GLAGOV: GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01813422
• Collaborator: (none)
• Enrollment: 970
• Locations: 226
• Arms: 2
• Actual Duration (Months): 39.4
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will evaluate whether low-density lipoprotein (LDL-C) lowering with evolocumab (AMG 145) results in greater change from baseline in percent atheroma volume (PAV) at week 78 than placebo in adults with coronary artery disease taking lipid lowering therapy.

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia	Biological: Evolocumab; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 970 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomized, Multi-center, Placebo-controlled, Parallel-group Study to Determine the Effects of Evolocumab (AMG 145) Treatment on Atherosclerotic Disease Burden as Measured by Intravascular Ultrasound in Subjects Undergoing Coronary Catheterization
• Actual Study Start Date: Apr 18, 2013
• Actual Primary Completion Date: Jul 12, 2016
• Actual Study Completion Date: Jul 29, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo to evolocumab administered by subcutaneous injection once a month for 76 weeks.	Drug: Placebo; Administered by subcutaneous injection
Experimental: Evolocumab Participants received 420 mg evolocumab administered by subcutaneous injection once a month for 76 weeks.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: AMG 145 Repatha®

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Percent Atheroma Volume at Week 78 [Baseline and week 78]

   Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. The extent of atherosclerosis was expressed as percent atheroma volume (PAV) in a ≥ 40 mm segment of one targeted (imaged) coronary artery, calculated as the percentage of the total vessel volume occupied by atheroma.

Secondary Outcome Measures

1. Change From Baseline in Total Atheroma Volume at Week 78 [Baseline and week 78]

   Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. Total atheroma volume (TAV) in a ≥ 40 mm segment of the targeted coronary artery was calculated as the average plaque area over the number of images that were evaluated by IVUS multiplied by the median vessel length to compensate for differences in segment length between participants.

2. Percentage of Participants With Regression in Percent Atheroma Volume [Baseline and week 78]

   Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. The extent of atherosclerosis was expressed as percent atheroma volume (PAV) in a ≥ 40 mm segment of one targeted (imaged) coronary artery, calculated as the percentage of the total vessel volume occupied by atheroma. Regression in PAV was defined as any reduction from baseline in PAV.

3. Percentage of Participants With Regression in Total Atheroma Volume [Baseline and week 78]

   Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. Total atheroma volume (TAV) in a ≥ 40 mm segment of the targeted coronary artery was calculated as the average plaque area over the number of images that were evaluated by IVUS multiplied by the median vessel length to compensate for differences in segment length between participants. Regression in TAV was defined as any reduction from baseline in TAV.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Clinical indication for coronary angiography

• Subjects already taking statin therapy, niacin or ezetimibe at screening must have been on a stable dose for at least 4 weeks prior to screening LDL-C. Subjects not taking lipid-regulating therapy must enter the study via a lipid stabilization period. Subjects who are intolerant to statins must meet statin intolerance entry criteria

• Fasting LDL-C ≥ 80 mg/dL (2.07 mmol/L) with or without additional risk factors, or, LDL-C ≥ 60 -< 80 mg/dL (1.55-2.07 mmol/L) in the presence of one major or three minor risk factors

Subjects must meet the following criteria at the qualifying coronary catheterization procedure:

• Evidence of coronary heart disease (at least one lesion in a native coronary artery that has > 20% reduction in lumen diameter) or prior percutaneous intervention (PCI)

• Left main coronary artery < 50% reduction in lumen diameter by visual estimation

• Target coronary artery for IVUS must be accessible to the IVUS catheter, must not have a > 50% reduction in lumen diameter within the target segment (and at least 40 mm in length); cannot have undergone prior PCI or coronary artery bypass graft (CABG) and is not a candidate for intervention over the next 18 months. It may not be a bypass graft, bypassed vessel or culprit vessel for previous myocardial infarction (MI).

Exclusion Criteria:

• Coronary artery bypass graft surgery < 6 weeks prior to the qualifying IVUS

• New York Heart Association (NYHA) III or IV heart failure, or last known left ventricular ejection fraction less than 30%

• Uncontrolled cardiac arrhythmia that is not controlled by medications in the 3 months prior to randomization

• Known hemorrhagic stroke

• Uncontrolled hypertension at randomization

• Fasting Triglycerides ≥ 400 mg/dL (4.5 mmol/L) at screening

• Type 1 diabetes or poorly controlled type 2 diabetes (hemoglobin A1c [HbA1c] > 9%) at screening.

• Moderate to severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73m²) at screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Huntsville	Alabama	United States	35801
2	Research Site	Mobile	Alabama	United States	36608
3	Research Site	Little Rock	Arkansas	United States	72211
4	Research Site	La Jolla	California	United States	92037
5	Research Site	La Jolla	California	United States	92093-0960
6	Research Site	Long Beach	California	United States	90822
7	Research Site	Newport Beach	California	United States	92663
8	Research Site	Orange	California	United States	92868
9	Research Site	San Diego	California	United States	92161
10	Research Site	Santa Monica	California	United States	90404
11	Research Site	Torrance	California	United States	90502
12	Research Site	Washington	District of Columbia	United States	20010
13	Research Site	Atlantis	Florida	United States	33462
14	Research Site	Clearwater	Florida	United States	33756
15	Research Site	Jacksonville	Florida	United States	32209
16	Research Site	Jacksonville	Florida	United States	32216
17	Research Site	Melbourne	Florida	United States	32901
18	Research Site	Safety Harbor	Florida	United States	34695
19	Research Site	Atlanta	Georgia	United States	30342
20	Research Site	Hammond	Indiana	United States	46320
21	Research Site	Valparaiso	Indiana	United States	46383
22	Research Site	Lexington	Kentucky	United States	40536
23	Research Site	Louisville	Kentucky	United States	40205
24	Research Site	Covington	Louisiana	United States	70433
25	Research Site	Bethesda	Maryland	United States	20814
26	Research Site	Columbia	Maryland	United States	21044
27	Research Site	Ann Arbor	Michigan	United States	48109
28	Research Site	Bay City	Michigan	United States	48708
29	Research Site	Grand Rapids	Michigan	United States	49503
30	Research Site	Marquette	Michigan	United States	49855
31	Research Site	Midland	Michigan	United States	48670
32	Research Site	Petoskey	Michigan	United States	49770
33	Research Site	Saginaw	Michigan	United States	48601
34	Research Site	Duluth	Minnesota	United States	55805
35	Research Site	Minneapolis	Minnesota	United States	55407
36	Research Site	Saint Cloud	Minnesota	United States	56303
37	Research Site	Saint Paul	Minnesota	United States	55102
38	Research Site	Columbia	Missouri	United States	65212
39	Research Site	Missoula	Montana	United States	59802
40	Research Site	Omaha	Nebraska	United States	68198
41	Research Site	Ridgewood	New Jersey	United States	07450
42	Research Site	Buffalo	New York	United States	14215
43	Research Site	Johnson City	New York	United States	13790
44	Research Site	Charlotte	North Carolina	United States	28204
45	Research Site	Fargo	North Dakota	United States	58122
46	Research Site	Canton	Ohio	United States	44710
47	Research Site	Elyria	Ohio	United States	44035
48	Research Site	Toledo	Ohio	United States	43614
49	Research Site	Oklahoma City	Oklahoma	United States	73104
50	Research Site	Tulsa	Oklahoma	United States	74104
51	Research Site	Hillsboro	Oregon	United States	97123
52	Research Site	Springfield	Oregon	United States	97477
53	Research Site	Doylestown	Pennsylvania	United States	18901
54	Research Site	Hershey	Pennsylvania	United States	17033
55	Research Site	Oak Ridge	Tennessee	United States	37830
56	Research Site	Amarillo	Texas	United States	79106
57	Research Site	Dallas	Texas	United States	75216
58	Research Site	San Antonio	Texas	United States	78229
59	Research Site	Wichita Falls	Texas	United States	76301
60	Research Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1199ABB
61	Research Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1428DCO
62	Research Site	La Plata	Buenos Aires	Argentina	1900
63	Research Site	Cordoba	Córdoba	Argentina	X5000JHQ
64	Research Site	Cordoba	Córdoba	Argentina	X5016KEH
65	Research Site	Rosario	Santa Fe	Argentina	2000
66	Research Site	Buenos Aires		Argentina	C1280AEB
67	Research Site	Corrientes		Argentina	W3400AMZ
68	Research Site	Córdoba		Argentina	X5003DCE
69	Research Site	Concord	New South Wales	Australia	2139
70	Research Site	Darlinghurst	New South Wales	Australia	2010
71	Research Site	Liverpool	New South Wales	Australia	2170
72	Research Site	New Lambton Heights	New South Wales	Australia	2305
73	Research Site	Chermside	Queensland	Australia	4032
74	Research Site	Herston	Queensland	Australia	4029
75	Research Site	Adelaide	South Australia	Australia	5000
76	Research Site	Bedford Park	South Australia	Australia	5042
77	Research Site	Epping	Victoria	Australia	3076
78	Research Site	Footscray	Victoria	Australia	3011
79	Research Site	Heidelberg	Victoria	Australia	3084
80	Research Site	Melbourne	Victoria	Australia	3004
81	Research Site	Nedlands	Western Australia	Australia	6009
82	Research Site	Antwerpen		Belgium	2020
83	Research Site	Brussels		Belgium	1090
84	Research Site	Bruxelles		Belgium	1200
85	Research Site	Edegem		Belgium	2650
86	Research Site	Genk		Belgium	3600
87	Research Site	Gent		Belgium	9000
88	Research Site	Hasselt		Belgium	3500
89	Research Site	Lodelinsart		Belgium	6042
90	Research Site	Cariacica	Espírito Santo	Brazil	29156-580
91	Research Site	Goiania	Goiás	Brazil	74223-130
92	Research Site	Curitiba	Paraná	Brazil	80320-320
93	Research Site	Porto Alegre	Rio Grande Do Sul	Brazil	90020-090
94	Research Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
95	Research Site	Porto Alegre	Rio Grande Do Sul	Brazil	90620-001
96	Research Site	Sao Paulo	São Paulo	Brazil	04012-909
97	Research Site	São Paulo		Brazil	05403-000
98	Research Site	Calgary	Alberta	Canada	T2N 4Z6
99	Research Site	Edmonton	Alberta	Canada	T5H 3V9
100	Research Site	Edmonton	Alberta	Canada	T6G 2B7
101	Research Site	Victoria	British Columbia	Canada	V8R 4R2
102	Research Site	Winnipeg	Manitoba	Canada	R2H 2A6
103	Research Site	Saint John	New Brunswick	Canada	E2L 4L2
104	Research Site	St. Johns	Newfoundland and Labrador	Canada	A1B 3V6
105	Research Site	Halifax	Nova Scotia	Canada	B3H 3A7
106	Research Site	London	Ontario	Canada	N6A 5A5
107	Research Site	Toronto	Ontario	Canada	M5B 1W8
108	Research Site	Toronto	Ontario	Canada	M5G 2C4
109	Research Site	Laval	Quebec	Canada	H7M 3L9
110	Research Site	Montreal	Quebec	Canada	H1T 2M4
111	Research Site	Montreal	Quebec	Canada	H3A 1A1
112	Research Site	Montreal	Quebec	Canada	H4J 1C5
113	Research Site	Quebec City	Quebec	Canada	G1V 4G5
114	Research Site	Temuco	Cautín	Chile	4781156
115	Research Site	Santiago		Chile	7650018
116	Research Site	Santiago		Chile	8207257
117	Research Site	Santiago		Chile	8330032
118	Research Site	Brno		Czechia	625 00
119	Research Site	Hradec Kralove		Czechia	500 05
120	Research Site	Praha 2		Czechia	128 08
121	Research Site	Praha 4		Czechia	140 21
122	Research Site	Usti nad Labem		Czechia	401 13
123	Research Site	Zlin		Czechia	762 75
124	Research Site	Aarhus N		Denmark	8200
125	Research Site	Odense C		Denmark	5000
126	Research Site	Besançon Cedex		France	25030
127	Research Site	Chambray les Tours		France	37170
128	Research Site	Creteil		France	94010
129	Research Site	Marseille cedex 5		France	13385
130	Research Site	Paris		France	75015
131	Research Site	Pessac Cedex		France	33604
132	Research Site	Aachen		Germany	52074
133	Research Site	Essen		Germany	45122
134	Research Site	München		Germany	81737
135	Research Site	Neuss		Germany	41464
136	Research Site	Regensburg		Germany	93053
137	Research Site	Ulm		Germany	89081
138	Research Site	Alexandroupoli		Greece	68100
139	Research Site	Athens		Greece	11527
140	Research Site	Athens		Greece	14561
141	Research Site	Athens		Greece	17674
142	Research Site	Heraklion		Greece	71110
143	Research Site	Budapest		Hungary	1023
144	Research Site	Budapest		Hungary	1106
145	Research Site	Budapest		Hungary	1122
146	Research Site	Budapest		Hungary	1134
147	Research Site	Debrecen		Hungary	4032
148	Research Site	Pecs		Hungary	7624
149	Research Site	Szeged		Hungary	6725
150	Research Site	Reykjavik		Iceland	101
151	Research Site	Dublin		Ireland	8
152	Research Site	Galway		Ireland
153	Research Site	Hadera		Israel	38100
154	Research Site	Jerusalem		Israel	91031
155	Research Site	Rehovot		Israel	76100
156	Research Site	Novara		Italy	28100
157	Research Site	Roma		Italy	00168
158	Research Site	Rozzano MI		Italy	20089
159	Research Site	Sesto San Giovanni (MI)		Italy	20099
160	Research Site	Torino		Italy	10154
161	Research Site	Daejeon		Korea, Republic of	301-723
162	Research Site	Seongnam-si		Korea, Republic of	463-707
163	Research Site	Seoul		Korea, Republic of	130-872
164	Research Site	Seoul		Korea, Republic of	156-707
165	Research Site	Kuantan	Pahang	Malaysia	25100
166	Research Site	Penang		Malaysia	10050
167	Research Site	Guadalajara	Jalisco	Mexico	44670
168	Research Site	Queretaro	Querétaro	Mexico	76000
169	Research Site	San Luis Potosi	San Luis Potosí	Mexico	78240
170	Research Site	Culiacan	Sinaloa	Mexico	80020
171	Research Site	Aguascalientes		Mexico	20230
172	Research Site	Puebla		Mexico	72490
173	Research Site	Alkmaar		Netherlands	1815 JD
174	Research Site	Amsterdam		Netherlands	1081 HV
175	Research Site	Amsterdam		Netherlands	1091 AC
176	Research Site	Eindhoven		Netherlands	5623 EJ
177	Research Site	Leeuwarden		Netherlands	8934 AD
178	Research Site	Nieuwegein		Netherlands	3435 CM
179	Research Site	Nijmegen		Netherlands	6532 SZ
180	Research Site	Rotterdam		Netherlands	3079 DZ
181	Research Site	Tilburg		Netherlands	5042 AD
182	Research Site	Utrecht		Netherlands	3584 CX
183	Research Site	Venlo		Netherlands	5912 BL
184	Research Site	Zwolle		Netherlands	8025 AB
185	Research Site	Oslo		Norway	0424
186	Research Site	Tromso		Norway	9038
187	Research Site	Pasig City		Philippines	1600
188	Research Site	Quezon City		Philippines	1100
189	Research Site	Quezon City		Philippines	1102
190	Research Site	Chrzanow		Poland	32-500
191	Research Site	Kedzierzyn Kozle		Poland	47-200
192	Research Site	Krakow		Poland	31-202
193	Research Site	Krakow		Poland	31-501
194	Research Site	Lodz		Poland	90-549
195	Research Site	Warszawa		Poland	04-628
196	Research Site	Kemerovo		Russian Federation	650002
197	Research Site	Moscow		Russian Federation	101990
198	Research Site	Moscow		Russian Federation	119991
199	Research Site	Moscow		Russian Federation	121552
200	Research Site	Singapore		Singapore	169609
201	Research Site	Boksburg	Gauteng	South Africa	1470
202	Research Site	Centurion	Gauteng	South Africa	0157
203	Research Site	Johannesburg	Gauteng	South Africa	2157
204	Research Site	Kuils River	Western Cape	South Africa	7580
205	Research Site	Pinelands, Cape Town	Western Cape	South Africa	7405
206	Research Site	Somerset West	Western Cape	South Africa	7130
207	Research Site	Malaga	Andalucía	Spain	29010
208	Research Site	Gijon	Asturias	Spain	33394
209	Research Site	Barcelona	Cataluña	Spain	08035
210	Research Site	L Hospitalet De Llobregat	Cataluña	Spain	08907
211	Research Site	Santiago de Compostela	Galicia	Spain	15706
212	Research Site	Madrid		Spain	28034
213	Research Site	Madrid		Spain	28046
214	Research Site	Göteborg		Sweden	413 45
215	Research Site	Helsingborg		Sweden	251 87
216	Research Site	Lund		Sweden	221 85
217	Research Site	Solna		Sweden	171 76
218	Research Site	Stockholm		Sweden	118 83
219	Research Site	Örebro		Sweden	701 85
220	Research Site	Geneva 14		Switzerland	1211
221	Research Site	St. Gallen		Switzerland	9007
222	Research Site	Kaohsiung		Taiwan	83301
223	Research Site	New Taipei		Taiwan	251
224	Research Site	Taichung City		Taiwan	402
225	Research Site	Taipei		Taiwan	11217
226	Research Site	Newcastle Upon Tyne		United Kingdom	NE7 7DN

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Scott R, Ungi I, Podolec J, Ophuis AO, Cornel JH, Borgman M, Brennan DM, Nissen SE. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016 Dec 13;316(22):2373-2384. doi: 10.1001/jama.2016.16951.
• Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJP, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Honda S, Shishikura D, Scherer DJ, Borgman M, Brennan DM, Wolski K, Nissen SE. Effect of Evolocumab on Coronary Plaque Composition. J Am Coll Cardiol. 2018 Oct 23;72(17):2012-2021. doi: 10.1016/j.jacc.2018.06.078.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01813422
• Other Study ID Numbers: 20120153; 2012-004208-37
• First Posted: Mar 19, 2013
• Last Update Posted: Feb 20, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Amgen: Cholesterol; High Cholesterol; Elevated Cholesterol; Raised Cholesterol
• Additional relevant MeSH terms: Hypercholesterolemia; Evolocumab

Study Results

Participant Flow

Recruitment Details	This study was conducted at 163 centers in 30 countries in Europe, North America, Asia Pacific, and Latin America. The first participant was enrolled on 18 April 2013 and the last participant enrolled on 12 January 2015.
Pre-assignment Detail	Participants who met all entry criteria were randomized 1:1 to receive evolocumab 420 mg once monthly (QM) subcutaneous (SC) or placebo QM SC for 76 weeks. Randomization was stratified by region.

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Participants received placebo to evolocumab administered by subcutaneous injection once a month for 76 weeks.	Participants received 420 mg evolocumab administered by subcutaneous injection once a month for 76 weeks.
Period Title: Overall Study
STARTED	486	484
Received Treatment	484	484
COMPLETED	466	468
NOT COMPLETED	20	16

Baseline Characteristics

Arm/Group Title	Placebo	Evolocumab	Total
Arm/Group Description	Participants received placebo to evolocumab administered by subcutaneous injection once a month for 76 weeks.	Participants received 420 mg evolocumab administered by subcutaneous injection once a month for 76 weeks.	Total of all reporting groups
Overall Participants	486	484	970
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.8 (8.8)	59.8 (9.6)	59.8 (9.2)
Sex: Female, Male (Count of Participants)
Female	135 27.8%	135 27.9%	270 27.8%
Male	351 72.2%	349 72.1%	700 72.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	24 4.9%	34 7%	58 6%
Not Hispanic or Latino	462 95.1%	450 93%	912 94%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	2 0.4%	0 0%	2 0.2%
Asian	17 3.5%	14 2.9%	31 3.2%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.2%	1 0.1%
Black or African American	5 1%	4 0.8%	9 0.9%
White	453 93.2%	456 94.2%	909 93.7%
Multiple	6 1.2%	7 1.4%	13 1.3%
Other	3 0.6%	2 0.4%	5 0.5%
Stratification Factor: Geographical Region (participants) [Number]
North America	88 18.1%	86 17.8%	174 17.9%
Europe	332 68.3%	332 68.6%	664 68.5%
Latin America	16 3.3%	15 3.1%	31 3.2%
Asia Pacific	50 10.3%	51 10.5%	101 10.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Percent Atheroma Volume at Week 78
Description	Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. The extent of atherosclerosis was expressed as percent atheroma volume (PAV) in a ≥ 40 mm segment of one targeted (imaged) coronary artery, calculated as the percentage of the total vessel volume occupied by atheroma.
Time Frame	Baseline and week 78

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug, with a baseline IVUS and an IVUS measurement conducted after week 52 (IVUS analysis set)

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Participants received placebo to evolocumab administered by subcutaneous injection once a month for 76 weeks.	Participants received 420 mg evolocumab administered by subcutaneous injection once a month for 76 weeks.
Measure Participants	423	423
Least Squares Mean (Standard Error) [percent atheroma volume]	0.053 (0.189)	-0.955 (0.190)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model included terms for the treatment group, the geographic region stratification factor, and baseline PAV.
Method of Estimation	Estimation Parameter	LS Mean Treatment Difference
	Estimated Value	-1.007
	Confidence Interval	(2-Sided) 95%; -1.375 to -0.640
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.187
	Estimation Comments	Treatment difference uses placebo as the reference.

2. Secondary Outcome

Title	Change From Baseline in Total Atheroma Volume at Week 78
Description	Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. Total atheroma volume (TAV) in a ≥ 40 mm segment of the targeted coronary artery was calculated as the average plaque area over the number of images that were evaluated by IVUS multiplied by the median vessel length to compensate for differences in segment length between participants.
Time Frame	Baseline and week 78

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug, with a baseline IVUS and an IVUS measurement conducted after week 52 (IVUS analysis set)

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Participants received placebo to evolocumab administered by subcutaneous injection once a month for 76 weeks.	Participants received 420 mg evolocumab administered by subcutaneous injection once a month for 76 weeks.
Measure Participants	423	423
Least Squares Mean (Standard Error) [mm³]	-0.910 (1.214)	-5.799 (1.216)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model included terms for the treatment group, the geographic region stratification factor, and baseline TAV.
Method of Estimation	Estimation Parameter	LS Mean Treatment Difference
	Estimated Value	-4.889
	Confidence Interval	(2-Sided) 95%; -7.247 to -2.531
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.201
	Estimation Comments	Treatment difference uses placebo as the reference.

3. Secondary Outcome

Title	Percentage of Participants With Regression in Percent Atheroma Volume
Description	Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. The extent of atherosclerosis was expressed as percent atheroma volume (PAV) in a ≥ 40 mm segment of one targeted (imaged) coronary artery, calculated as the percentage of the total vessel volume occupied by atheroma. Regression in PAV was defined as any reduction from baseline in PAV.
Time Frame	Baseline and week 78

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug, with a baseline IVUS and an IVUS measurement conducted after week 52 (IVUS analysis set)

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Participants received placebo to evolocumab administered by subcutaneous injection once a month for 76 weeks.	Participants received 420 mg evolocumab administered by subcutaneous injection once a month for 76 weeks.
Measure Participants	423	423
Number (95% Confidence Interval) [percentage of participants]	47.3 9.7%	64.3 13.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Based on CMH test stratified by geographic region.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	17.0
	Confidence Interval	(2-Sided) 95%; 10.3 to 23.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference uses placebo as the reference.

4. Secondary Outcome

Title	Percentage of Participants With Regression in Total Atheroma Volume
Description	Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. Total atheroma volume (TAV) in a ≥ 40 mm segment of the targeted coronary artery was calculated as the average plaque area over the number of images that were evaluated by IVUS multiplied by the median vessel length to compensate for differences in segment length between participants. Regression in TAV was defined as any reduction from baseline in TAV.
Time Frame	Baseline and week 78

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug, with a baseline IVUS and an IVUS measurement conducted after week 52 (IVUS analysis set)

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Participants received placebo to evolocumab administered by subcutaneous injection once a month for 76 weeks.	Participants received 420 mg evolocumab administered by subcutaneous injection once a month for 76 weeks.
Measure Participants	423	423
Number (95% Confidence Interval) [percentage of participants]	48.9 10.1%	61.5 12.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Based on CMH test stratified by geographic region.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	12.5
	Confidence Interval	(2-Sided) 95%; 5.8 to 19.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference uses placebo as the reference.

Adverse Events

Time Frame	From first dose of study drug until week 80
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo		Evolocumab
Arm/Group Description	Participants received placebo to evolocumab administered by subcutaneous injection once a month for 76 weeks.		Participants received 420 mg evolocumab administered by subcutaneous injection once a month for 76 weeks.
All Cause Mortality
	Placebo		Evolocumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Evolocumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	142/484 (29.3%)		135/484 (27.9%)
Blood and lymphatic system disorders
Anaemia	1/484 (0.2%)		2/484 (0.4%)
Cardiac disorders
Acute coronary syndrome	3/484 (0.6%)		1/484 (0.2%)
Acute myocardial infarction	5/484 (1%)		6/484 (1.2%)
Angina pectoris	11/484 (2.3%)		17/484 (3.5%)
Angina unstable	7/484 (1.4%)		8/484 (1.7%)
Aortic valve stenosis	1/484 (0.2%)		1/484 (0.2%)
Arteriosclerosis coronary artery	5/484 (1%)		0/484 (0%)
Atrial fibrillation	4/484 (0.8%)		6/484 (1.2%)
Atrial flutter	0/484 (0%)		1/484 (0.2%)
Atrioventricular block	0/484 (0%)		1/484 (0.2%)
Atrioventricular block complete	1/484 (0.2%)		0/484 (0%)
Atrioventricular block second degree	0/484 (0%)		1/484 (0.2%)
Bradycardia	0/484 (0%)		1/484 (0.2%)
Cardiac disorder	0/484 (0%)		1/484 (0.2%)
Cardiac failure	2/484 (0.4%)		0/484 (0%)
Cardiac failure chronic	1/484 (0.2%)		0/484 (0%)
Cardiac failure congestive	0/484 (0%)		1/484 (0.2%)
Cardiac tamponade	0/484 (0%)		1/484 (0.2%)
Coronary artery disease	13/484 (2.7%)		7/484 (1.4%)
Coronary artery dissection	2/484 (0.4%)		1/484 (0.2%)
Coronary artery occlusion	1/484 (0.2%)		3/484 (0.6%)
Coronary artery stenosis	5/484 (1%)		3/484 (0.6%)
Left ventricular dysfunction	1/484 (0.2%)		0/484 (0%)
Mitral valve incompetence	2/484 (0.4%)		0/484 (0%)
Myocardial infarction	4/484 (0.8%)		0/484 (0%)
Myocardial ischaemia	3/484 (0.6%)		1/484 (0.2%)
Palpitations	2/484 (0.4%)		0/484 (0%)
Pericarditis	0/484 (0%)		1/484 (0.2%)
Sinoatrial block	0/484 (0%)		1/484 (0.2%)
Supraventricular tachycardia	2/484 (0.4%)		0/484 (0%)
Ventricular arrhythmia	0/484 (0%)		1/484 (0.2%)
Ventricular fibrillation	1/484 (0.2%)		0/484 (0%)
Ventricular tachycardia	2/484 (0.4%)		0/484 (0%)
Ear and labyrinth disorders
Vertigo	1/484 (0.2%)		0/484 (0%)
Eye disorders
Amaurosis fugax	1/484 (0.2%)		0/484 (0%)
Cataract	0/484 (0%)		1/484 (0.2%)
Diabetic retinopathy	1/484 (0.2%)		0/484 (0%)
Retinopathy	1/484 (0.2%)		0/484 (0%)
Gastrointestinal disorders
Diverticular perforation	1/484 (0.2%)		0/484 (0%)
Dysphagia	1/484 (0.2%)		0/484 (0%)
Erosive duodenitis	0/484 (0%)		1/484 (0.2%)
Gastric ulcer	0/484 (0%)		1/484 (0.2%)
Gastric ulcer haemorrhage	0/484 (0%)		1/484 (0.2%)
Gastritis	0/484 (0%)		2/484 (0.4%)
Ileal perforation	1/484 (0.2%)		0/484 (0%)
Inguinal hernia	2/484 (0.4%)		0/484 (0%)
Large intestine polyp	0/484 (0%)		1/484 (0.2%)
Lower gastrointestinal haemorrhage	0/484 (0%)		1/484 (0.2%)
Nausea	0/484 (0%)		1/484 (0.2%)
Oesophagitis	0/484 (0%)		1/484 (0.2%)
Pancreatitis acute	0/484 (0%)		1/484 (0.2%)
Small intestinal obstruction	1/484 (0.2%)		0/484 (0%)
Upper gastrointestinal haemorrhage	0/484 (0%)		1/484 (0.2%)
Vomiting	1/484 (0.2%)		1/484 (0.2%)
General disorders
Chest discomfort	1/484 (0.2%)		1/484 (0.2%)
Chest pain	0/484 (0%)		1/484 (0.2%)
Malaise	0/484 (0%)		1/484 (0.2%)
Non-cardiac chest pain	6/484 (1.2%)		11/484 (2.3%)
Oedema peripheral	0/484 (0%)		1/484 (0.2%)
Puncture site haemorrhage	0/484 (0%)		1/484 (0.2%)
Sudden death	1/484 (0.2%)		1/484 (0.2%)
Systemic inflammatory response syndrome	0/484 (0%)		1/484 (0.2%)
Vascular stent restenosis	2/484 (0.4%)		3/484 (0.6%)
Vascular stent stenosis	0/484 (0%)		1/484 (0.2%)
Vessel puncture site haemorrhage	0/484 (0%)		1/484 (0.2%)
Hepatobiliary disorders
Cholecystitis acute	2/484 (0.4%)		0/484 (0%)
Cholelithiasis	1/484 (0.2%)		0/484 (0%)
Gallbladder enlargement	1/484 (0.2%)		0/484 (0%)
Immune system disorders
Drug hypersensitivity	0/484 (0%)		1/484 (0.2%)
Infections and infestations
Abdominal abscess	1/484 (0.2%)		0/484 (0%)
Appendicitis	1/484 (0.2%)		1/484 (0.2%)
Brain abscess	0/484 (0%)		1/484 (0.2%)
Bronchitis	0/484 (0%)		2/484 (0.4%)
Bursitis infective staphylococcal	1/484 (0.2%)		0/484 (0%)
Clostridium difficile colitis	0/484 (0%)		1/484 (0.2%)
Diverticulitis	1/484 (0.2%)		1/484 (0.2%)
Eye infection toxoplasmal	1/484 (0.2%)		0/484 (0%)
Gastroenteritis	1/484 (0.2%)		1/484 (0.2%)
Gastroenteritis viral	1/484 (0.2%)		0/484 (0%)
Kidney infection	0/484 (0%)		1/484 (0.2%)
Pneumonia	5/484 (1%)		0/484 (0%)
Postoperative wound infection	1/484 (0.2%)		0/484 (0%)
Pyelonephritis acute	1/484 (0.2%)		0/484 (0%)
Pyonephrosis	0/484 (0%)		1/484 (0.2%)
Sepsis	0/484 (0%)		1/484 (0.2%)
Sinusitis	0/484 (0%)		1/484 (0.2%)
Staphylococcal sepsis	1/484 (0.2%)		0/484 (0%)
Urinary tract infection	0/484 (0%)		2/484 (0.4%)
Vestibular neuronitis	1/484 (0.2%)		1/484 (0.2%)
Injury, poisoning and procedural complications
Cervical vertebral fracture	1/484 (0.2%)		0/484 (0%)
Contusion	0/484 (0%)		1/484 (0.2%)
Fall	0/484 (0%)		2/484 (0.4%)
Head injury	0/484 (0%)		2/484 (0.4%)
Humerus fracture	0/484 (0%)		1/484 (0.2%)
Joint dislocation	1/484 (0.2%)		0/484 (0%)
Laceration	0/484 (0%)		1/484 (0.2%)
Limb traumatic amputation	0/484 (0%)		1/484 (0.2%)
Lumbar vertebral fracture	1/484 (0.2%)		0/484 (0%)
Post procedural haematoma	0/484 (0%)		1/484 (0.2%)
Post procedural haemorrhage	1/484 (0.2%)		1/484 (0.2%)
Procedural dizziness	0/484 (0%)		1/484 (0.2%)
Road traffic accident	1/484 (0.2%)		0/484 (0%)
Skeletal injury	0/484 (0%)		1/484 (0.2%)
Subdural haematoma	1/484 (0.2%)		1/484 (0.2%)
Vascular pseudoaneurysm	0/484 (0%)		1/484 (0.2%)
Investigations
Alanine aminotransferase increased	1/484 (0.2%)		2/484 (0.4%)
Arteriogram coronary	0/484 (0%)		1/484 (0.2%)
Blood creatinine increased	2/484 (0.4%)		0/484 (0%)
Blood pressure increased	0/484 (0%)		1/484 (0.2%)
Liver function test increased	1/484 (0.2%)		0/484 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	2/484 (0.4%)		2/484 (0.4%)
Hypokalaemia	0/484 (0%)		1/484 (0.2%)
Obesity	1/484 (0.2%)		0/484 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/484 (0%)		1/484 (0.2%)
Back pain	3/484 (0.6%)		0/484 (0%)
Bursitis	1/484 (0.2%)		0/484 (0%)
Costochondritis	0/484 (0%)		1/484 (0.2%)
Intervertebral disc degeneration	1/484 (0.2%)		1/484 (0.2%)
Intervertebral disc protrusion	1/484 (0.2%)		2/484 (0.4%)
Joint effusion	1/484 (0.2%)		0/484 (0%)
Musculoskeletal chest pain	1/484 (0.2%)		0/484 (0%)
Musculoskeletal pain	0/484 (0%)		1/484 (0.2%)
Myalgia	1/484 (0.2%)		2/484 (0.4%)
Osteoarthritis	4/484 (0.8%)		1/484 (0.2%)
Osteochondrosis	0/484 (0%)		1/484 (0.2%)
Osteoporosis	0/484 (0%)		1/484 (0.2%)
Rheumatoid arthritis	1/484 (0.2%)		0/484 (0%)
Spinal column stenosis	0/484 (0%)		1/484 (0.2%)
Spinal osteoarthritis	1/484 (0.2%)		1/484 (0.2%)
Spinal pain	1/484 (0.2%)		0/484 (0%)
Spondylitis	1/484 (0.2%)		0/484 (0%)
Spondylolisthesis	0/484 (0%)		1/484 (0.2%)
Vertebral foraminal stenosis	1/484 (0.2%)		0/484 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma	0/484 (0%)		1/484 (0.2%)
Adenocarcinoma of colon	0/484 (0%)		1/484 (0.2%)
Basosquamous carcinoma of skin	1/484 (0.2%)		0/484 (0%)
Benign pancreatic neoplasm	0/484 (0%)		1/484 (0.2%)
Bladder cancer	1/484 (0.2%)		0/484 (0%)
Bladder cancer stage I, with cancer in situ	1/484 (0.2%)		0/484 (0%)
Breast cancer	2/484 (0.4%)		0/484 (0%)
Cervix carcinoma stage 0	0/484 (0%)		1/484 (0.2%)
Chemodectoma	1/484 (0.2%)		0/484 (0%)
Endometrial adenocarcinoma	0/484 (0%)		1/484 (0.2%)
Gastrointestinal tract adenoma	1/484 (0.2%)		0/484 (0%)
Hepatic neoplasm	0/484 (0%)		1/484 (0.2%)
Lung adenocarcinoma	1/484 (0.2%)		1/484 (0.2%)
Lung adenocarcinoma metastatic	1/484 (0.2%)		0/484 (0%)
Lung carcinoma cell type unspecified stage III	0/484 (0%)		1/484 (0.2%)
Lung neoplasm malignant	0/484 (0%)		1/484 (0.2%)
Malignant melanoma	1/484 (0.2%)		0/484 (0%)
Prostate cancer	2/484 (0.4%)		0/484 (0%)
Rectal adenocarcinoma	1/484 (0.2%)		0/484 (0%)
Rectal cancer	0/484 (0%)		1/484 (0.2%)
Renal cancer	0/484 (0%)		1/484 (0.2%)
Renal cell carcinoma	0/484 (0%)		1/484 (0.2%)
Skin cancer	1/484 (0.2%)		0/484 (0%)
Transitional cell carcinoma	0/484 (0%)		1/484 (0.2%)
Ureteral neoplasm	1/484 (0.2%)		0/484 (0%)
Uterine leiomyoma	1/484 (0.2%)		0/484 (0%)
Nervous system disorders
Carotid artery stenosis	0/484 (0%)		1/484 (0.2%)
Cerebral ischaemia	0/484 (0%)		1/484 (0.2%)
Cerebrovascular accident	2/484 (0.4%)		0/484 (0%)
Epilepsy	0/484 (0%)		1/484 (0.2%)
Facial paresis	0/484 (0%)		1/484 (0.2%)
Intracranial aneurysm	1/484 (0.2%)		0/484 (0%)
Loss of consciousness	0/484 (0%)		1/484 (0.2%)
Sciatica	0/484 (0%)		1/484 (0.2%)
Sensory disturbance	0/484 (0%)		1/484 (0.2%)
Syncope	1/484 (0.2%)		3/484 (0.6%)
Transient ischaemic attack	1/484 (0.2%)		1/484 (0.2%)
Tremor	0/484 (0%)		1/484 (0.2%)
Product Issues
Device leakage	1/484 (0.2%)		0/484 (0%)
Psychiatric disorders
Anxiety disorder	0/484 (0%)		1/484 (0.2%)
Depression	1/484 (0.2%)		3/484 (0.6%)
Mental status changes	1/484 (0.2%)		0/484 (0%)
Paranoia	0/484 (0%)		1/484 (0.2%)
Renal and urinary disorders
Acute kidney injury	1/484 (0.2%)		0/484 (0%)
Bladder prolapse	0/484 (0%)		1/484 (0.2%)
Chronic kidney disease	1/484 (0.2%)		0/484 (0%)
Nephrolithiasis	0/484 (0%)		3/484 (0.6%)
Renal artery stenosis	1/484 (0.2%)		0/484 (0%)
Renal colic	0/484 (0%)		1/484 (0.2%)
Stress urinary incontinence	1/484 (0.2%)		0/484 (0%)
Ureteric obstruction	0/484 (0%)		1/484 (0.2%)
Urinary retention	2/484 (0.4%)		0/484 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/484 (0%)		2/484 (0.4%)
Cervical polyp	0/484 (0%)		1/484 (0.2%)
Uterine haemorrhage	1/484 (0.2%)		0/484 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/484 (0.2%)		1/484 (0.2%)
Chronic obstructive pulmonary disease	1/484 (0.2%)		4/484 (0.8%)
Dyspnoea	1/484 (0.2%)		0/484 (0%)
Dyspnoea exertional	1/484 (0.2%)		0/484 (0%)
Epistaxis	1/484 (0.2%)		0/484 (0%)
Pneumonia aspiration	1/484 (0.2%)		0/484 (0%)
Pulmonary embolism	1/484 (0.2%)		2/484 (0.4%)
Pulmonary hypertension	0/484 (0%)		1/484 (0.2%)
Respiratory failure	0/484 (0%)		1/484 (0.2%)
Sleep apnoea syndrome	0/484 (0%)		1/484 (0.2%)
Skin and subcutaneous tissue disorders
Skin ulcer	0/484 (0%)		1/484 (0.2%)
Surgical and medical procedures
Coronary arterial stent insertion	1/484 (0.2%)		0/484 (0%)
Coronary revascularisation	1/484 (0.2%)		1/484 (0.2%)
Hip arthroplasty	0/484 (0%)		1/484 (0.2%)
Mammoplasty	0/484 (0%)		1/484 (0.2%)
Vascular disorders
Aortic aneurysm	0/484 (0%)		2/484 (0.4%)
Arteriosclerosis	2/484 (0.4%)		0/484 (0%)
Hypertension	4/484 (0.8%)		0/484 (0%)
Hypotension	0/484 (0%)		3/484 (0.6%)
Peripheral arterial occlusive disease	2/484 (0.4%)		1/484 (0.2%)
Peripheral artery thrombosis	0/484 (0%)		1/484 (0.2%)
Peripheral vascular disorder	0/484 (0%)		1/484 (0.2%)
Raynaud's phenomenon	1/484 (0.2%)		0/484 (0%)
Vasoconstriction	0/484 (0%)		1/484 (0.2%)
Vessel perforation	0/484 (0%)		1/484 (0.2%)
Other (Not Including Serious) Adverse Events
	Placebo		Evolocumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	120/484 (24.8%)		114/484 (23.6%)
Cardiac disorders
Angina pectoris	32/484 (6.6%)		21/484 (4.3%)
General disorders
Chest pain	26/484 (5.4%)		33/484 (6.8%)
Musculoskeletal and connective tissue disorders
Myalgia	27/484 (5.6%)		34/484 (7%)
Nervous system disorders
Headache	29/484 (6%)		19/484 (3.9%)
Vascular disorders
Hypertension	34/484 (7%)		29/484 (6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.