An Adaptive Two-Part Phase 2, Multi-Center, Randomized, Double Blind, Placebo-Controlled Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 Administered Once Monthly in Adult Subjects With Confirmed Non-Alcoholic Steatohepatitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 160
- 试验地点
- 43
- 主要终点
- Percentage of Participants With at Least 2-point Reduction in Non-alcoholic Fatty Liver Disease Activity Score (NAS) With at least 1-point Improvement in Hepatocellular Ballooning or Lobular Inflammation, and Without Worsening in Fibrosis Stage at EOT
研究概览
简要总结
The purpose of this study is to assess the effect of multiple ION224 doses when administered by subcutaneous (SC) injection for 49 weeks (end of the treatment [EOT]) on non-alcoholic steatohepatitis (NASH) histologic improvement and to assess the effect on liver steatosis by magnetic resonance imaging-determined proton density fat fraction (MRI-PDFF), additional changes in NASH histologic features, liver biochemistry tests, and plasma lipid profile.
详细描述
This is a Phase 2, double-blind, randomized, placebo-controlled study of ION224 in up to 150 participants. The study consists of 3 periods: 1) Screening Period: Week -8 to Week -1 (up to 8 weeks); 2) Treatment Period up to Week 49; and 3) Post-Treatment Period: Week 50 to Week 62 (12 weeks).
Initially, 48 patients will be enrolled in three different dose cohorts to receive ION224 or placebo every four weeks and based on safety and effects on liver steatosis (assessed at Week 15), two dose cohorts will be selected to be expanded. After dose selection, an additional 102 patients will be enrolled in the 2 selected dose cohorts and will receive ION224 or placebo for up to 49 weeks. Participants in the 3rd cohort (not selected) will continue to complete up to 49 weeks of treatment without any cohort expansion.
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
- Double (Participant, Investigator)
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 greater than or equal to (≥) 18 and less than or equal to (≤) 75 years old at the time of informed consent
- •Body mass index ≥ 25 kg/m^2 and ≥ 22 kg/m^2 for participants of Asian race, as assessed during screening
- •Liver fat ≥ 10% as assessed by MRI-PDFF before randomization
- •Presence of NASH confirmed by centrally read liver biopsy
- •Weight loss < 5% after historical biopsy. Otherwise, weight loss < 5% in the previous 3 months prior to randomization
- •ALT and AST ≤ 200 units per liter (U/L) and confirmed to be stable
- •Total Bilirubin ≤ 1.3 milligrams per deciliter (mg/dL) and confirmed to be stable
排除标准
- •Prior or planned (during the Study Period) bariatric surgery or previous bariatric surgery within 2 years prior to screening
- •History of solid organ transplant
- •Screening laboratory values that would render a participant unsuitable for inclusion, including but not limited to:
- •Clinically significant albuminuria or proteinuria
- •Positive test for blood on urinalysis
- •Estimated glomerular filtration rate (eGFR) < 60 milliliters (mL)/minute (min)/1.73 square meter (m^2)
- •Hemoglobin A1c (HbA1c) > 9.5%
- •Platelet count < 170 × 10^9/liter (L)
- •Diagnosis of Gilbert's syndrome
- •Known history of or evidence of liver disease other than NASH
- •Clinical evidence of liver decompensation
- •Active SARS-CoV-2 infection (COVID-19) or confirmed SARS-CoV-2 infection-related complication within 8 weeks of Screening
- •Uncontrolled arterial hypertension
- •History of bleeding diathesis or coagulopathy
- •Participants with known intolerance to magnetic resonance imaging (MRI) or with conditions contraindicated for MRI Procedures
- •History of, or current hard drug or alcohol abuse within 2 years prior to Screening
- •Use of drugs historically associated with NAFLD for more than 2 weeks in the year prior to Screening
- •Use of obeticholic acid, ursodeoxycholic acid, icosapent ethyl, niacin, PCSK9 inhibitors, and bile acid sequestrants
- •Participants taking the following medicines UNLESS on a stable dose:
- •Anti-diabetic medications
- •statins, fenofibrate, and ezetimibe
- •Estrogen containing contraceptives
- •Glucagon-like peptide (GLP)-1 agonists
- •Pioglitazone
- •Vitamin E at doses ≤ 800 international unit (IU)/day
- •Herbal medicines, other prescription medicines, vitamins or supplements known to affect lipid metabolism
- •Other protocol-defined inclusion/exclusion criteria could apply
研究组 & 干预措施
ION224
Multiple doses of ION224 will be administered by SC injection once every 4 weeks for up to 49 weeks.
干预措施: ION224 (Drug)
Placebo
Multiple doses of matching placebo will be administered by SC injection once every 4 weeks for up to 49 weeks.
干预措施: Placebo (Other)
结局指标
主要结局
Percentage of Participants With at Least 2-point Reduction in Non-alcoholic Fatty Liver Disease Activity Score (NAS) With at least 1-point Improvement in Hepatocellular Ballooning or Lobular Inflammation, and Without Worsening in Fibrosis Stage at EOT
时间窗: Up to Week 49
The NAS is a histology grading score composed on the assessment of steatosis (scale 0-3), hepatocellular ballooning (scale 0-2), and lobular inflammation (scale 0-3), with higher scores indicating more severe hepatitis. Worsening of fibrosis is defined as an increase in fibrosis of at least one stage on the Kleiner fibrosis classification: fibrosis stages range from 0-4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis).
次要结局
- Percentage of Participants Achieving Non-alcoholic Steatohepatitis (NASH) Resolution, as Defined by Scores of 0 for Ballooning and 0 or 1 for Inflammation by the NAS, and Without Worsening of Fibrosis, Assessed Through Liver Biopsy at the EOT(Up to Week 49)
- Percentage of Participants Achieving Reduction of at Least 1 Stage in the Fibrosis Score, and Without Worsening of Steatohepatitis by the NAS, Assessed Through Liver Biopsy at the EOT(Up to Week 49)
- Percentage of Participants With Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Less than or Equal to (≤) 1.5 Upper Limit of Normal (ULN) at the EOT(Up to Week 49)
- Absolute Change From Baseline in Liver-related Laboratory Test - AST(Baseline up to Week 49)
- Absolute Change From Baseline in Liver-related Laboratory Test - Total Bilirubin(Baseline up to Week 49)
- Change From Baseline in Hepatic Fat Content Measurement as Evaluated by MRI-PDFF and Calculated by an Independent, Blinded-To-Treatment, Central Reader(Baseline up to Week 15, Week 29 and Week 49)
- Absolute Change From Baseline in Liver-related Laboratory Test - ALT(Baseline up to Week 49)
- Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - High-density Lipoprotein-cholesterol (HDL-c)(Baseline up to Week 49)
- Percentage of Participants Achieving a Combination of NASH Resolution and a 1 Stage Improvement in Fibrosis at the EOT(Up to Week 49)
- Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Triglyceride (TG)(Baseline up to Week 49)
- Time to Cmax (Tmax) of ION224 and Metabolites(Baseline up to Week 49)
- Plasma Half-life (t½) of ION224 and Metabolites(Baseline up to Week 49)
- Absolute Change From Baseline in Liver-related Laboratory Test - Gamma-glutamyl Transferase(Baseline up to Week 49)
- Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Total Cholesterol(Baseline up to Week 49)
- Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Low-density Lipoprotein-cholesterol (LDL-c)(Baseline up to Week 49)
- Maximum Observed Plasma Concentration (Cmax) of ION224 and Metabolites(Baseline up to Week 49)
- Area Under the Plasma Concentration-time Curve (AUC) of ION224 and Metabolites(Baseline up to Week 49)