A Double-blind, Randomized, Placebo and Ezetimibe Controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 on LDL-C in Combination With Statin Therapy in Subjects With Primary Hypercholesterolemia and Mixed Dyslipidemia
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 2,067
- 试验地点
- 1
- 主要终点
- Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
研究概览
简要总结
The primary objective was to evaluate the effect of 12 weeks of evolocumab administered subcutaneously every 2 weeks (Q2W) and monthly (QM) when used in combination with a statin, compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia.
详细描述
Prior to the first randomization, participants entered a screening period to determine eligibility. During screening, all participants received subcutaneous placebo corresponding to the once monthly dose volume. Participants who completed the screening period and met eligibility criteria were randomized to 1 of 5 open-label statin cohorts (atorvastatin 10 mg or 80 mg, rosuvastatin 5 mg or 40 mg, or simvastatin 40 mg) for a 4 week lipid stabilization period based on statin therapy at the time of study entry (no statin use vs non-intensive statin use vs intensive statin use).
After the 4-week lipid-stabilization period, eligible patients taking rosuvastatin or simvastatin during the lipid-stabilization phase were then randomized to 1 of 4 treatment groups: evolocumab (140 mg, subcutaneous, every 2 weeks) or matching placebo (subcutaneous, every 2 weeks), or evolocumab (420 mg, subcutaneous, monthly) or matching placebo (subcutaneous, monthly). Patients taking atorvastatin during the lipid-stabilization phase were then randomized to 1 of 6 treatment groups: evolocumab (140 mg, subcutaneous, every 2 weeks) and placebo (oral, daily), evolocumab (420 mg, subcutaneous, monthly) and placebo (oral, daily), placebo (subcutaneous, every 2 weeks) and placebo (oral, daily) or ezetimibe (10 mg, oral, daily), or placebo (subcutaneous, monthly) and placebo (oral, daily) or ezetimibe (10 mg, oral, daily).
A participant was considered randomized into the study after successfully completing the screening period, meeting all inclusion/exclusion criteria, and undergoing both randomization procedures.
Participants randomized to simvastatin who were taking verapamil or diltiazem prior to randomization received simvastatin 10 mg once daily (QD) while participants who were taking amlodipine, amiodarone or ranolazine prior to randomization received simvastatin 20 mg QD. All other participants randomized to simvastatin received simvastatin 40 mg QD.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female ≥ 18 to ≤ 80 years of age
- •Subjects not taking a statin must have fasting LDL-C of at least 150 mg/dL (4.0 mmol/L)
- •Subjects already on a non-intensive statin must have fasting LDL-C at screening ≥ 100 mg/dL (2.6 mmol/L)
- •Subjects already on a intensive statin must have fasting LDL-C at screening ≥ 80 mg/dL (2.1 mmol/L)
- •Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L)
排除标准
- •Statin intolerance
- •New York Heart association (NYHA) III or IV heart failure
- •Uncontrolled hypertension
- •Uncontrolled cardiac arrhythmia
- •Type 1 diabetes, poorly controlled type 2 diabetes
- •Uncontrolled hypothyroidism or hyperthyroidism
研究组 & 干预措施
A10 PBO Q2W
Participants received atorvastatin 10 mg once daily during the 4 week lipid stabilization period and then in combination with placebo (PBO) subcutaneous injection once every 2 weeks (Q2W) and placebo tablets once daily for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
A10 PBO Q2W
Participants received atorvastatin 10 mg once daily during the 4 week lipid stabilization period and then in combination with placebo (PBO) subcutaneous injection once every 2 weeks (Q2W) and placebo tablets once daily for up to 12 weeks.
干预措施: Placebo to Ezetimibe (Drug)
A10 PBO Q2W
Participants received atorvastatin 10 mg once daily during the 4 week lipid stabilization period and then in combination with placebo (PBO) subcutaneous injection once every 2 weeks (Q2W) and placebo tablets once daily for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A10 PBO QM
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month (QM) and placebo tablets once a day for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
A10 PBO QM
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month (QM) and placebo tablets once a day for up to 12 weeks.
干预措施: Placebo to Ezetimibe (Drug)
A10 PBO QM
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month (QM) and placebo tablets once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A10 EZE (Q2W)
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe (EZE) orally once a day for up to 12 weeks.
干预措施: Ezetimibe (Drug)
A10 EZE (Q2W)
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe (EZE) orally once a day for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
A10 EZE (Q2W)
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe (EZE) orally once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A10 EZE (QM)
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for up to 12 weeks.
干预措施: Ezetimibe (Drug)
A10 EZE (QM)
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
A10 EZE (QM)
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A10 EvoMab Q2W
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab (EvoMab) by subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
干预措施: Evolocumab (Biological)
A10 EvoMab Q2W
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab (EvoMab) by subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
干预措施: Placebo to Ezetimibe (Drug)
A10 EvoMab Q2W
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab (EvoMab) by subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A10 EvoMab QM
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for up to 12 weeks
干预措施: Evolocumab (Biological)
A10 EvoMab QM
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for up to 12 weeks
干预措施: Placebo to Ezetimibe (Drug)
A10 EvoMab QM
Participants received atorvastatin 10 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for up to 12 weeks
干预措施: Atorvastatin (Drug)
A80 PBO Q2W
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
A80 PBO Q2W
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
干预措施: Placebo to Ezetimibe (Drug)
A80 EvoMab Q2W
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A80 PBO Q2W
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A80 PBO QM
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month and placebo tablets once a day for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
A80 PBO QM
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month and placebo tablets once a day for up to 12 weeks.
干预措施: Placebo to Ezetimibe (Drug)
A80 PBO QM
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month and placebo tablets once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A80 EZE (Q2W)
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for up to 12 weeks.
干预措施: Ezetimibe (Drug)
A80 EZE (Q2W)
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
A80 EZE (Q2W)
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A80 EZE (QM)
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for up to 12 weeks.
干预措施: Ezetimibe (Drug)
A80 EZE (QM)
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
A80 EZE (QM)
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
A80 EvoMab Q2W
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
干预措施: Evolocumab (Biological)
A80 EvoMab Q2W
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks and placebo tablets once a day for up to 12 weeks.
干预措施: Placebo to Ezetimibe (Drug)
A80 EvoMab QM
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for up to 12 weeks.
干预措施: Evolocumab (Biological)
A80 EvoMab QM
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for up to 12 weeks.
干预措施: Placebo to Ezetimibe (Drug)
A80 EvoMab QM
Participants received atorvastatin 80 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for up to 12 weeks.
干预措施: Atorvastatin (Drug)
R5 PBO Q2W
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
R5 PBO Q2W
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Rosuvastatin (Drug)
R5 PBO QM
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
R5 PBO QM
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month for up to 12 weeks.
干预措施: Rosuvastatin (Drug)
R5 EvoMab Q2W
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Evolocumab (Biological)
R5 EvoMab Q2W
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Rosuvastatin (Drug)
R5 EvoMab QM
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
干预措施: Evolocumab (Biological)
R5 EvoMab QM
Participants received rosuvastatin 5 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
干预措施: Rosuvastatin (Drug)
R40 PBO Q2W
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
R40 PBO Q2W
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Rosuvastatin (Drug)
R40 PBO QM
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
R40 PBO QM
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month for up to 12 weeks.
干预措施: Rosuvastatin (Drug)
R40 EvoMab Q2W
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Evolocumab (Biological)
R40 EvoMab Q2W
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Rosuvastatin (Drug)
R40 EvoMab QM
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
干预措施: Evolocumab (Biological)
R40 EvoMab QM
Participants received rosuvastatin 40 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
干预措施: Rosuvastatin (Drug)
S40 PBO Q2W
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
S40 PBO Q2W
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Simvastatin (Drug)
S40 PBO QM
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month for up to 12 weeks.
干预措施: Placebo to Evolocumab (Drug)
S40 PBO QM
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with placebo subcutaneous injection once every month for up to 12 weeks.
干预措施: Simvastatin (Drug)
S40 EvoMab Q2W
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Evolocumab (Biological)
S40 EvoMab Q2W
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with 140 mg evolocumab by subcutaneous injection once every 2 weeks for up to 12 weeks.
干预措施: Simvastatin (Drug)
S40 EvoMab QM
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
干预措施: Evolocumab (Biological)
S40 EvoMab QM
Participants received simvastatin 40 mg a day during the 4-week lipid stabilization period and then with 420 mg evolocumab by subcutaneous injection once a month for up to 12 weeks.
干预措施: Simvastatin (Drug)
结局指标
主要结局
Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12
时间窗: Baseline and Weeks 10 and 12
Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12
时间窗: Baseline and Week 12
次要结局
- Percent Change From Baseline in Non-HDL-C at Week 12(Baseline and Week 12)
- Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Change From Baseline in LDL-C at Week 12(Baseline and Week 12)
- Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12(Baseline and Week 12)
- Change From Baseline in LDL-C at at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Percent Change From Baseline in Apolipoprotein B at Week 12(Baseline and Week 12)
- Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12(Baseline and Week 12)
- Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Percentage of Participants Who Achieved a Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL(Weeks 10 and 12)
- Percentage of Participants Who Achieved LDL-C < 70 mg/dL at Week 12(Week 12)
- Percent Change From Baseline in Lipoprotein(a) at Week 12(Baseline and Week 12)
- Percent Change From Baseline in Triglycerides at Week 12(Baseline and Week 12)
- Percent Change From Baseline in Very Low-Density Cholesterol (VLDL-C) at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Percent Change From Baseline in Very Low-Density Cholesterol (VLDL-C) at Week 12(Baseline and Week 12)
- Percent Change From Baseline in HDL-C at Week 12(Baseline and Week 12)