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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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Amgen
ClinicalTrials.gov Identifier:
NCT01133522
First received: May 27, 2010
Last updated: September 23, 2015
Last verified: September 2015

May 27, 2010
September 23, 2015
June 2010
September 2011   (final data collection date for primary outcome measure)
  • Number of Participants With Adverse Events [ Time Frame: From the first dose of study drug until Day 85 ] [ Designated as safety issue: Yes ]

    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 ] [ Designated as safety issue: Yes ]
    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
The subject incidence of treatment-emergent adverse events and incidence of binding and neutralizing antibodies to AMG 145 as well as changes in vital signs, clinical laboratory safety tests, and electrocardiograms (ECGs). [ Time Frame: Including a 35-day screening period, the maximum subject participation is 122 days. ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01133522 on ClinicalTrials.gov Archive Site
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
    Serum PCSK9 concentrations were determined by using a qualified enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 15 ng/mL.
  • PK (pharmacokinetics) concentrations as well as derived PK parameters of unbound AMG 145 [ Time Frame: Including a 35-day screening period, the maximum subject participation is 122 days. ] [ Designated as safety issue: No ]
  • Ratio to baseline and unadjusted LDL-C and PCSK9 (proprotein convertase subtilisin/kexin type 9) [ Time Frame: Including a 35-day screening period, the maximum subject participation is 122 days. ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
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.

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).

Interventional
Phase 1
Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Hyperlipidemia
  • Biological: Evolocumab
    Administered by subcutaneous injection
    Other Names:
    • AMG 145
    • Repatha
  • Biological: Placebo
    Administered by subcutaneous injection
  • Experimental: Evolocumab
    Participants received one of 5 dose levels of evolocumab administered as multiple subcutaneous doses.
    Intervention: Biological: Evolocumab
  • Placebo Comparator: Placebo
    Participants received matching placebo dose regimens by subcutaneous injection.
    Intervention: Biological: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
60
September 2011
September 2011   (final data collection date for primary outcome measure)

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
Both
18 Years to 70 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
United States
 
NCT01133522
20080398
No
Not Provided
Not Provided
Amgen
Amgen
Not Provided
Study Director: MD Amgen
Amgen
September 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP