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

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Ascending Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 145 in Subjects With Hyperlipidemia on Stable Doses of a Statin

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.

Study Overview

• Status: Completed
• Conditions: Hyperlipidemia
• Intervention / Treatment: Biological: Evolocumab; Biological: Placebo

Detailed 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).

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Evolocumab; Participants received one of 5 dose levels of evolocumab administered as multiple subcutaneous doses.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: Repatha; AMG 145
PLACEBO_COMPARATOR: Placebo; Participants received matching placebo dose regimens by subcutaneous injection.	Biological: Placebo; Administered by subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	The relationship of each adverse event to the investigational product was assessed by the investigator. A serious adverse event (SAE) is defined as an adverse event that; is fatal; is life threatening (places the subject at immediate risk of death); requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; other significant medical hazard.	From the first dose of study drug until Day 85
Number of Participants With Anti-Evolocumab Antibodies	Serum samples were analyzed by an electrochemiluminescence (ECL)-based immunoassay for anti-evolocumab binding antibodies. Positive samples were subsequently tested in a receptor-ligand binding bioassay for anti-evolocumab neutralizing antibodies	From the first dose of study drug until Day 85

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Evolocumab	Serum concentrations of evolocumab were measured by a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 800 ng/mL.	Day 1, predose and Days 4, 8, 15, 22, 29, 36, 40, 43, 50, 57, 64, 71, 78, and 85
Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab	Area under the unbound evolocumab serum concentration-time curve from time of last dose to time of last quantifiable concentration following the last dose of evolocumab.	Day 29 predose (last dose for Cohorts 3-7) and Days 36 (predose for Cohorts 1 and 2), 40, 43, 50, 57, 64, 71, 78, and 85
Percent Change From Baseline to End of the Dosing Interval in LDL-C		Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group
Percent Change From Baseline to End of the Dosing Interval in PCSK9	Serum PCSK9 concentrations were determined by using a qualified enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 15 ng/mL.	Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B, Stolman DS, Crispino CP, Smirnakis KV, Emery MG, Colbert A, Gibbs JP, Retter MW, Cooke BP, Uy ST, Matson M, Stein EA. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012 Nov 6;60(19):1888-98. doi: 10.1016/j.jacc.2012.08.986. Epub 2012 Oct 17.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2010
• Primary Completion (ACTUAL): September 14, 2011
• Study Completion (ACTUAL): September 14, 2011

Study Registration Dates

• First Submitted: May 27, 2010
• First Submitted That Met QC Criteria: May 27, 2010
• First Posted (ESTIMATE): May 31, 2010

Study Record Updates

• Last Update Posted (ACTUAL): November 2, 2018
• Last Update Submitted That Met QC Criteria: November 1, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Statin; Multiple Dose; Ascending; AMG145
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: 20080398