A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Ascending Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 145 in Subjects With Hyperlipidemia on Stable Doses of a Statin
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 60
- 主要终点
- Number of Participants With Adverse Events
研究概览
简要总结
The purpose of the study is to evaluate the safety and tolerability of multiple doses of evolocumab when given as an add-on to stable statin therapy.
详细描述
Participants receiving low-to-moderate-dose statins were randomized in a 1:3 ratio to receive subcutaneous placebo or evolocumab and enrolled sequentially into one of 5 dose-escalation cohorts:
- Evolocumab 14 mg/placebo once weekly (QW) × 6 doses
- Evolocumab 35 mg/placebo once weekly (QW) × 6 doses
- Evolocumab 140 mg/placebo every 2 weeks (Q2W) × 3 doses
- Evolocumab 280 mg/placebo every 2 weeks (Q2W) × 3 doses
- Evolocumab 420 mg/placebo every 4 weeks (Q2W) × 2 doses.
Participants receiving high-dose statins were randomized 1:3 to receive subcutaneous placebo or evolocumab 140 mg every 2 weeks × 3 doses (Cohort 6).
Participants diagnosed with familial hypercholesterolemia (HeFH) were randomized 1:2 to receive subcutaneous placebo or evolocumab 140 mg every 2 weeks × 3 doses (Cohort 7).
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women ages 18 to 70 years (inclusive) at the time of screening with hyperlipidemia
- •Body mass index (BMI) ≥18 and ≤ 35 kg/m^2 at the time of screening
- •Low-density lipoprotein cholesterol (LDL-C) level of 70-220 mg/dL (inclusive) at screening as measured by direct assay
- •For Cohorts 1-5: On a stable dose of rosuvastatin (Crestor) < 40 mg/day, atorvastatin (Lipitor) < 80 mg/day, or simvastatin (Zocor) 20-80 mg/day for ≥ 1 month prior to enrollment and expected to remain on this dose for the remainder of the study
- •For Cohort 6: On a stable dose of rosuvastatin (Crestor) 40 mg/day or atorvastatin (Lipitor) 80 mg/day for ≥ 1 month prior to enrollment and expected to remain on this dose for the remainder of the study
- •For Cohort 7: Diagnosis of heterozygous familial hypercholesterolemia, based on a score of ≥ 9 points using the World health Organization (WHO) criteria
排除标准
- •Diagnosis of homozygous familial hypercholesterolemia
- •History of heart failure, coronary artery bypass graft, or cardiac arrhythmia
- •History of acute coronary syndrome (e.g. myocardial infarction, hospitalization for unstable angina) or percutaneous coronary intervention, within 12 months prior to enrollment
- •Planned cardiac surgery or revascularization
- •Known aortic, peripheral vascular or cerebrovascular disease (including history of stroke or transient ischemic attack)
- •Diabetes mellitus with any of the following:
- •known microvascular or macrovascular disease
- •HbA1c > 8.0% at screening
- •use of any hypoglycemic medication other than metformin
- •Uncontrolled hypertension (systolic blood pressure ≥ 150 or diastolic blood pressure ≥ 90 mmHg) either on or off therapy at screening or at baseline
研究组 & 干预措施
Placebo
Participants received matching placebo dose regimens by subcutaneous injection.
干预措施: Placebo (Biological)
Evolocumab
Participants received one of 5 dose levels of evolocumab administered as multiple subcutaneous doses.
干预措施: Evolocumab (Biological)
结局指标
主要结局
Number of Participants With Adverse Events
时间窗: From the first dose of study drug until Day 85
The relationship of each adverse event to the investigational product was assessed by the investigator. A serious adverse event (SAE) is defined as an adverse event that * is fatal * is life threatening (places the subject at immediate risk of death) * requires in-patient hospitalization or prolongation of existing hospitalization * results in persistent or significant disability/incapacity * is a congenital anomaly/birth defect * other significant medical hazard.
Number of Participants With Anti-Evolocumab Antibodies
时间窗: From the first dose of study drug until Day 85
Serum samples were analyzed by an electrochemiluminescence (ECL)-based immunoassay for anti-evolocumab binding antibodies. Positive samples were subsequently tested in a receptor-ligand binding bioassay for anti-evolocumab neutralizing antibodies
次要结局
- Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab(Day 29 predose (last dose for Cohorts 3-7) and Days 36 (predose for Cohorts 1 and 2), 40, 43, 50, 57, 64, 71, 78, and 85)
- Percent Change From Baseline to End of the Dosing Interval in LDL-C(Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group)
- Maximum Observed Plasma Concentration (Cmax) of Evolocumab(Day 1, predose and Days 4, 8, 15, 22, 29, 36, 40, 43, 50, 57, 64, 71, 78, and 85)
- Percent Change From Baseline to End of the Dosing Interval in PCSK9(Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group)