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

Study Overview
=================
Brief Summary
-----------------
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.

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

Official Title
-----------------
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

Conditions
-----------------
Hyperlipidemia

Intervention / Treatment
-----------------
* Biological: Evolocumab
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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: known microvascular or macrovascular disease HbA1c > 8.0% at screening 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evolocumab<br>Participants received one of 5 dose levels of evolocumab administered as multiple subcutaneous doses. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;|
| Placebo Comparator: Placebo<br>Participants received matching placebo dose regimens by subcutaneous injection. | Biological: Placebo<br>* Administered by subcutaneous injection<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AMG145, Multiple Dose, Statin, Ascending