LAPLACE-TIMI 57: Low-density Lipoprotein Cholesterol (LDL-C) Assessment With PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy (LAPLACE)

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Hyperlipidemia
Interventions:	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
This study enrolled adults aged 18 - 80 years who were on a statin, with or without ezetimibe, with stable dose(s) for at least 4 weeks, and fasting low-density lipoprotein cholesterol (LDL-C) ≥ 85 mg/dL. The first patient enrolled on 18 July 2011 and the last patient enrolled on 22 December 2011.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Eligible participants were randomized equally into 1 of 8 treatment groups. Randomization was stratified by screening LDL-C level (< 130 mg/dL or ≥ 130 mg/dL) and ezetimibe use at baseline (yes or no).

Reporting Groups

	Description
Placebo Q2W	Participants received placebo subcutaneous injection once every 2 weeks (Q2W) for 12 weeks.
Placebo Q4W	Participants received placebo subcutaneous injection once every 4 weeks (Q4W) for 12 weeks.
Evolocumab 70 mg Q2W	Participants received 70 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
Evolocumab 105 mg Q2W	Participants received 105 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
Evolocumab 140 mg Q2W	Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
Evolocumab 280 mg Q4W	Participants received 280 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks.
Evolocumab 350 mg Q4W	Participants received 350 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks.
Evolocumab 420 mg Q4W	Participants received 420 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks.

Participant Flow:   Overall Study

	Placebo Q2W	Placebo Q4W	Evolocumab 70 mg Q2W	Evolocumab 105 mg Q2W	Evolocumab 140 mg Q2W	Evolocumab 280 mg Q4W	Evolocumab 350 mg Q4W	Evolocumab 420 mg Q4W
STARTED	78	79	79	79	78	79	79	80
Received Treatment	78	77 [1]	79	79	78	79	79	80
COMPLETED	78	79	79	79	77	79	79	80
NOT COMPLETED	0	0	0	0	1	0	0	0
Death	0	0	0	0	1	0	0	0

[1]	2 participants did not receive treatment but were followed until the end of study

  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 received at least 1 dose of investigational product).

Reporting Groups

	Description
Placebo Q2W	Participants received placebo subcutaneous injection once every 2 weeks (Q2W) for 12 weeks.
Placebo Q4W	Participants received placebo subcutaneous injection once every 4 weeks (Q4W) for 12 weeks.
Evolocumab 70 mg Q2W	Participants received 70 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
Evolocumab 105 mg Q2W	Participants received 105 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
Evolocumab 140 mg Q2W	Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks for 12 weeks.
Evolocumab 280 mg Q4W	Participants received 280 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks.
Evolocumab 350 mg Q4W	Participants received 350 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks.
Evolocumab 420 mg Q4W	Participants received 420 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks.
Total	Total of all reporting groups

Baseline Measures

	Placebo Q2W	Placebo Q4W	Evolocumab 70 mg Q2W	Evolocumab 105 mg Q2W	Evolocumab 140 mg Q2W	Evolocumab 280 mg Q4W	Evolocumab 350 mg Q4W	Evolocumab 420 mg Q4W	Total
Overall Participants Analyzed; [Units: Participants]	78	77	79	79	78	79	79	80	629
Age; [Units: Years]; Mean (Standard Deviation)	60.2 (8.8)	60.1 (9.6)	59.4 (9.9)	58.8 (9.7)	62.4 (10.2)	60.3 (8.4)	61.9 (8.8)	60.9 (10.3)	60.5 (9.5)
Gender; [Units: Participants]
Female	42	41	44	25	45	40	38	44	319
Male	36	36	35	54	33	39	41	36	310
Race/Ethnicity, Customized; [Units: Participants]
American Indian or Alaska Native	0	1	0	0	1	1	0	0	3
Asian	0	2	1	3	1	2	2	1	12
Black or African American	6	0	6	8	9	8	4	9	50
Native Hawaiian or Other Pacific Islander	0	0	0	1	0	2	0	0	3
White	72	74	72	67	67	64	72	70	558
Other	0	0	0	0	0	2	1	0	3
Race/Ethnicity, Customized; [Units: Participants]
Hispanic or Latino	1	6	5	0	6	1	0	2	21
Not Hispanic or Latino	77	71	74	79	72	78	79	78	608
Stratification Factor: LDL-C Level; [Units: Participants]
< 130 mg/dL	51	51	51	51	52	51	52	53	412
≥ 130 mg/dL	27	26	28	28	26	28	27	27	217
Stratification Factor: Baseline Ezetimibe Use; [Units: Participants]
No	71	69	72	72	71	72	72	73	572
Yes	7	8	7	7	7	7	7	7	57
LDL-C Concentration [1]; [Units: mg/dL]; Mean (Standard Deviation)	122.2 (27.1)	124.9 (30.6)	121.4 (24.4)	127.4 (32.1)	120.9 (25.1)	122.0 (28.8)	123.2 (27.1)	120.8 (26.5)	122.8 (27.7)
[1] LDL-C was measured using ultracentrifugation.
Non-High-Density Lipoprotein Cholesterol (non-HDL-C) Concentration; [Units: mg/dL]; Mean (Standard Deviation)	146.9 (29.9)	150.2 (36.5)	145.3 (29.9)	151.2 (37.2)	145.3 (26.2)	146.3 (33.3)	150.0 (29.1)	144.4 (31.2)	147.4 (31.8)
Apolipoprotein B Concentration; [Units: mg/dL]; Mean (Standard Deviation)	99.9 (17.0)	101.6 (20.0)	99.9 (16.8)	103.6 (22.3)	98.8 (16.6)	101.3 (21.2)	102.6 (18.9)	99.9 (18.6)	100.9 (19.0)
Total Cholesterol/HDL-C ratio; [Units: Ratio]; Mean (Standard Deviation)	3.940 (1.016)	4.057 (1.303)	4.002 (1.243)	4.128 (1.473)	3.932 (1.022)	4.007 (1.300)	4.118 (0.963)	3.885 (1.090)	4.008 (1.184)
Apolipoprotein B/Apolipoprotein A-1 Ratio; [Units: Ratio]; Mean (Standard Deviation)	0.660 (0.155)	0.676 (0.194)	0.675 (0.191)	0.695 (0.219)	0.649 (0.155)	0.662 (0.199)	0.687 (0.175)	0.653 (0.177)	0.670 (0.184)

  Outcome Measures

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1. Primary:

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

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2. Secondary:

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

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3. Secondary:

Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12 [ Time Frame: Baseline and Week 12 ]

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4. Secondary:

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

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5. Secondary:

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

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6. Secondary:

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

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  Serious Adverse Events

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  Other Adverse Events

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  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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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: 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. 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. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.; Restriction Description: The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

Results Point of Contact:  

Name/Title: Study Director
Organization: Amgen Inc.
phone: 866-572-6436

Publications:

Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, Liu T, Mohanavelu S, Hoffman EB, McDonald ST, Abrahamsen TE, Wasserman SM, Scott R, Sabatine MS; LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012 Dec 8;380(9858):2007-17. doi: 10.1016/S0140-6736(12)61770-X. Epub 2012 Nov 6.

Kohli P, Desai NR, Giugliano RP, Kim JB, Somaratne R, Huang F, Knusel B, McDonald S, Abrahamsen T, Wasserman SM, Scott R, Sabatine MS. Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy. Clin Cardiol. 2012;35(7):385-91. doi: 10.1002/clc.22014. Epub 2012 Jun 19.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Desai NR, Kohli P, Giugliano RP, O'Donoghue ML, Somaratne R, Zhou J, Hoffman EB, Huang F, Rogers WJ, Wasserman SM, Scott R, Sabatine MS. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation. 2013 Aug 27;128(9):962-9. doi: 10.1161/CIRCULATIONAHA.113.001969. Epub 2013 Jul 24.

Responsible Party:	Amgen
ClinicalTrials.gov Identifier:	NCT01380730 History of Changes
Other Study ID Numbers:	20101155
First Submitted:	June 23, 2011
First Posted:	June 27, 2011
Results First Submitted:	September 1, 2015
Results First Posted:	October 1, 2015
Last Update Posted:	July 11, 2016