LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-2

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hyperlipidemia

Intervention / Treatment
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* Biological: Evolocumab
* Drug: Ezetimibe
* Drug: Placebo to Evolocumab
* Drug: Placebo to Ezetimibe
* Drug: Atorvastatin
* Drug: Rosuvastatin
* Drug: Simvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: A10 PBO Q2W<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Placebo to Ezetimibe<br>* Administered orally once a day<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Placebo Comparator: A10 PBO QM<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Placebo to Ezetimibe<br>* Administered orally once a day<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Active Comparator: A10 EZE (Q2W)<br>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. | Drug: Ezetimibe<br>* Administered orally once a day<br>* Other names: Zetia;Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Active Comparator: A10 EZE (QM)<br>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. | Drug: Ezetimibe<br>* Administered orally once a day<br>* Other names: Zetia;Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Experimental: A10 EvoMab Q2W<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Placebo to Ezetimibe<br>* Administered orally once a day<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Experimental: A10 EvoMab QM<br>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 | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Placebo to Ezetimibe<br>* Administered orally once a day<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Placebo Comparator: A80 PBO Q2W<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Placebo to Ezetimibe<br>* Administered orally once a day<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Placebo Comparator: A80 PBO QM<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Placebo to Ezetimibe<br>* Administered orally once a day<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Active Comparator: A80 EZE (Q2W)<br>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. | Drug: Ezetimibe<br>* Administered orally once a day<br>* Other names: Zetia;Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Active Comparator: A80 EZE (QM)<br>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. | Drug: Ezetimibe<br>* Administered orally once a day<br>* Other names: Zetia;Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Experimental: A80 EvoMab Q2W<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Placebo to Ezetimibe<br>* Administered orally once a day<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Experimental: A80 EvoMab QM<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Placebo to Ezetimibe<br>* Administered orally once a day<br>Drug: Atorvastatin<br>* Administered orally once a day<br>* Other names: Lipitor;|
| Placebo Comparator: R5 PBO Q2W<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Rosuvastatin<br>* Administered orally once a day<br>* Other names: Crestor;|
| Placebo Comparator: R5 PBO QM<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Rosuvastatin<br>* Administered orally once a day<br>* Other names: Crestor;|
| Experimental: R5 EvoMab Q2W<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Rosuvastatin<br>* Administered orally once a day<br>* Other names: Crestor;|
| Experimental: R5 EvoMab QM<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Rosuvastatin<br>* Administered orally once a day<br>* Other names: Crestor;|
| Placebo Comparator: R40 PBO Q2W<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Rosuvastatin<br>* Administered orally once a day<br>* Other names: Crestor;|
| Placebo Comparator: R40 PBO QM<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Rosuvastatin<br>* Administered orally once a day<br>* Other names: Crestor;|
| Experimental: R40 EvoMab Q2W<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Rosuvastatin<br>* Administered orally once a day<br>* Other names: Crestor;|
| Experimental: R40 EvoMab QM<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Rosuvastatin<br>* Administered orally once a day<br>* Other names: Crestor;|
| Placebo Comparator: S40 PBO Q2W<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Simvastatin<br>* Administered orally once a day<br>* Other names: Zocor;|
| Placebo Comparator: S40 PBO QM<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Simvastatin<br>* Administered orally once a day<br>* Other names: Zocor;|
| Experimental: S40 EvoMab Q2W<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Simvastatin<br>* Administered orally once a day<br>* Other names: Zocor;|
| Experimental: S40 EvoMab QM<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Simvastatin<br>* Administered orally once a day<br>* Other names: Zocor;|

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 Week 12 |  | Baseline and Week 12 | 
| Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12 |  | Baseline and Weeks 10 and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in LDL-C at 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-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 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 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 A1 Ratio at the Mean of Weeks 10 and 12 |  | Baseline and Weeks 10 and 12 | 
| Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 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 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 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High cholesterol, Treatment for high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia