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Study of Low-Density Lipoprotein Cholesterol (LDL-C) Reduction Using Evolocumab (AMG 145) in Japanese Patients With Advanced Cardiovascular Risk (AMG145)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Amgen
ClinicalTrials.gov Identifier:
NCT01953328
First received: September 26, 2013
Last updated: November 19, 2015
Last verified: November 2015
Results First Received: September 23, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator);   Primary Purpose: Treatment
Condition: Hyperlipidemia or Mixed Dyslipidemia at High Risk for Cardiovascular Events
Interventions: Drug: Atorvastatin
Biological: Evolocumab
Other: Placebo to Evolocumab

  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
Japanese men and women ≥ 20 to ≤ 85 years of age, with fasting low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (2.6 mmol/L), fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L), and at high risk for cardiovascular events were eligible to participate. First patient enrolled on 07 October 2013 and last patient enrolled on 17 February 2014.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
409 participants were randomized to 1 of 2 open-label atorvastatin cohorts (5 mg or 20 mg) for the lipid stabilization period; 404 were then randomized to blinded investigational product. Both randomizations were stratified by heterozygous familial hypercholesterolemia (HeFH) diagnosis and lipid-lowering therapy.

Reporting Groups
  Description
A5 Placebo Q2W Participants received atorvastatin 5 mg (A5) daily during the 4 week lipid stabilization period and then in combination with placebo subcutaneous injection once every 2 weeks (Q2W) for 12 weeks.
A5 Placebo QM Participants received atorvastatin 5 mg daily during the 4-week lipid stabilization period and then in combination with placebo subcutaneous injection once every month (QM) for 12 weeks.
A5 Evolocumab Q2W Participants received atorvastatin 5 mg daily during the 4-week lipid stabilization period and then in combination with 140 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
A5 Evolocumab QM Participants received atorvastatin 5 mg daily during the 4-week lipid stabilization period and then in combination with 420 mg evolocumab by subcutaneous injection once a month for 12 weeks.
A20 Placebo Q2W Participants received atorvastatin 20 mg (A20) daily during the 4 week lipid stabilization period and then in combination with placebo subcutaneous injection once every 2 weeks for 12 weeks.
A20 Placebo QM Participants received atorvastatin 20 mg daily during the 4-week lipid stabilization period and then in combination with placebo subcutaneous injection once every month for 12 weeks.
A20 Evolocumab Q2W Participants received atorvastatin 20 mg daily during the 4-week lipid stabilization period and then in combination with 140 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
A20 Evolocumab QM Participants received atorvastatin 20 mg daily during the 4-week lipid stabilization period and then in combination with 420 mg evolocumab by subcutaneous injection once a month for 12 weeks.

Participant Flow:   Overall Study
    A5 Placebo Q2W   A5 Placebo QM   A5 Evolocumab Q2W   A5 Evolocumab QM   A20 Placebo Q2W   A20 Placebo QM   A20 Evolocumab Q2W   A20 Evolocumab QM
STARTED   49   50   50   50   52   51   51   51 
Received Treatment   49   50   50   50   52   51   51   51 
COMPLETED   49   50   50   50   50   51   51   51 
NOT COMPLETED   0   0   0   0   2   0   0   0 
Withdrawal by Subject                0                0                0                0                1                0                0                0 
Lost to Follow-up                0                0                0                0                1                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.
Full analysis set (all randomized participants who reveid at least 1 dose of blinded investigational product).

Reporting Groups
  Description
A5 Placebo Q2W Participants received atorvastatin 5 mg (A5) daily during the 4 week lipid stabilization period and then in combination with placebo subcutaneous injection once every 2 weeks (Q2W) for 12 weeks.
A5 Placebo QM Participants received atorvastatin 5 mg daily during the 4-week lipid stabilization period and then in combination with placebo subcutaneous injection once every month (QM) for 12 weeks.
A5 Evolocumab Q2W Participants received atorvastatin 5 mg daily during the 4-week lipid stabilization period and then in combination with 140 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
A5 Evolocumab QM Participants received atorvastatin 5 mg daily during the 4-week lipid stabilization period and then in combination with 420 mg evolocumab by subcutaneous injection once a month for 12 weeks.
A20 Placebo Q2W Participants received atorvastatin 20 mg (A20) daily during the 4 week lipid stabilization period and then in combination with placebo subcutaneous injection once every 2 weeks for 12 weeks.
A20 Placebo QM Participants received atorvastatin 20 mg daily during the 4-week lipid stabilization period and then in combination with placebo subcutaneous injection once every month for 12 weeks.
A20 Evolocumab Q2W Participants received atorvastatin 20 mg daily during the 4-week lipid stabilization period and then in combination with 140 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
A20 Evolocumab QM Participants received atorvastatin 20 mg daily during the 4-week lipid stabilization period and then in combination with 420 mg evolocumab by subcutaneous injection once a month for 12 weeks.
Total Total of all reporting groups

Baseline Measures
   A5 Placebo Q2W   A5 Placebo QM   A5 Evolocumab Q2W   A5 Evolocumab QM   A20 Placebo Q2W   A20 Placebo QM   A20 Evolocumab Q2W   A20 Evolocumab QM   Total 
Overall Participants Analyzed 
[Units: Participants]
 49   50   50   50   52   51   51   51   404 
Age 
[Units: Years]
Mean (Standard Deviation)
 62.1  (9.9)   60.6  (9.9)   65.2  (7.8)   60.1  (11.6)   60.4  (10.4)   60.4  (10.5)   60.1  (9.9)   61.8  (11.9)   61.3  (10.3) 
Gender 
[Units: Participants]
                 
Female   22   15   23   18   24   18   16   24   160 
Male   27   35   27   32   28   33   35   27   244 
Race/Ethnicity, Customized 
[Units: Participants]
                 
American Indian or Alaska Native   0   0   0   0   0   0   0   0   0 
Asian   49   50   50   50   52   51   51   51   404 
Black or African American   0   0   0   0   0   0   0   0   0 
Native Hawaiian or Other Pacific Islander   0   0   0   0   0   0   0   0   0 
White   0   0   0   0   0   0   0   0   0 
Stratification Factor [1] 
[Units: Participants]
                 
Diagnosis of HeFH   3   2   2   3   3   2   3   3   21 
Non-HeFH and Intensive Statin Use   10   10   11   10   11   11   11   11   85 
Non-HeFH and Non-Intensive Statin Use   36   38   37   37   38   38   37   37   298 
[1] Intensive statin use was defined as daily atorvastatin ≥ 10 mg, fluvastatin ≥ 80 mg, lovastatin ≥ 40 mg, pitavastatin ≥ 2 mg, pravastatin ≥ 40 mg, rosuvastatin ≥ 5 mg, simvastatin ≥ 20 mg, or any statin plus ezetimibe. Non-intensive is defined as any dose of a statin at least weekly for the last 4 weeks prior to screening and not included in the above.
LDL-C Concentration [1] 
[Units: mg/dL]
Mean (Standard Deviation)
 115.7  (26.0)   114.0  (29.2)   121.9  (44.6)   118.8  (36.6)   90.9  (25.5)   90.7  (20.8)   95.8  (23.6)   98.0  (25.6)   105.5  (32.0) 
[1] Baseline lipid parameters were measured after the lipid-stabilization period and prior to administration of first dose of investigational study drug.
Non-High-Density Lipoprotein Cholesterol (non-HDL-C) Concentration 
[Units: mg/dL]
Mean (Standard Deviation)
 142.0  (30.4)   141.2  (31.8)   151.8  (48.8)   147.8  (39.6)   118.2  (28.6)   117.5  (25.1)   121.8  (29.8)   122.7  (29.5)   132.7  (35.9) 
Apolipoprotein B Concentration 
[Units: mg/dL]
Mean (Standard Deviation)
 99.0  (20.0)   100.6  (20.0)   105.1  (31.2)   102.2  (24.7)   85.7  (18.4)   82.7  (14.6)   87.2  (19.1)   87.7  (19.6)   93.7  (22.8) 
Total Cholesterol Concentration 
[Units: mg/dL]
Mean (Standard Deviation)
 199.5  (30.7)   199.4  (33.2)   210.4  (47.9)   202.5  (38.4)   177.8  (33.0)   173.6  (29.2)   177.7  (26.2)   179.0  (29.4)   189.8  (36.3) 
Total Cholesterol/HDL-C Ratio 
[Units: Ratio]
Mean (Standard Deviation)
 3.618  (0.891)   3.579  (0.827)   3.743  (1.186)   3.933  (1.295)   3.116  (0.760)   3.170  (0.612)   3.392  (1.112)   3.400  (1.071)   3.491  (1.018) 
Apolipoprotein B/Apolipoprotein A-1 Ratio 
[Units: Ratio]
Mean (Standard Deviation)
 0.633  (0.160)   0.628  (0.152)   0.643  (0.223)   0.658  (0.235)   0.529  (0.118)   0.524  (0.108)   0.575  (0.177)   0.576  (0.176)   0.595  (0.179) 
Lipoprotein(a) Concentration 
[Units: nmol/L]
Median (Inter-Quartile Range)
 35.0 
 (16.5 to 52.5) 
 29.5 
 (9.0 to 47.0) 
 36.0 
 (16.0 to 69.0) 
 36.5 
 (16.0 to 74.0) 
 30.0 
 (11.0 to 45.0) 
 35.0 
 (11.0 to 57.0) 
 33.0 
 (14.0 to 49.0) 
 28.0 
 (11.0 to 60.0) 
 33.0 
 (13.0 to 57.0) 
Triglyceride Concentration 
[Units: mg/dL]
Median (Inter-Quartile Range)
 125.0 
 (90.0 to 174.0) 
 128.5 
 (99.0 to 164.0) 
 125.0 
 (97.0 to 172.0) 
 132.0 
 (103.0 to 171.0) 
 120.0 
 (91.5 to 187.0) 
 120.0 
 (87.0 to 154.0) 
 109.0 
 (82.0 to 149.0) 
 113.0 
 (95.0 to 137.0) 
 121.5 
 (92.0 to 161.5) 
HDL-C Concentration 
[Units: mg/dL]
Mean (Standard Deviation)
 57.5  (13.6)   58.3  (14.6)   58.6  (12.7)   54.7  (13.9)   59.6  (15.4)   56.0  (11.3)   55.9  (14.4)   56.3  (15.7)   57.1  (14.0) 
Very-Low-Density Lipoprotein Cholesterol (VLDL-C) Concentration 
[Units: mg/dL]
Mean (Standard Deviation)
 26.3  (11.0)   26.8  (10.2)   29.2  (14.7)   29.0  (12.8)   27.4  (12.0)   25.1  (9.4)   24.3  (10.7)   24.7  (10.3)   26.6  (11.5) 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

2.  Primary:   Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12   [ Time Frame: Baseline and Week 12 ]

3.  Secondary:   Change From Baseline in LDL-C at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

4.  Secondary:   Change From Baseline in LDL-C at Week 12   [ Time Frame: Baseline and Week 12 ]

5.  Secondary:   Percent Change From Baseline in Non-HDL-C at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

6.  Secondary:   Percent Change From Baseline in Non-HDL-C at Week 12   [ Time Frame: Baseline and Week 12 ]

7.  Secondary:   Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

8.  Secondary:   Percent Change From Baseline in Apolipoprotein B at Week 12   [ Time Frame: Baseline and Week 12 ]

9.  Secondary:   Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

10.  Secondary:   Percent Change From Baseline in Total Cholesterol at Week 12   [ Time Frame: Baseline and Week 12 ]

11.  Secondary:   Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

12.  Secondary:   Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12   [ Time Frame: Baseline and Week 12 ]

13.  Secondary:   Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A-1 Ratio at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

14.  Secondary:   Percent Change From Baseline in the Apolipoprotein B/Apolipoprotein A-1 Ratio at Week 12   [ Time Frame: Baseline and Week 12 ]

15.  Secondary:   Percentage of Participants Who Achieved a Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL   [ Time Frame: Weeks 10 and 12 ]

16.  Secondary:   Percentage of Participants Who Achieved LDL-C < 70 mg/dL at Week 12   [ Time Frame: Week 12 ]

17.  Secondary:   Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

18.  Secondary:   Percent Change From Baseline in Lipoprotein(a) at Week 12   [ Time Frame: Baseline and Week 12 ]

19.  Secondary:   Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

20.  Secondary:   Percent Change From Baseline in Triglycerides at Week 12   [ Time Frame: Baseline and Week 12 ]

21.  Secondary:   Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

22.  Secondary:   Percent Change From Baseline in HDL-C at Week 12   [ Time Frame: Baseline and Week 12 ]

23.  Secondary:   Percent Change From Baseline in VLDL-C at the Mean of Weeks 10 and 12   [ Time Frame: Baseline and Weeks 10 and 12 ]

24.  Secondary:   Percent Change From Baseline in VLDL-C at Week 12   [ Time Frame: Baseline and Week 12 ]


  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



Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01953328     History of Changes
Other Study ID Numbers: 20120122
Study First Received: September 26, 2013
Results First Received: September 23, 2015
Last Updated: November 19, 2015
Health Authority: Japan: Pharmaceuticals and Medical Devices Agency