Ascending Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Evolocumab (AMG 145) in Adults With Hyperlipidemia on Stable Doses of a Statin

Amgen

Status and phase: Completed; Phase 1

Conditions: Hyperlipidemia

Treatments: Biological: Evolocumab; Biological: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT01133522

20080398

Details and patient eligibility

About

The purpose of the study is to evaluate the safety and tolerability of multiple doses of evolocumab when given as an add-on to stable statin therapy.

Full description

Participants receiving low-to-moderate-dose statins were randomized in a 1:3 ratio to receive subcutaneous placebo or evolocumab and enrolled sequentially into one of 5 dose-escalation cohorts:

1. Evolocumab 14 mg/placebo once weekly (QW) × 6 doses
2. Evolocumab 35 mg/placebo once weekly (QW) × 6 doses
3. Evolocumab 140 mg/placebo every 2 weeks (Q2W) × 3 doses
4. Evolocumab 280 mg/placebo every 2 weeks (Q2W) × 3 doses
5. Evolocumab 420 mg/placebo every 4 weeks (Q2W) × 2 doses.

Participants receiving high-dose statins were randomized 1:3 to receive subcutaneous placebo or evolocumab 140 mg every 2 weeks × 3 doses (Cohort 6).

Participants diagnosed with familial hypercholesterolemia (HeFH) were randomized 1:2 to receive subcutaneous placebo or evolocumab 140 mg every 2 weeks × 3 doses (Cohort 7).

Enrollment: 60 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Men and women ages 18 to 70 years (inclusive) at the time of screening with hyperlipidemia
• Body mass index (BMI) ≥18 and ≤ 35 kg/m^2 at the time of screening
• Low-density lipoprotein cholesterol (LDL-C) level of 70-220 mg/dL (inclusive) at screening as measured by direct assay
• For Cohorts 1-5: On a stable dose of rosuvastatin (Crestor) < 40 mg/day, atorvastatin (Lipitor) < 80 mg/day, or simvastatin (Zocor) 20-80 mg/day for ≥ 1 month prior to enrollment and expected to remain on this dose for the remainder of the study
• For Cohort 6: On a stable dose of rosuvastatin (Crestor) 40 mg/day or atorvastatin (Lipitor) 80 mg/day for ≥ 1 month prior to enrollment and expected to remain on this dose for the remainder of the study
• For Cohort 7: Diagnosis of heterozygous familial hypercholesterolemia, based on a score of ≥ 9 points using the World health Organization (WHO) criteria

Exclusion criteria

• Diagnosis of homozygous familial hypercholesterolemia

• History of heart failure, coronary artery bypass graft, or cardiac arrhythmia

• History of acute coronary syndrome (e.g. myocardial infarction, hospitalization for unstable angina) or percutaneous coronary intervention, within 12 months prior to enrollment

• Planned cardiac surgery or revascularization

• Known aortic, peripheral vascular or cerebrovascular disease (including history of stroke or transient ischemic attack)

• Diabetes mellitus with any of the following:

  1. known microvascular or macrovascular disease
  2. HbA1c > 8.0% at screening
  3. use of any hypoglycemic medication other than metformin

• Uncontrolled hypertension (systolic blood pressure ≥ 150 or diastolic blood pressure ≥ 90 mmHg) either on or off therapy at screening or at baseline

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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60 participants in 2 patient groups, including a placebo group

Evolocumab

Experimental group

Description:

Participants received one of 5 dose levels of evolocumab administered as multiple subcutaneous doses.

Treatment:

Biological: Evolocumab

Placebo

Placebo Comparator group

Description:

Participants received matching placebo dose regimens by subcutaneous injection.

Treatment:

Biological: Placebo