Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-4

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 (SC) evolocumab compared with ezetimibe, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic adults unable to tolerate an effective dose of a statin.

Detailed Description
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After screening participants who met all inclusion/exclusion criteria were randomized with an allocation ratio of 2:2:1:1 into 4 groups: evolocumab (AMG 145) 420 mg administered by subcutaneous injection monthly and placebo pill daily; evolocumab 140 mg administered by subcutaneous injection every two weeks and placebo pill by mouth daily; placebo 420 mg administered by subcutaneous injection monthly and ezetimibe 10 mg pill daily; placebo 140 mg administered subcutaneous injection every two weeks and ezetimibe 10 mg pill daily. Randomization was stratified by screening LDL-C level and baseline statin use. Participants on low or atypical statin dose therapy must have been on a stable dose for at least 4 weeks prior to screening and throughout the blinded portion of the study; the dose could not be adjusted during screening and for the duration of the study. After Week 12, ezetimibe was discontinued and participants moved to an open-label dose of evolocumab administered by subcutaneous injection either every two weeks or monthly and their standard of care.

Official Title
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A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of Evolocumab, Compared With Ezetimibe, in Hypercholesterolemic Japanese Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Biological: Evolocumab
* Drug: Ezetimibe
* Drug: Placebo to Evolocumab
* Drug: Placebo Ezetimibe


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 20 to ≤ 80 years of age Japanese by self-identification Not on a statin or on a low dose statin with stable dose for at least 4 weeks. Subject not at LDL-C goal History of statin intolerance to at least 2 statins Lipid lowering therapy has been stable prior to screening for at least 4 weeks Fasting triglycerides ≤ 400 mg/dL 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: 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 |
| --- | --- |
| Active Comparator: Ezetimibe (Q2W)<br>Participants received placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 140 mg subcutaneously once every 2 weeks until week 48. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Ezetimibe<br>* Tablet for oral administration<br>* Other names: Zetia;Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>|
| Active Comparator: Ezetimibe (QM)<br>Participants received placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 420 mg subcutaneously once a month until week 48. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Ezetimibe<br>* Tablet for oral administration<br>* Other names: Zetia;Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>|
| Experimental: Evolocumab Q2W<br>Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks and placebo tablets once a day for 12 weeks. From week 12 participants received open-label evolocumab 140 mg subcutaneously once every 2 weeks until week 48. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Placebo Ezetimibe<br>* Tablet for oral administration<br>|
| Experimental: Evolocumab QM<br>Participants received 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for 12 weeks. From week 12 participants received open-label evolocumab 420 mg subcutaneously once a month until week 48. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Placebo Ezetimibe<br>* Tablet for oral administration<br>|

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 | For all efficacy endpoints the two dosing regimens (every 2 weeks and every month) for each treatment were pooled for analysis. | 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 | 
| Percentage of Participants Who Achieved a Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL | Mean low density lipoprotein-cholesterol response was defined as LDL-C < 70 mg/dL [1.8 mol/L]. | Weeks 10 and 12 | 
| Percentage of Participants Who Achieved a LDL-C of Less Than 70 mg/dL at Week 12 |  | 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 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 A-1 Ratio at the Mean of Weeks 10 and 12 |  | Baseline and weeks 10 and 12 | 
| Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A-1 Ratio at Week 12 |  | Baseline and 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, Treatment of high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia, Statin intolerant