared to placebo)
时间窗: 234 weeks
Time to first occurrence of any event from the following composite clinical outcome: death from any cause; histopathologic progression to cirrhosis; liver transplant; Model for End-Stage Liver Disease (MELD) score ≥15; Liver decompensation event defined by: Ascites requiring chronic diuretic treatment, Hepatic encephalopathy grade 2 or above requiring at least a 24-hour hospitalization, Variceal hemorrhage requiring hospitalization and transfusion of blood.
次要结局
未报告次要终点