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 Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|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|
- Number of Participants With Adverse Events [ Time Frame: From the first dose of study drug until Day 85 ]
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.
- Number of Participants With Anti-Evolocumab Antibodies [ Time Frame: From the first dose of study drug until Day 85 ]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
- Maximum Observed Plasma Concentration (Cmax) of Evolocumab [ Time Frame: Day 1, predose and Days 4, 8, 15, 22, 29, 36, 40, 43, 50, 57, 64, 71, 78, and 85 ]Serum concentrations of evolocumab were measured by a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 800 ng/mL.
- Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab [ Time Frame: 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 ]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.
- Percent Change From Baseline to End of the Dosing Interval in LDL-C [ Time Frame: 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 [ Time Frame: Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group ]Serum PCSK9 concentrations were determined by using a qualified enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 15 ng/mL.
|Study Start Date:||June 2010|
|Study Completion Date:||September 2011|
|Primary Completion Date:||September 2011 (Final data collection date for primary outcome measure)|
Participants received one of 5 dose levels of evolocumab administered as multiple subcutaneous doses.
Administered by subcutaneous injection
Placebo Comparator: Placebo
Participants received matching placebo dose regimens by subcutaneous injection.
Administered by subcutaneous injection
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).
Please refer to this study by its ClinicalTrials.gov identifier: NCT01133522