Clinical trial NCT01133522: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hyperlipidemia
Keywords: AMG145
Multiple Dose
Statin
Ascending
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2010-05-31
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

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).

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:

  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

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: From the first dose of study drug until Day 85
measure: Number of Participants With Anti-Evolocumab Antibodies
timeFrame: From the first dose of study drug until Day 85
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Evolocumab
timeFrame: Day 1, predose and Days 4, 8, 15, 22, 29, 36, 40, 43, 50, 57, 64, 71, 78, and 85
measure: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab
timeFrame: 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
measure: Percent Change From Baseline to End of the Dosing Interval in LDL-C
timeFrame: Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group
measure: Percent Change From Baseline to End of the Dosing Interval in PCSK9
timeFrame: Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group
Other outcomes:
Locations:
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.