Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3

Study Overview
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Brief Summary
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The primary objective of this study was to evaluate the effect of 24 weeks of evolocumab administered subcutaneously (SC) every month, compared with ezetimibe, on low-density lipoprotein cholesterol (LDL-C) levels in adults with high cholesterol who are unable to tolerate an effective dose of a statin due to muscle-related side effects (MRSE).

Detailed Description
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The study is divided into 3 parts (A, B, C). After an initial 4-week washout period in which any statins, ezetimibe, or other lipid-lowering agents were discontinued, participants were enrolled in phase A, a double-blind, placebo-controlled crossover procedure to rechallenge patients with atorvastatin. Patients were randomly assigned in a 1:1 ratio to receive either atorvastatin (20 mg daily) or matching placebo for the first 10 weeks (period 1), then underwent a 2-week washout period, followed by crossover to the alternate therapy for a second 10-week period (period 2). Patients who experienced intolerable muscle symptoms during the first period did not complete the full 10 weeks of exposure but entered a 2-week washout period before proceeding to period 2. Participants who did not develop muscle-related side effects were removed from the study, as were patients who reported muscle-related side effects during a placebo period. After completion of phase A, patients who experienced muscle-related adverse effects while taking atorvastatin but not placebo were eligible for phase B, a 24-week, double-blind randomization to ezetimibe or evolocumab using a double-dummy design in which patients received either injectable placebo and oral ezetimibe or injectable evolocumab and oral placebo. A patient could proceed directly to phase B if they had a documented history of creatine kinase (CK) elevation more than 10 times the upper limit of normal accompanied by muscle symptoms while taking statin therapy, with documented resolution of both CK elevation and symptoms upon discontinuation of statin therapy. These study procedures were designed to ensure that only patients with reproducible statin-associated muscle symptoms entered phase B of the study. For phase B, participants were randomized 2:1 to receive subcutaneously administered evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Randomization in part B was stratified by screening LDL-C level (< 180 mg/dL [4.66 mmol/L] vs. ≥ 180 mg/dL) at study baseline. Participants who completed phase B and did not discontinue SC investigational product for any reason, including an adverse event, were eligible to proceed to the 2-year open-label extension phase C to evaluate the long-term safety and efficacy of evolocumab in statin-intolerant patients. Participants in phase C were allowed to choose quarterly between evolocumab 420 mg SC QM or evolocumab 140 mg SC every 2 weeks (Q2W).

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 Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects

Conditions
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Hyperlipidemia

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 18 to ≤ 80 years of age Subject not at LDL-C goal History of statin intolerance Lipid lowering therapy has been stable prior to enrolment 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: 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 |
| --- | --- |
| Other: Part A: Atorvastatin 20 mg => Placebo<br>Participants received atorvastatin 20 mg orally for 10 weeks (period 1) followed by placebo orally for 10 weeks (period 2), separated by a 2-week washout period. | Drug: Atorvastatin<br>* Atorvastatin was supplied as over-encapsulated 20 mg tablets<br>* Other names: Lipitor;Drug: Placebo to Atorvastatin<br>* Placebo matching to atorvastatin supplied as over-encapsulated tablets<br>|
| Other: Part A: Placebo => Atorvastatin 20 mg<br>Participants received placebo orally for 10 weeks (period 1) followed by atorvastatin 20 mg orally for 10 weeks (period 2), separated by a 2-week washout period. | Drug: Atorvastatin<br>* Atorvastatin was supplied as over-encapsulated 20 mg tablets<br>* Other names: Lipitor;Drug: Placebo to Atorvastatin<br>* Placebo matching to atorvastatin supplied as over-encapsulated tablets<br>|
| Active Comparator: Part B: Ezetimibe<br>Participants received 10 mg ezetimibe orally only a day and placebo to evolocumab by subcutaneous injection once a month for 24 weeks. | Drug: Ezetimibe<br>* Ezetimibe was supplied as 10 mg tablets, over-encapsulated for blinding.<br>* Other names: Zetia;Other: Placebo to Evolocumab<br>* Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s)<br>|
| Experimental: Part B: Evolocumab<br>Participants received 420 mg evolocumab by subcutaneous injection once a month and placebo to ezetimibe orally once a day for 24 weeks. | Other: Placebo to Ezetimibe<br>* Placebo matching to Ezetimibe supplied as over-encapsulated tablets.<br>Drug: Evolocumab<br>* Evolocumab supplied as single-use prefilled autoinjector/pen(s)<br>* Other names: Repatha;|
| Experimental: Part C: Open-label Evolocumab<br>Participants who completed part B and were eligible to proceed to open-label extension part C and could choose quarterly between evolocumab 420 mg once a month or evolocumab 140 mg every 2 weeks for up to 2 years. | Drug: Evolocumab<br>* Evolocumab supplied as single-use prefilled autoinjector/pen(s)<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 LDL-C at the Mean of Weeks 22 and 24 |  | Baseline and weeks 22 and 24 | 
| Percent Change From Baseline in LDL-C at Week 24 |  | Baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 |  | Baselie and weeks 22 and 24 | 
| Change From Baseline in LDL-C at Week 24 |  | Baseline and week 24 | 
| Percentage of Participants Who Achieved a Mean LDL-C at Weeks 22 and 24 of Less Than 70 mg/dL |  | Weeks 22 and 24 | 
| Percentage of Participants Who Achieved LDL-C at Week 24 of Less Than 70 mg/dL |  | Week 24 | 
| Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24 |  | Baseline and weeks 22 and 24 | 
| Percent Change From Baseline in Total Cholesterol at Week 24 |  | Baseline and week 24 | 
| Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 22 and 24 |  | Baseline and weeks 22 and 24 | 
| Percent Change From Baseline in Non-HDL-C at Week 24 |  | Baseline and week 24 | 
| Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24 |  | Baseline and weeks 22 and 24 | 
| Percent Change From Baseline in Apolipoprotein B at Week 24 |  | Baseline and week 24 | 
| Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24 |  | Baseline and weeks 22 and 24 | 
| Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24 |  | Baseline and week 24 | 
| Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24 |  | Baseline and Weeks 22 and 24 | 
| Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 |  | Baseline and week 24 | 
| Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24 |  | Baseline and Weeks 22 and 24 | 
| Percent Change From Baseline in Lipoprotein(a) at Week 24 |  | Baseline and week 24 | 
| Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24 |  | Baseline and weeks 22 and 24 | 
| Percent Change From Baseline in Triglycerides at Week 24 |  | Baseline and week 24 | 
| Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 24 |  | Baseline and weeks 22 and 24 | 
| Percent Change From Baseline in HDL-C at Week 24 |  | Baseline and week 24 | 
| Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at the Mean of Weeks 22 and 24 |  | Baseline and weeks 22 and 24 | 
| Percent Change From Baseline in VLDL-C at Week 24 |  | Baseline and week 24 | 

 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