Durable Effect of PCSK9 Antibody CompARed wiTh placEbo Study

Study Overview
=================
Brief Summary
-----------------
To evaluate the efficacy, safety, and tolerability of 52 weeks of subcutaneous (SC) evolocumab (AMG 145) compared with placebo when added to assigned background lipid-lowering therapy.

Detailed Description
-----------------
Eligible participants with screening central laboratory low-density lipoprotein cholesterol (LDL-C) values ≥ 75 mg/dL (1.9 mmol/L) were instructed to follow National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP) Therapeutic Lifestyle Changes (TLC) diet and were assigned to 1 of the following 4 background lipid-lowering therapies for a 4-week stabilization period based upon their screening LDL-C and its distance from the individual's required goal as stipulated by their NCEP ATP III risk category: no drug therapy required - diet alone low dose drug therapy required - diet plus atorvastatin 10 mg orally (PO) once daily (QD) high dose drug therapy required - diet plus atorvastatin 80 mg PO QD maximal drug therapy required - diet plus atorvastatin 80 mg PO QD plus ezetimibe 10 mg PO QD. If the participant met entry criteria at the end of the lipid stabilization period they were randomized 2:1 to receive evolocumab 420 mg or placebo subcutaneously once a month for 52 weeks in addition to their background therapy.

Official Title
-----------------
A Double-Blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Long-Term Tolerability and Durable Efficacy of AMG 145 (Evolocumab) on LDL-C in Hyperlipidemic Subjects

Conditions
-----------------
Hypercholesterolemia

Intervention / Treatment
-----------------
* Biological: Evolocumab
* Biological: Placebo
* Drug: Atorvastatin
* Drug: Ezetimibe
* Other: Diet Only


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject has provided informed consent. Fasting LDL-C ≥ 75 mg/dL and meeting the following LDL-C values on background lipid-lowering therapy: < 100 mg/dL for subjects with diagnosed coronary heart disease (CHD) or CHD risk equivalent < 130 mg/dL for subjects without diagnosed CHD or CHD risk equivalent OR on maximal background lipid-lowering therapy defined as atorvastatin 80 mg PO QD and ezetimibe 10 mg PO QD Fasting triglycerides ≤ 400 mg/dL Exclusion Criteria: New York Heart Association (NYHA) II-IV heart failure, or last known left ventricular ejection fraction < 30% Uncontrolled cardiac arrhythmia Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization, type 1 diabetes, newly diagnosed or poorly controlled type 2 diabetes Uncontrolled hypertension

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evolocumab<br>Participants received evolocumab 420 mg subcutaneously once a month for 52 weeks in addition to background lipid-lowering therapy. | Biological: Evolocumab<br>* Administered by subcutaneous injection once a month<br>* Other names: Repatha;Drug: Atorvastatin<br>* Background lipid lowering therapy: 10 mg or 80 mg atorvastatin orally once daily.<br>Drug: Ezetimibe<br>* Background lipid lowering therapy: ezetimibe 10 mg orally once a day<br>Other: Diet Only<br>* Diet only, no lipid lowering background drug given<br>|
| Placebo Comparator: Placebo<br>Participants received placebo subcutaneously once a month for 52 weeks in addition to background lipid-lowering therapy. | Biological: Placebo<br>* Administered by subcutaneous injection once a month<br>Drug: Atorvastatin<br>* Background lipid lowering therapy: 10 mg or 80 mg atorvastatin orally once daily.<br>Drug: Ezetimibe<br>* Background lipid lowering therapy: ezetimibe 10 mg orally once a day<br>Other: Diet Only<br>* Diet only, no lipid lowering background drug given<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in LDL-C at Week 52 | Cholesterol was measured by means of ultracentrifugation. | Baseline and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in LDL-C at Week 52 | Cholesterol was measured by means of ultracentrifugation. | Baseline and Week 52 | 
| Percentage of Participants With an LDL-C Response at Week 52 | An LDL-C response is defined as LDL-C level < 70 mg/dL (1.8 mmol/L) at Week 52. | Week 52 | 
| Percent Change From Baseline in LDL-C at Week 12 | Cholesterol was measured by means of ultracentrifugation. | Baseline and Week 12 | 
| Percent Change From Baseline in Total Cholesterol at Week 12 |  | Baseline and Week 12 | 
| Percent Change From Baseline in Total Cholesterol at Week 52 |  | Baseline and Week 52 | 
| Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at Week 52 |  | Baseline and Week 52 | 
| Percent Change From Baseline in Apolipoprotein B at Week 52 |  | Baseline and Week 52 | 
| Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 52 |  | Baseline and Week 52 | 
| Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 52 |  | Baseline and Week 52 | 
| Percent Change From Baseline in Lipoprotein(a) at Week 52 |  | Baseline and Week 52 | 
| Percent Change From Baseline in Triglycerides at Week 52 |  | Baseline and Week 52 | 
| Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 52 |  | Baseline and Week 52 | 
| Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 52 | Cholesterol was measured by means of ultracentrifugation. | Baseline and Week 52 | 
| Percent Change From Week 12 to Week 52 in LDL-C | Cholesterol was measured by means of ultracentrifugation. | Week 12 and Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cholesterol, High Cholesterol, Elevated Cholesterol, Raised Cholesterol