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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

Primary Purpose

Hyperlipidemia

Status

Completed

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

Evolocumab

Placebo

About this trial

This is an interventional treatment trial for Hyperlipidemia focused on measuring AMG145, Multiple Dose, Statin, Ascending

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Evolocumab

Placebo

Arm Description

Participants received one of 5 dose levels of evolocumab administered as multiple subcutaneous doses.

Participants received matching placebo dose regimens by subcutaneous injection.

Outcomes

Primary Outcome Measures

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.

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

Secondary Outcome Measures

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.

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.

Percent Change From Baseline to End of the Dosing Interval in LDL-C

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.

Full Information

NCT ID

NCT01133522

First Posted

May 27, 2010

Last Updated

November 1, 2018

Sponsor

Amgen

1. Study Identification

Unique Protocol Identification Number

NCT01133522

Brief Title

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

2. Study Status

Record Verification Date

November 2018

Overall Recruitment Status

Completed

Study Start Date

June 1, 2010 (Actual)

Primary Completion Date

September 14, 2011 (Actual)

Study Completion Date

September 14, 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Amgen

4. Oversight

Data Monitoring Committee

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hyperlipidemia

Keywords

AMG145, Multiple Dose, Statin, Ascending

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

60 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Evolocumab

Arm Type

Experimental

Arm Description

Participants received one of 5 dose levels of evolocumab administered as multiple subcutaneous doses.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants received matching placebo dose regimens by subcutaneous injection.

Intervention Type

Biological

Intervention Name(s)

Evolocumab

Other Intervention Name(s)

AMG 145, Repatha

Intervention Description

Administered by subcutaneous injection

Intervention Type

Biological

Intervention Name(s)

Placebo

Intervention Description

Administered by subcutaneous injection

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events

Description

Time Frame

From the first dose of study drug until Day 85

Title

Number of Participants With Anti-Evolocumab Antibodies

Description

Time Frame

From the first dose of study drug until Day 85

Secondary Outcome Measure Information:

Title

Maximum Observed Plasma Concentration (Cmax) of Evolocumab

Description

Serum concentrations of evolocumab were measured by a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 800 ng/mL.

Time Frame

Day 1, predose and Days 4, 8, 15, 22, 29, 36, 40, 43, 50, 57, 64, 71, 78, and 85

Title

Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab

Description

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.

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

Title

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

Title

Percent Change From Baseline to End of the Dosing Interval in PCSK9

Description

Serum PCSK9 concentrations were determined by using a qualified enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 15 ng/mL.

Time Frame

Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Organizational Affiliation

Amgen

Official's Role

Study Director

12. IPD Sharing Statement

Citations:

PubMed Identifier

23083772

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.

Results Reference

background

Links:

URL

http://www.amgentrials.com

Description

AmgenTrials clinical trials website

Learn more about this trial

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

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