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

Amgen

Status and phase: Completed; Phase 3

Conditions: Hyperlipidemia

Treatments: Biological: Evolocumab; Drug: Ezetimibe; Drug: Placebo to Evolocumab; Drug: Placebo to Ezetimibe; Drug: Atorvastatin; Drug: Simvastatin; Drug: Rosuvastatin

Study type: Interventional

Funder types: Industry

Identifiers

NCT01763866

20110115

2012-001363-70 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 2,067 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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2,067 participants in 24 patient groups, including a placebo group

A10 PBO Q2W

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Atorvastatin

Drug: Placebo to Ezetimibe

A10 PBO QM

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Atorvastatin

Drug: Placebo to Ezetimibe

A10 EZE (Q2W)

Active Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Atorvastatin

Drug: Ezetimibe

A10 EZE (QM)

Active Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Atorvastatin

Drug: Ezetimibe

A10 EvoMab Q2W

Experimental group

Description:

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.

Treatment:

Drug: Atorvastatin

Biological: Evolocumab

Drug: Placebo to Ezetimibe

A10 EvoMab QM

Experimental group

Description:

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

Treatment:

Drug: Atorvastatin

Biological: Evolocumab

Drug: Placebo to Ezetimibe

A80 PBO Q2W

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Atorvastatin

Drug: Placebo to Ezetimibe

A80 PBO QM

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Atorvastatin

Drug: Placebo to Ezetimibe

A80 EZE (Q2W)

Active Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Atorvastatin

Drug: Ezetimibe

A80 EZE (QM)

Active Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Atorvastatin

Drug: Ezetimibe

A80 EvoMab Q2W

Experimental group

Description:

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.

Treatment:

Drug: Atorvastatin

Biological: Evolocumab

Drug: Placebo to Ezetimibe

A80 EvoMab QM

Experimental group

Description:

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.

Treatment:

Drug: Atorvastatin

Biological: Evolocumab

Drug: Placebo to Ezetimibe

R5 PBO Q2W

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Rosuvastatin

R5 PBO QM

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Rosuvastatin

R5 EvoMab Q2W

Experimental group

Description:

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.

Treatment:

Drug: Rosuvastatin

Biological: Evolocumab

R5 EvoMab QM

Experimental group

Description:

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.

Treatment:

Drug: Rosuvastatin

Biological: Evolocumab

R40 PBO Q2W

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Rosuvastatin

R40 PBO QM

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Rosuvastatin

R40 EvoMab Q2W

Experimental group

Description:

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.

Treatment:

Drug: Rosuvastatin

Biological: Evolocumab

R40 EvoMab QM

Experimental group

Description:

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.

Treatment:

Drug: Rosuvastatin

Biological: Evolocumab

S40 PBO Q2W

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Simvastatin

S40 PBO QM

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo to Evolocumab

Drug: Simvastatin

S40 EvoMab Q2W

Experimental group

Description:

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.

Treatment:

Drug: Simvastatin

Biological: Evolocumab

S40 EvoMab QM

Experimental group

Description:

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.

Treatment:

Drug: Simvastatin

Biological: Evolocumab