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

Phase 3

Completed

• Conditions: Hyperlipidemia
• Interventions: Biological: Evolocumab; Drug: Ezetimibe; Drug: Placebo to Ezetimibe; Drug: Placebo to Evolocumab; Drug: Rosuvastatin; Drug: Simvastatin; Drug: Atorvastatin

• Registration Number: NCT01763866
• Lead Sponsor: Amgen

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2013-01-07
• Study First Submitted QC: 2013-01-08
• Study First Posted: 2013-01-09
• Study Start: 2013-01-15
• Primary Completion: 2013-11-12
• Study Completion: 2013-12-04
• Disposition First Submitted: 2014-05-02
• Disposition First Submitted QC: 2014-05-02
• Disposition First Posted: 2014-05-20
• Results First Submitted: 2015-09-01
• Results First Submitted QC: 2015-11-18
• Results First Posted: 2015-12-22
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-04
• Last Update Posted: 2022-11-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 2067

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)

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
A10 PBO QM	Placebo to Ezetimibe	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.
A10 EvoMab Q2W	Evolocumab	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.
A10 EZE (QM)	Placebo to Evolocumab	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.
A10 PBO QM	Placebo to Evolocumab	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.
A10 PBO Q2W	Placebo to Ezetimibe	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.
A80 EZE (Q2W)	Placebo to Evolocumab	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.
A10 EvoMab Q2W	Placebo to Ezetimibe	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.
A10 PBO Q2W	Placebo to Evolocumab	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.
A80 PBO Q2W	Placebo to Ezetimibe	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.
A80 EvoMab QM	Placebo to Ezetimibe	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.
A80 PBO QM	Placebo to Ezetimibe	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.
A10 EZE (Q2W)	Placebo to Evolocumab	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.
A10 EvoMab QM	Evolocumab	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
A10 EvoMab QM	Placebo to Ezetimibe	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
A80 PBO Q2W	Placebo to Evolocumab	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.
A80 EvoMab Q2W	Evolocumab	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.
R5 PBO Q2W	Placebo to Evolocumab	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.
R5 PBO QM	Placebo to Evolocumab	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.
R40 PBO Q2W	Placebo to Evolocumab	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.
R40 PBO QM	Placebo to Evolocumab	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.
A80 PBO QM	Placebo to Evolocumab	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.
A80 EZE (QM)	Placebo to Evolocumab	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.
A80 EvoMab Q2W	Placebo to Ezetimibe	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.
R5 EvoMab Q2W	Evolocumab	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.
R40 EvoMab Q2W	Evolocumab	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.
S40 PBO Q2W	Placebo to Evolocumab	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.
A80 EvoMab QM	Evolocumab	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.
R5 EvoMab QM	Evolocumab	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.
R40 EvoMab QM	Evolocumab	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.
S40 PBO QM	Placebo to Evolocumab	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.
S40 EvoMab Q2W	Evolocumab	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.
S40 EvoMab QM	Evolocumab	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.
A10 PBO Q2W	Atorvastatin	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.
A10 EZE (Q2W)	Ezetimibe	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.
A10 PBO QM	Atorvastatin	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.
A10 EZE (Q2W)	Atorvastatin	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.
A10 EZE (QM)	Ezetimibe	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.
A10 EZE (QM)	Atorvastatin	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.
A10 EvoMab Q2W	Atorvastatin	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.
A10 EvoMab QM	Atorvastatin	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
A80 PBO Q2W	Atorvastatin	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.
A80 PBO QM	Atorvastatin	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.
A80 EZE (Q2W)	Ezetimibe	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.
A80 EZE (QM)	Ezetimibe	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.
A80 EZE (Q2W)	Atorvastatin	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.
A80 EZE (QM)	Atorvastatin	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.
A80 EvoMab Q2W	Atorvastatin	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.
A80 EvoMab QM	Atorvastatin	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.
R5 PBO Q2W	Rosuvastatin	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.
R5 PBO QM	Rosuvastatin	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.
R5 EvoMab Q2W	Rosuvastatin	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.
R5 EvoMab QM	Rosuvastatin	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.
R40 PBO Q2W	Rosuvastatin	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.
R40 PBO QM	Rosuvastatin	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.
R40 EvoMab Q2W	Rosuvastatin	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.
S40 PBO Q2W	Simvastatin	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.
R40 EvoMab QM	Rosuvastatin	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.
S40 PBO QM	Simvastatin	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.
S40 EvoMab Q2W	Simvastatin	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.
S40 EvoMab QM	Simvastatin	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.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in 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

Name	Time	Method
Percent Change From Baseline in Non-HDL-C 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
Change From Baseline in LDL-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 the Total Cholesterol/HDL-C Ratio at Week 12	Baseline and Week 12
Change From Baseline in LDL-C at at the Mean of Weeks 10 and 12	Baseline and Weeks 10 and 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 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 Lipoprotein(a) 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
Percent Change From Baseline in Triglycerides 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 HDL-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 the Mean of Weeks 10 and 12	Baseline and Weeks 10 and 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 Week 12	Baseline and Week 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 Week 12	Baseline and Week 12

Trial Locations

Locations (1)

Research Site; 🇬🇧 Whitby, United Kingdom