Study of Low-Density Lipoprotein Cholesterol (LDL-C) Reduction Using Evolocumab (AMG 145) in Japanese Patients With Advanced Cardiovascular Risk

Study Overview
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Brief Summary
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The primary objective of the study was to evaluate the effect of 12 weeks of subcutaneous evolocumab administered every 2 weeks and once a month, compared with placebo, on percent change from baseline in LDL-C when used in combination with statin therapy in adults with high cardiovascular risk and with hyperlipidemia or mixed dyslipidemia.

Detailed Description
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After a screening and placebo run-in period, eligible patients were randomized in a 1:1 ratio to 1 of 2 open-label background statin treatments (atorvastatin 5 mg or 20 mg daily [QD]) and entered a 4-week lipid stabilization period. After the lipid stabilization period, eligible patients were randomized in a 1:1:1:1 ratio to investigational product (evolocumab or placebo) for the 12-week treatment period. Both randomizations were stratified by subject diagnosis and lipid-lowering therapy as follows: current or prior diagnosis of heterozygous familial hypercholesterolemia (HeFH) no diagnosis of HeFH and receiving intensive lipid-lowering therapy no diagnosis of HeFH and receiving non-intensive lipid-lowering therapy. A participant was considered randomized into the study after successfully completing the screening period, meeting all inclusion/exclusion criteria including meeting final laboratory safety criteria, and undergoing both randomization procedures.

Official Title
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A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of Evolocumab (AMG 145) on LDL-C in Combination With Statin Therapy in Japanese Subjects With High Cardiovascular Risk and With Hyperlipidemia or Mixed Dyslipidemia

Conditions
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Hyperlipidemia or Mixed Dyslipidemia at High Risk for Cardiovascular Events

Intervention / Treatment
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* Drug: Atorvastatin
* Biological: Evolocumab
* Other: Placebo to Evolocumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, Japanese adult, 20-85 years of age; Subjects on stable dose of statin for greater than equal to 4 weeks; Fasting LDL-C greater than equal to 100 mg/dL; Fasting triglycerides less than equal to 400 mg/dL; Subject is at high risk for cardiovascular events. Exclusion Criteria: New York heart Association (NYHA) III or IV - heart failure; Uncontrolled cardiac arrhythmia; Uncontrolled hypertension; Type 1 diabetes, poorly controlled type 2 diabetes; Uncontrolled hypothyroidism or hyperthyroidism

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: A5 Placebo Q2W<br>Participants received atorvastatin 5 mg (A5) once daily during the 4 week lipid stabilization period and then in combination with placebo subcutaneous injection once every 2 weeks (Q2W) for 12 weeks. | Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;Other: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>|
| Placebo Comparator: A5 Placebo QM<br>Participants received atorvastatin 5 mg a day during the 4-week lipid stabilization period and then in combination with placebo subcutaneous injection once every month (QM) for 12 weeks. | Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;Other: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>|
| Experimental: A5 Evolocumab Q2W<br>Participants received atorvastatin 5 mg a day during the 4-week lipid stabilization period and then in combination with 140 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks. | Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;|
| Experimental: A5 Evolocumab QM<br>Participants received atorvastatin 5 mg a day during the 4-week lipid stabilization period and then in combination with 420 mg evolocumab by subcutaneous injection once a month for 12 weeks. | Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;|
| Placebo Comparator: A20 Placebo Q2W<br>Participants received atorvastatin 20 mg (A20) once daily during the 4 week lipid stabilization period and then in combination with placebo subcutaneous injection once every 2 weeks for 12 weeks. | Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;Other: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>|
| Other: A20 Placebo QM<br>Participants received atorvastatin 20 mg a day during the 4-week lipid stabilization period and then in combination with placebo subcutaneous injection once every month for 12 weeks. | Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;Other: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>|
| Experimental: A20 Evolocumab Q2W<br>Participants received atorvastatin 20 mg a day during the 4-week lipid stabilization period and then in combination with 140 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks. | Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;|
| Experimental: A20 Evolocumab QM<br>Participants received atorvastatin 20 mg a day during the 4-week lipid stabilization period and then in combination with 420 mg evolocumab by subcutaneous injection once a month for 12 weeks. | Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at the Mean of Weeks 10 and 12 |  | Baseline and Weeks 10 and 12 | 
| Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 |  | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in LDL-C 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 Non-HDL-C at the Mean of Weeks 10 and 12 |  | Baseline and Weeks 10 and 12 | 
| Percent Change From Baseline in Non-HDL-C at Week 12 |  | Baseline and Week 12 | 
| Percent Change From Baseline in Apolipoprotein B 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 Total Cholesterol at the Mean of Weeks 10 and 12 |  | Baseline and Weeks 10 and 12 | 
| Percent Change From Baseline in Total Cholesterol at Week 12 |  | Baseline and Week 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 the Total Cholesterol/HDL-C Ratio at Week 12 |  | Baseline and Week 12 | 
| Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A-1 Ratio at the Mean of Weeks 10 and 12 |  | Baseline and Weeks 10 and 12 | 
| Percent Change From Baseline in the Apolipoprotein B/Apolipoprotein A-1 Ratio at Week 12 |  | Baseline and Week 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 the Mean of Weeks 10 and 12 |  | Baseline and Weeks 10 and 12 | 
| Percent Change From Baseline in Lipoprotein(a) 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 Triglycerides at Week 12 |  | Baseline and Week 12 | 
| Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12 |  | Baseline and Weeks 10 and 12 | 
| Percent Change From Baseline in HDL-C at Week 12 |  | Baseline and Week 12 | 
| Percent Change From Baseline in VLDL-C at the Mean of Weeks 10 and 12 |  | Baseline and Weeks 10 and 12 | 
| Percent Change From Baseline in VLDL-C at Week 12 |  | Baseline and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Japanese, high cholesterol, LDL-C, High Cardiovascular Risk