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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
Results First Received: September 23, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Hyperlipidemia
Interventions: Biological: Evolocumab
Biological: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study enrolled hypercholesterolemic adults receiving stable statin therapy (7 cohorts: 5 on low-to-moderate-dose statins, 1 on high-dose statin therapy, and 1 with heterozygous familial hypercholesterolemia (HeFH) (score ≥9, World Health Organization criteria). First patient enrolled 28 June 2010. Last patient enrolled 24 June 2011.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants receiving low-to-moderate-dose statins were randomized 1:3 to placebo or evolocumab and sequentially assigned to 1 of 5 dose-escalation cohorts. The high-dose statin and HeFH cohorts were randomized 1:3 and 1:2 respectively to placebo or evolocumab. Placebo participants were pooled for the 5 dose-escalation cohorts.

Reporting Groups
  Description
Placebo Cohorts 1-5 Combined: Participants on low-to-moderate dose statin therapy received placebo subcutaneous injections matching active investigational product in volume and frequency.
Evolocumab 14 mg QW × 6 Cohort 1: Participants on low-to-moderate-dose stain therapy received evolocumab 14 mg subcutaneous injection once weekly (QW) for 6 weeks.
Evolocumab 35 mg QW × 6 Cohort 2: Participants on low-to-moderate-dose statin therapy received evolocumab 35 mg subcutaneous injection once weekly for 6 weeks.
Evolocumab 140 mg Q2W × 3 Cohort 3: Participants on low-to-moderate-dose statin therapy received evolocumab 140 mg subcutaneous injection every 2 weeks (Q2W) for 6 weeks.
Evolocumab 280 mg Q2W × 3 Cohort 4: Participants on low-to-moderate-dose statin therapy received evolocumab 280 mg subcutaneous injection every 2 weeks for 6 weeks.
Evolocumab 420 mg Q4W × 2 Cohort 5: participants on low-to-moderate-dose statin therapy received evolocumab 420 mg subcutaneous injection every 4 weeks (Q4W) for 8 weeks.
High Dose Statin - Placebo Cohort 6: Participants on high-dose statin therapy received placebo subcutaneous injection every 2 weeks for 6 weeks.
High Dose Statin - Evolocumab 140 mg Q2W × 3 Cohort 6: Participants on high-dose statin therapy received evolocumab 140 mg subcutaneous injection every 2 weeks for 6 weeks.
HeFH - Placebo Cohort 7: Participants diagnosed with HeFH received placebo subcutaneous injection every 2 weeks for 6 weeks.
HeFH - Evolocumab 140 mg Q2W × 3 Cohort 7: Participants diagnosed with HeFH received evolocumab 140 mg subcutaneous injection every 2 weeks for 6 weeks.

Participant Flow:   Overall Study
    Placebo   Evolocumab 14 mg QW × 6   Evolocumab 35 mg QW × 6   Evolocumab 140 mg Q2W × 3   Evolocumab 280 mg Q2W × 3   Evolocumab 420 mg Q4W × 2   High Dose Statin - Placebo   High Dose Statin - Evolocumab 140 mg Q2W × 3   HeFH - Placebo   HeFH - Evolocumab 140 mg Q2W × 3
STARTED   10   7   6   7   7   6   2   9   2   4 
Received Treatment   10   6   6   6   6   6   2   9   2   4 
COMPLETED   10   6   6   6   6   6   2   9   2   4 
NOT COMPLETED   0   1   0   1   1   0   0   0   0   0 
Withdrawal by Subject                0                1                0                1                0                0                0                0                0                0 
Physician Decision                0                0                0                0                1                0                0                0                0                0 



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety analysis set (all participants who received at least 1 dose of study drug).

Reporting Groups
  Description
Placebo Cohorts 1-5 Combined: Participants on low-to-moderate dose statin therapy received placebo subcutaneous injections matching active investigational product in volume and frequency.
Evolocumab 14 mg QW × 6 Cohort 1: Participants on low-to-moderate-dose stain therapy received evolocumab 14 mg subcutaneous injection once weekly for 6 weeks.
Evolocumab 35 mg QW × 6 Cohort 2: Participants on low-to-moderate-dose statin therapy received evolocumab 35 mg subcutaneous injection once weekly for 6 weeks.
Evolocumab 140 mg Q2W × 3 Cohort 3: Participants on low-to-moderate-dose statin therapy received evolocumab 140 mg subcutaneous injection every 2 weeks for 6 weeks.
Evolocumab 280 mg Q2W × 3 Cohort 4: Participants on low-to-moderate-dose statin therapy received evolocumab 280 mg subcutaneous injection every 2 weeks for 6 weeks.
Evolocumab 420 mg Q4W × 2 Cohort 5: participants on low-to-moderate-dose statin therapy received evolocumab 420 mg subcutaneous injection every 4 weeks for 8 weeks.
High Dose Statin - Placebo Cohort 6: Participants on high-dose statin therapy received placebo subcutaneous injection every 2 weeks for 6 weeks.
High Dose Statin - Evolocumab 140 mg Q2W × 3 Cohort 6: Participants on high-dose statin therapy received evolocumab 140 mg subcutaneous injection every 2 weeks for 6 weeks.
HeFH - Placebo Cohort 7: Participants diagnosed with HeFH received placebo subcutaneous injection every 2 weeks for 6 weeks.
HeFH - Evolocumab 140 mg Q2W × 3 Cohort 7: Participants diagnosed with HeFH received evolocumab 140 mg subcutaneous injection every 2 weeks for 6 weeks.
Total Total of all reporting groups

Baseline Measures
   Placebo   Evolocumab 14 mg QW × 6   Evolocumab 35 mg QW × 6   Evolocumab 140 mg Q2W × 3   Evolocumab 280 mg Q2W × 3   Evolocumab 420 mg Q4W × 2   High Dose Statin - Placebo   High Dose Statin - Evolocumab 140 mg Q2W × 3   HeFH - Placebo   HeFH - Evolocumab 140 mg Q2W × 3   Total 
Overall Participants Analyzed 
[Units: Participants]
 10   6   6   6   6   6   2   9   2   4   57 
Age 
[Units: Years]
Mean (Standard Deviation)
 55.8  (7.5)   61.3  (4.0)   63.7  (6.3)   56.2  (7.3)   56.3  (8.6)   53.8  (4.9)   62.0  (1.4)   58.2  (7.6)   54.5  (10.6)   45.0  (15.1)   56.9  (8.4) 
Gender 
[Units: Participants]
                     
Female   6   4   1   3   4   3   1   3   1   0   26 
Male   4   2   5   3   2   3   1   6   1   4   31 
Race/Ethnicity, Customized 
[Units: Participants]
                     
White or Caucasian   9   6   6   4   6   3   2   7   2   2   47 
Black or African American   0   0   0   0   0   0   0   0   0   2   2 
Hispanic or Latino   1   0   0   1   0   3   0   2   0   0   7 
Asian   0   0   0   1   0   0   0   0   0   0   1 
Japanese   0   0   0   0   0   0   0   0   0   0   0 
American Indian or Alaska Native   0   0   0   0   0   0   0   0   0   0   0 
Native Hawaiian or Other Pacific Islander   0   0   0   0   0   0   0   0   0   0   0 
Aborigine   0   0   0   0   0   0   0   0   0   0   0 
Low-Density Lipoprotein Cholesterol (LDL-C) Concentration 
[Units: mg/dL]
Mean (Standard Deviation)
 108.9  (21.9)   126.7  (22.1)   106.5  (29.4)   113.7  (14.5)   105.8  (17.0)   120.3  (33.0)   99.0  (31.1)   100.2  (25.5)   168.5  (57.3)   134.5  (31.1)   114.1  (27.8) 
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration 
[Units: ng/mL]
Mean (Standard Deviation)
 429.0  (93.1)   491.2  (157.9)   399.8  (116.7)   384.8  (88.0)   373.7  (96.0)   459.0  (163.4)   382.5  (82.7)   486.6  (214.0)   478.5  (94.0)   396.0  (86.4)   432.0  (133.6) 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Participants With Adverse Events   [ Time Frame: From the first dose of study drug until Day 85 ]

2.  Primary:   Number of Participants With Anti-Evolocumab Antibodies   [ Time Frame: From the first dose of study drug until Day 85 ]

3.  Secondary:   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 ]

4.  Secondary:   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 ]

5.  Secondary:   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 ]

6.  Secondary:   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 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Study Director
Organization: Amgen Inc.
phone: 866-572-6436


Publications:

Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01133522     History of Changes
Other Study ID Numbers: 20080398
Study First Received: May 27, 2010
Results First Received: September 23, 2015
Last Updated: September 23, 2015
Health Authority: United States: Food and Drug Administration