OSLER-2: Open-label Extension Study of Evolocumab (AMG 145) in Adults With Hyperlipidemia and Mixed Dyslipidemia

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01854918
• Collaborator: (none)
• Enrollment: 3,681
• Locations: 363
• Arms: 2
• Actual Duration (Months): 61.2
• Patients Per Site: 10.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will contribute to the evaluation of long-term safety, tolerability and efficacy of evolocumab (AMG 145) in adults with hyperlipidemia and adults with mixed dyslipidemia.

Condition or Disease	Intervention/Treatment	Phase
Hyperlipidemia and Mixed Dyslipidemia	Biological: Evolocumab; Drug: Standard of Care	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 3681 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Controlled, Open-label Extension (OLE) Study to Assess the Long-term Safety and Efficacy of AMG 145
• Actual Study Start Date: Apr 23, 2013
• Actual Primary Completion Date: May 31, 2018
• Actual Study Completion Date: May 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard of Care Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period). At week 48, participants began treatment with evolocumab at a dose of either 140 mg every 2 weeks (Q2W) or 420 mg every month (QM), based on participant choice, for approximately 2 years during the all-investigational product [all-IP] period.	Biological: Evolocumab; Administered by subcutaneous injection either every 2 weeks or once a month (patient preference) using a prefilled autoinjector pen; Other Names: AMG 145 Repatha ; Drug: Standard of Care; Standard of care therapy as per local practices. This could include prescribed therapies and/or dietary/exercise regimes
Experimental: Evolocumab + Standard of Care Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period) and for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.	Biological: Evolocumab; Administered by subcutaneous injection either every 2 weeks or once a month (patient preference) using a prefilled autoinjector pen; Other Names: AMG 145 Repatha ; Drug: Standard of Care; Standard of care therapy as per local practices. This could include prescribed therapies and/or dietary/exercise regimes

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [48 weeks in the SOC-controlled period and up to 2 years in the All-IP period]

   Adverse event (AE) severity assessments were made using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grading, version 4.0, where grade 1 = mild AE, grade 2 = moderate AE, Grade 3 = severe AE, grade 4 = life-threatening AE and Grade 5 = death due to AE.

Secondary Outcome Measures

1. Percent Change From Baseline in LDL-C at Weeks 48 and 104 [Baseline of the parent study and weeks 48 amd 104]

2. Change From Baseline in LDL-C at Weeks 48 and 104 [Baseline of the parent study and weeks 48 amd 104]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Complete a qualifying evolocumab (AMG 145) parent study (ie, Study 20110114 [NCT01763827], 20110115 [NCT01763866], 20110116 [NCT01763905], 20110117 [NCT01763918], 20110109 [NCT01516879], 20120122 [NCT01953328], 20120332 [NCT01984424], 20120348 [NCT01849497], or 20120356 [NCT01879319]).

Exclusion Criteria:

• Experienced a treatment-related serious adverse event that led to study drug discontinuation in the parent study

• Have an unstable medical condition, in the judgment of the investigator

• Known sensitivity to any of the products to be administered during dosing

• Currently enrolled in another investigational device or drug study (excluding evolocumab (AMG 145) parent study), or less than 30 days since ending another investigational device or drug study(s),or receiving other investigational agent(s)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35216
2	Research Site	Birmingham	Alabama	United States	35294
3	Research Site	Chandler	Arizona	United States	85224
4	Research Site	Phoenix	Arizona	United States	85020
5	Research Site	Tucson	Arizona	United States	85712
6	Research Site	Little Rock	Arkansas	United States	72205
7	Research Site	Beverly Hills	California	United States	90211
8	Research Site	Carmichael	California	United States	95608
9	Research Site	Encinitas	California	United States	92024
10	Research Site	Huntington Beach	California	United States	92648
11	Research Site	Los Angeles	California	United States	90048
12	Research Site	Mission Viejo	California	United States	92691
13	Research Site	Newport Beach	California	United States	92663
14	Research Site	San Diego	California	United States	92111
15	Research Site	Santa Ana	California	United States	92705
16	Research Site	Santa Rosa	California	United States	95405
17	Research Site	Spring Valley	California	United States	91978
18	Research Site	Thousand Oaks	California	United States	91360
19	Research Site	Torrance	California	United States	90509
20	Research Site	Tustin	California	United States	92780
21	Research Site	Ventura	California	United States	93003
22	Research Site	Littleton	Colorado	United States	80120
23	Research Site	Daytona Beach	Florida	United States	32117
24	Research Site	DeLand	Florida	United States	32720
25	Research Site	Jacksonville	Florida	United States	32216
26	Research Site	Melbourne	Florida	United States	32901
27	Research Site	Miami	Florida	United States	33144
28	Research Site	Miami	Florida	United States	33173
29	Research Site	Ponte Vedra	Florida	United States	32081
30	Research Site	Port Charlotte	Florida	United States	33952
31	Research Site	Sanford	Florida	United States	32771
32	Research Site	Atlanta	Georgia	United States	30328
33	Research Site	Atlanta	Georgia	United States	30338
34	Research Site	Atlanta	Georgia	United States	30342
35	Research Site	Gainesville	Georgia	United States	30501
36	Research Site	Savannah	Georgia	United States	31406
37	Research Site	Chicago	Illinois	United States	60654
38	Research Site	Sterling	Illinois	United States	61081
39	Research Site	Indianapolis	Indiana	United States	46260
40	Research Site	Munster	Indiana	United States	46321
41	Research Site	Iowa City	Iowa	United States	52242
42	Research Site	Kansas City	Kansas	United States	66160
43	Research Site	Lexington	Kentucky	United States	40504
44	Research Site	Louisville	Kentucky	United States	40213
45	Research Site	Monroe	Louisiana	United States	71201
46	Research Site	Auburn	Maine	United States	04210
47	Research Site	Bangor	Maine	United States	04401
48	Research Site	Portland	Maine	United States	04101
49	Research Site	Bethesda	Maryland	United States	20817
50	Research Site	Columbia	Maryland	United States	21045
51	Research Site	Towson	Maryland	United States	21204
52	Research Site	Ayer	Massachusetts	United States	01432
53	Research Site	Quincy	Massachusetts	United States	02169
54	Research Site	Ypsilanti	Michigan	United States	48197
55	Research Site	Edina	Minnesota	United States	55435
56	Research Site	Olive Branch	Mississippi	United States	38654
57	Research Site	Tupelo	Mississippi	United States	38801
58	Research Site	Saint Louis	Missouri	United States	63110
59	Research Site	Henderson	Nevada	United States	89052
60	Research Site	Las Vegas	Nevada	United States	89148
61	Research Site	Endwell	New York	United States	13760
62	Research Site	Manlius	New York	United States	13104
63	Research Site	New Windsor	New York	United States	12553
64	Research Site	New York	New York	United States	10029
65	Research Site	Rochester	New York	United States	14609
66	Research Site	Williamsville	New York	United States	14221
67	Research Site	Raleigh	North Carolina	United States	27609
68	Research Site	Raleigh	North Carolina	United States	27612
69	Research Site	Winston-Salem	North Carolina	United States	27103
70	Research Site	Fargo	North Dakota	United States	58103
71	Research Site	Akron	Ohio	United States	44311
72	Research Site	Cadiz	Ohio	United States	43907
73	Research Site	Canton	Ohio	United States	44710
74	Research Site	Cincinnati	Ohio	United States	45219
75	Research Site	Cincinnati	Ohio	United States	45227
76	Research Site	Cincinnati	Ohio	United States	45236
77	Research Site	Cleveland	Ohio	United States	44195
78	Research Site	Dayton	Ohio	United States	45414
79	Research Site	Mansfield	Ohio	United States	44906
80	Research Site	Marion	Ohio	United States	43302
81	Research Site	Sandusky	Ohio	United States	44870
82	Research Site	Norman	Oklahoma	United States	73069
83	Research Site	Oklahoma City	Oklahoma	United States	73103
84	Research Site	Hillsboro	Oregon	United States	97123
85	Research Site	Duncansville	Pennsylvania	United States	16635
86	Research Site	Lansdale	Pennsylvania	United States	19446
87	Research Site	Pittsburgh	Pennsylvania	United States	15216
88	Research Site	York	Pennsylvania	United States	17405
89	Research Site	Anderson	South Carolina	United States	29621
90	Research Site	Charleston	South Carolina	United States	29425
91	Research Site	Mount Pleasant	South Carolina	United States	29464
92	Research Site	Rapid City	South Dakota	United States	57701
93	Research Site	Rapid City	South Dakota	United States	57702
94	Research Site	Jackson	Tennessee	United States	38305
95	Research Site	Nashville	Tennessee	United States	37203
96	Research Site	Austin	Texas	United States	78731
97	Research Site	Dallas	Texas	United States	75230
98	Research Site	Dallas	Texas	United States	75231
99	Research Site	Houston	Texas	United States	77030
100	Research Site	Houston	Texas	United States	77074
101	Research Site	San Antonio	Texas	United States	78229
102	Research Site	Norfolk	Virginia	United States	23502
103	Research Site	Richmond	Virginia	United States	23294
104	Research Site	Suffolk	Virginia	United States	23435
105	Research Site	Renton	Washington	United States	98057
106	Research Site	Seattle	Washington	United States	98104
107	Research Site	Tacoma	Washington	United States	98405
108	Research Site	Camperdown	New South Wales	Australia	2015
109	Research Site	Maroubra	New South Wales	Australia	2035
110	Research Site	Sydney	New South Wales	Australia	2010
111	Research Site	Sydney	New South Wales	Australia	2022
112	Research Site	Auchenflower	Queensland	Australia	4066
113	Research Site	Carina Heights	Queensland	Australia	4152
114	Research Site	Sherwood	Queensland	Australia	4075
115	Research Site	Woolloongabba	Queensland	Australia	4102
116	Research Site	Ashford	South Australia	Australia	5035
117	Research Site	Fullarton	South Australia	Australia	5063
118	Research Site	Heidelberg Heights	Victoria	Australia	3081
119	Research Site	Melbourne	Victoria	Australia	3004
120	Research Site	Perth	Western Australia	Australia	6000
121	Research Site	Salzburg		Austria	5020
122	Research Site	Anthée		Belgium	5520
123	Research Site	Blankenberge		Belgium	8370
124	Research Site	Bruxelles		Belgium	1080
125	Research Site	Bruxelles		Belgium	1200
126	Research Site	Chênée		Belgium	4032
127	Research Site	Gent		Belgium	9000
128	Research Site	Gozee		Belgium	6534
129	Research Site	Gribomont		Belgium	6887
130	Research Site	Halen		Belgium	3545
131	Research Site	Ham		Belgium	3945
132	Research Site	Hasselt		Belgium	3500
133	Research Site	La Louvière		Belgium	7100
134	Research Site	Linkebeek		Belgium	1630
135	Research Site	Oostende		Belgium	8400
136	Research Site	Tessenderlo		Belgium	3980
137	Research Site	Tremelo		Belgium	3120
138	Research Site	Vilvoorde		Belgium	1800
139	Research Site	Burnaby	British Columbia	Canada	V5G 1T4
140	Research Site	Kelowna	British Columbia	Canada	V1Y 1V6
141	Research Site	Surrey	British Columbia	Canada	V3V 1N1
142	Research Site	Vancouver	British Columbia	Canada	V6Z 1Y6
143	Research Site	Bay Roberts	Newfoundland and Labrador	Canada	A0A 1G0
144	Research Site	Mount Pearl	Newfoundland and Labrador	Canada	A1N 1W7
145	Research Site	St. John's	Newfoundland and Labrador	Canada	A1A 3R5
146	Research Site	Cambridge	Ontario	Canada	N1R 6V6
147	Research Site	Hamilton	Ontario	Canada	L8L 2X2
148	Research Site	London	Ontario	Canada	N5W 6A2
149	Research Site	London	Ontario	Canada	N6A 5K8
150	Research Site	Newmarket	Ontario	Canada	L3Y 5G8
151	Research Site	Oshawa	Ontario	Canada	L1J 2K1
152	Research Site	Peterborough	Ontario	Canada	K9J 0B2
153	Research Site	Sarnia	Ontario	Canada	N7T 4X3
154	Research Site	Toronto	Ontario	Canada	M8V 3X8
155	Research Site	Toronto	Ontario	Canada	M9V 4B4
156	Research Site	Toronto	Ontario	Canada	M9W 4L6
157	Research Site	Woodstock	Ontario	Canada	N4S 5P5
158	Research Site	Chicoutimi	Quebec	Canada	G7H 7K9
159	Research Site	Granby	Quebec	Canada	J2G 8Z9
160	Research Site	Greenfield Park	Quebec	Canada	J4V 2G8
161	Research Site	Lachine	Quebec	Canada	H8S 2E4
162	Research Site	Montreal	Quebec	Canada	H2W 1R7
163	Research Site	Montreal	Quebec	Canada	H3A 1A1
164	Research Site	Montreal	Quebec	Canada	H4N 2W2
165	Research Site	Pointe-Claire	Quebec	Canada	H9R 3J1
166	Research Site	Quebec		Canada	G1V 4M6
167	Research Site	Brno		Czechia	602 00
168	Research Site	Brno		Czechia	603 00
169	Research Site	Chomutov		Czechia	430 02
170	Research Site	Hradec Kralove		Czechia	500 05
171	Research Site	Kladno		Czechia	272 01
172	Research Site	Litomerice		Czechia	412 01
173	Research Site	Moravske Budejovice		Czechia	676 02
174	Research Site	Olomouc		Czechia	775 20
175	Research Site	Pardubice		Czechia	530 02
176	Research Site	Plzen		Czechia	305 99
177	Research Site	Praha 2		Czechia	128 08
178	Research Site	Praha 3		Czechia	130 00
179	Research Site	Praha 4		Czechia	140 21
180	Research Site	Praha 5		Czechia	150 06
181	Research Site	Slany		Czechia	274 01
182	Research Site	Svitavy		Czechia	568 25
183	Research Site	Aalborg		Denmark	9000
184	Research Site	Aarhus N		Denmark	8200
185	Research Site	Ballerup		Denmark	2750
186	Research Site	Glostrup		Denmark	2600
187	Research Site	Vejle		Denmark	7100
188	Research Site	Brest Cedex 2		France	29200
189	Research Site	Bron		France	69677
190	Research Site	Caen Cedex 9		France	14033
191	Research Site	Dijon		France	21034
192	Research Site	Montpellier cedex 05		France	34295
193	Research Site	Nantes Cedex 1		France	44093
194	Research Site	Paris Cedex 12		France	75571
195	Research Site	Paris Cedex 13		France	75651
196	Research Site	Vénissieux		France	69200
197	Research Site	Bad Krozingen		Germany	79189
198	Research Site	Berlin (Hellersdorf)		Germany	12627
199	Research Site	Berlin		Germany	10787
200	Research Site	Berlin		Germany	13353
201	Research Site	Dresden		Germany	01307
202	Research Site	Heppenheim		Germany	64646
203	Research Site	Homburg		Germany	66421
204	Research Site	Köln		Germany	50937
205	Research Site	Leipzig		Germany	04103
206	Research Site	Magdeburg		Germany	39112
207	Research Site	Messkirch		Germany	88605
208	Research Site	München		Germany	80638
209	Research Site	Witten		Germany	58455
210	Research Site	Hong Kong		Hong Kong
211	Research Site	New Territories		Hong Kong
212	Research Site	Baja		Hungary	6500
213	Research Site	Berettyoujfalu		Hungary	4100
214	Research Site	Budapest		Hungary	1085
215	Research Site	Eger		Hungary	3300
216	Research Site	Gyongyos		Hungary	3200
217	Research Site	Hodmezovasarhely		Hungary	6800
218	Research Site	Jaszbereny		Hungary	5100
219	Research Site	Komarom		Hungary	2921
220	Research Site	Mosonmagyarovar		Hungary	9200
221	Research Site	Pecs		Hungary	7624
222	Research Site	Szeged		Hungary	6720
223	Research Site	Bologna		Italy	40138
224	Research Site	Cagliari		Italy	09134
225	Research Site	Chieti		Italy	66100
226	Research Site	Cinisello Balsamo (MI)		Italy	20092
227	Research Site	Ferrara		Italy	44124
228	Research Site	Milano		Italy	20162
229	Research Site	Napoli		Italy	80131
230	Research Site	Padova		Italy	35128
231	Research Site	Perugia		Italy	06129
232	Research Site	Pisa		Italy	56100
233	Research Site	Pisa		Italy	56124
234	Research Site	Trieste		Italy	34149
235	Research Site	Noda-shi	Chiba	Japan	278-0004
236	Research Site	Fukuoka-shi	Fukuoka	Japan	810-0014
237	Research Site	Fukuoka-shi	Fukuoka	Japan	810-0066
238	Research Site	Fukuoka-shi	Fukuoka	Japan	819-8551
239	Research Site	Kitakyusyu-shi	Fukuoka	Japan	807-0856
240	Research Site	Koriyama-shi	Fukushima	Japan	963-0209
241	Research Site	Koriyama-shi	Fukushima	Japan	963-8026
242	Research Site	Koriyama-shi	Fukushima	Japan	963-8041
243	Research Site	Koriyama-shi	Fukushima	Japan	963-8832
244	Research Site	Koriyama-shi	Fukushima	Japan	963-8862
245	Research Site	Maebashi-shi	Gunma	Japan	371-0022
246	Research Site	Takasaki-shi	Gunma	Japan	370-3524
247	Research Site	Sapporo-shi	Hokkaido	Japan	003-0026
248	Research Site	Sapporo-shi	Hokkaido	Japan	003-0825
249	Research Site	Sapporo-shi	Hokkaido	Japan	060-0063
250	Research Site	Tsuchiura-shi	Ibaraki	Japan	300-0047
251	Research Site	Morioka-shi	Iwate	Japan	020-0066
252	Research Site	Takamatsu-shi	Kagawa	Japan	760-0018
253	Research Site	Takamatsu-shi	Kagawa	Japan	760-0076
254	Research Site	Yokohama-shi	Kanagawa	Japan	231-0023
255	Research Site	Kyoto-shi	Kyoto	Japan	615-8125
256	Research Site	Sendai-shi	Miyagi	Japan	983-0039
257	Research Site	Sendai-shi	Miyagi	Japan	983-0835
258	Research Site	Sendai-shi	Miyagi	Japan	989-3122
259	Research Site	Tomigusuku-shi	Okinawa	Japan	901-0243
260	Research Site	Ibaraki-shi	Osaka	Japan	567-0876
261	Research Site	Toyonaka-shi	Osaka	Japan	560-0082
262	Research Site	Koshigaya-shi	Saitama	Japan	343-0828
263	Research Site	Niiza-shi	Saitama	Japan	352-0014
264	Research Site	Arakawa-ku	Tokyo	Japan	116-0002
265	Research Site	Chiyoda-ku	Tokyo	Japan	101-0041
266	Research Site	Chofu-shi	Tokyo	Japan	182-0006
267	Research Site	Edogawa-ku	Tokyo	Japan	133-0061
268	Research Site	Hachioji-shi	Tokyo	Japan	192-0046
269	Research Site	Katsushika-ku	Tokyo	Japan	124-0024
270	Research Site	Koto-ku	Tokyo	Japan	135-0011
271	Research Site	Minato-ku	Tokyo	Japan	105-7390
272	Research Site	Minato-ku	Tokyo	Japan	108-0075
273	Research Site	Ota-ku	Tokyo	Japan	144-0034
274	Research Site	Setagaya-ku	Tokyo	Japan	155-0031
275	Research Site	Shibuya-ku	Tokyo	Japan	150-0012
276	Research Site	Shinagawa-ku	Tokyo	Japan	140-0011
277	Research Site	Shinagawa-ku	Tokyo	Japan	141-0001
278	Research Site	Shinagawa-ku	Tokyo	Japan	141-6003
279	Research Site	Shinagawa-ku	Tokyo	Japan	142-0053
280	Research Site	Toshima-ku	Tokyo	Japan	171-0021
281	Research Site	Seoul		Korea, Republic of	120-752
282	Research Site	Seoul		Korea, Republic of	135-710
283	Research Site	Amsterdam		Netherlands	1105 AZ
284	Research Site	Den Helder		Netherlands	1782 GZ
285	Research Site	Groningen		Netherlands	9713 GZ
286	Research Site	Groningen		Netherlands	9728 NT
287	Research Site	Hoogeveen		Netherlands	7909 AA
288	Research Site	Hoorn		Netherlands	1625 HV
289	Research Site	Nijmegen		Netherlands	6525 EZ
290	Research Site	Rotterdam		Netherlands	3045 PM
291	Research Site	Tilburg		Netherlands	5022 GC
292	Research Site	Utrecht		Netherlands	3584 CX
293	Research Site	Waalwijk		Netherlands	5141 BM
294	Research Site	Zwijndrecht		Netherlands	3331 LZ
295	Research Site	Christchurch		New Zealand	8011
296	Research Site	Oslo		Norway	0373
297	Research Site	Ålesund		Norway	6003
298	Research Site	Lodz		Poland	91-078
299	Research Site	Barnaul		Russian Federation	656055
300	Research Site	Kemerovo		Russian Federation	650002
301	Research Site	Moscow		Russian Federation	121552
302	Research Site	Novosibirsk		Russian Federation	630047
303	Research Site	Saint Petersburg		Russian Federation	197022
304	Research Site	Saratov		Russian Federation	410054
305	Research Site	Centurion	Gauteng	South Africa	0157
306	Research Site	Johannesburg	Gauteng	South Africa	2193
307	Research Site	Midrand	Gauteng	South Africa	1685
308	Research Site	Sunninghill	Gauteng	South Africa	2157
309	Research Site	Amanzimtoti	KwaZulu-Natal	South Africa	4126
310	Research Site	Observatory	Western Cape	South Africa	7925
311	Research Site	Paarl	Western Cape	South Africa	7646
312	Research Site	Parow	Western Cape	South Africa	7505
313	Research Site	Somerset West	Western Cape	South Africa	7130
314	Research Site	Bloemfontein		South Africa	9301
315	Research Site	Cordoba	Andalucía	Spain	14004
316	Research Site	Zaragoza	Aragón	Spain	50009
317	Research Site	L'Hospitalet de Llobregat	Cataluña	Spain	08907
318	Research Site	Reus	Cataluña	Spain	43204
319	Research Site	Madrid		Spain	28007
320	Research Site	Madrid		Spain	28029
321	Research Site	Madrid		Spain	28040
322	Research Site	Göteborg		Sweden	413 45
323	Research Site	Lund		Sweden	222 21
324	Research Site	Stockholm		Sweden	111 57
325	Research Site	Stockholm		Sweden	141 86
326	Research Site	Stockholm		Sweden	171 45
327	Research Site	Uddevalla		Sweden	451 50
328	Research Site	Örebro		Sweden	701 46
329	Research Site	Bellinzona		Switzerland	6500
330	Research Site	Geneva 14		Switzerland	1211
331	Research Site	Lausanne		Switzerland	1011
332	Research Site	Lugano		Switzerland	6900
333	Research Site	Muensterlingen		Switzerland	8596
334	Research Site	Reinach		Switzerland	4153
335	Research Site	St. Gallen		Switzerland	9007
336	Research Site	Zurich		Switzerland	8063
337	Research Site	Zurich		Switzerland	8091
338	Research Site	Kaohsiung		Taiwan	83301
339	Research Site	Taipei		Taiwan	100
340	Research Site	Birmingham		United Kingdom	B15 2SQ
341	Research Site	Birmingham		United Kingdom	B15 2TH
342	Research Site	Blackpool		United Kingdom	FY3 7EN
343	Research Site	Cardiff		United Kingdom	CF14 5GJ
344	Research Site	Chesterfield		United Kingdom	S40 4AA
345	Research Site	Chorley		United Kingdom	PR7 7NA
346	Research Site	Coventry		United Kingdom	CV2 2DX
347	Research Site	Doncaster		United Kingdom	DN9 1EP
348	Research Site	Glasgow		United Kingdom	G12 8TA
349	Research Site	Glasgow		United Kingdom	G20 0SP
350	Research Site	Glasgow		United Kingdom	G45 9AW
351	Research Site	Liverpool		United Kingdom	L22 0LG
352	Research Site	Liverpool		United Kingdom	L7 8XP
353	Research Site	London		United Kingdom	NW3 2QG
354	Research Site	London		United Kingdom	SE1 7EH
355	Research Site	London		United Kingdom	W6 8RF
356	Research Site	Manchester		United Kingdom	M13 9WL
357	Research Site	Manchester		United Kingdom	M15 6SX
358	Research Site	Newcastle upon Tyne		United Kingdom	NE1 4LP
359	Research Site	Reading		United Kingdom	RG2 0TG
360	Research Site	Telford		United Kingdom	TF1 6TF
361	Research Site	Wakefield		United Kingdom	WF1 4DG
362	Research Site	West Bromwich		United Kingdom	B71 4HJ
363	Research Site	Whitby		United Kingdom	YO21 1SD

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Apr 3, 2015
• Statistical Analysis Plan - Nov 18, 2013

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Kasichayanula S, Grover A, Emery MG, Gibbs MA, Somaratne R, Wasserman SM, Gibbs JP. Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor. Clin Pharmacokinet. 2018 Jul;57(7):769-779. doi: 10.1007/s40262-017-0620-7. Review.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01854918
• Other Study ID Numbers: 20120138; 2012-004357-83
• First Posted: May 16, 2013
• Last Update Posted: Jun 11, 2019
• Last Verified: May 1, 2019

• Keywords provided by Amgen: High cholesterol; Raised cholesterol; Cholesterol; Elevated Cholesterol
• Additional relevant MeSH terms: Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias; Evolocumab

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 365 study centers in 24 countries in Europe, North America, and Asia Pacific from 23 April 2013 to 31 August 2015.
Pre-assignment Detail	Participants were randomized in a 2:1 ratio to receive evolocumab plus standard of care (SOC) or SOC alone for the first year. In years 2 and 3 all participants received evolocumab. Randomization was stratified by the parent study and parent study dose frequency (every 2 weeks [Q2W] or once monthly [QM]).

Arm/Group Title	Standard of Care	Evolocumab + Standard of Care
Arm/Group Description	Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period). At week 48, participants began treatment with evolocumab at a dose of either 140 mg every 2 weeks (Q2W) or 420 mg every month (QM), based on participant choice, for approximately 2 years during the all-investigational product [all-IP] period.	Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period) and for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.
Period Title: SOC-controlled Period (Year 1)
STARTED	1227	2454
Received Evolocumab	5	2452
COMPLETED	1197	2391
NOT COMPLETED	30	63
Period Title: SOC-controlled Period (Year 1)
STARTED	1197	2391
Received Evolocumab	1152	2291
COMPLETED	1079	2196
NOT COMPLETED	118	195

Baseline Characteristics

Arm/Group Title	Standard of Care	Evolocumab + Standard of Care	Total
Arm/Group Description	Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period). At week 48, participants began treatment with evolocumab at a dose of either 140 mg every 2 weeks (Q2W) or 420 mg every month (QM), based on participant choice, for approximately 2 years during the all-investigational product [all-IP] period.	Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period) and for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.	Total of all reporting groups
Overall Participants	1227	2454	3681
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.8 (10.7)	58.6 (10.7)	58.7 (10.7)
Age, Customized (Count of Participants)
< 65 years	823 67.1%	1665 67.8%	2488 67.6%
≥ 65 years	404 32.9%	789 32.2%	1193 32.4%
Sex: Female, Male (Count of Participants)
Female	560 45.6%	1176 47.9%	1736 47.2%
Male	667 54.4%	1278 52.1%	1945 52.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	58 4.7%	109 4.4%	167 4.5%
Not Hispanic or Latino	1169 95.3%	2345 95.6%	3514 95.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	2 0.2%	5 0.2%	7 0.2%
Asian	152 12.4%	288 11.7%	440 12%
Black or African American	49 4%	84 3.4%	133 3.6%
Native Hawaiian or Other Pacific Islander	2 0.2%	2 0.1%	4 0.1%
White	1003 81.7%	2041 83.2%	3044 82.7%
Other	16 1.3%	30 1.2%	46 1.2%
Mixed Race	3 0.2%	4 0.2%	7 0.2%
Region (Count of Participants)
North America	514 41.9%	1001 40.8%	1515 41.2%
Europe	504 41.1%	1018 41.5%	1522 41.3%
Asia Pacific	209 17%	435 17.7%	644 17.5%
Parent Study Baseline Low-density Lipoprotein Cholesterol (LDL-C) Concentration (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	125.8 (49.3)	127.4 (51.7)	126.9 (50.9)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Adverse event (AE) severity assessments were made using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grading, version 4.0, where grade 1 = mild AE, grade 2 = moderate AE, Grade 3 = severe AE, grade 4 = life-threatening AE and Grade 5 = death due to AE.
Time Frame	48 weeks in the SOC-controlled period and up to 2 years in the All-IP period

Outcome Measure Data

Analysis Population Description

All randomized participants (year 1) and randomized participants on study and who received at least 1 dose of evolocumab in the all-IP period (years 2-3).

Arm/Group Title	Year 1: Standard of Care	Year 1: Evolocumab + Standard of Care	Years 2-3: SOC / Evolocumab + SOC	Years 2-3: Evolocumab + SOC / Evolocumab + SOC
Arm/Group Description	Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period).	Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period). Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.	At week 48, participants began treatment with evolocumab at a dose of either 140 mg Q2W or 420 mg QM, based on participant choice, plus SOC, for approximately 2 years during the all-IP period.	Participants continued to receive evolocumab plus SOC for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg Q2W or 420 mg QM based on participant choice.
Measure Participants	1227	2454	1152	2291
All adverse events	796 64.9%	1655 67.4%	929 25.2%	1789 NaN
Adverse events ≥ grade 2	519 42.3%	1070 43.6%	700 19%	1339 NaN
Adverse events ≥ grade 3	124 10.1%	225 9.2%	214 5.8%	379 NaN
Adverse events ≥ grade 4	7 0.6%	17 0.7%	11 0.3%	35 NaN
Serious adverse events	104 8.5%	195 7.9%	178 4.8%	332 NaN
AEs leading to discontinuation of evolocumab	0 0%	55 2.2%	26 0.7%	42 NaN
Fatal adverse events	5 0.4%	5 0.2%	3 0.1%	16 NaN
Device related adverse events	0 0%	57 2.3%	25 0.7%	45 NaN

2. Secondary Outcome

Title	Percent Change From Baseline in LDL-C at Weeks 48 and 104
Time Frame	Baseline of the parent study and weeks 48 amd 104

Outcome Measure Data

Analysis Population Description

Participants who were randomized in 20120138 and on-study and with known dosing information in the All-IP period, and with non-missing data at each time point.

Arm/Group Title	Standard of Care	Evolocumab + Standard of Care
Arm/Group Description	Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period). At week 48, participants began treatment with evolocumab at a dose of either 140 mg every 2 weeks (Q2W) or 420 mg every month (QM), based on participant choice, for approximately 2 years during the all-investigational product [all-IP] period.	Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period) and for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.
Measure Participants	1152	2291
Week 48	7.43 (38.93)	-51.59 (28.88)
Week 104	-49.96 (33.29)	-50.31 (30.34)

3. Secondary Outcome

Title	Change From Baseline in LDL-C at Weeks 48 and 104
Time Frame	Baseline of the parent study and weeks 48 amd 104

Outcome Measure Data

Analysis Population Description

Participants who were randomized in 20120138 and on-study and with known dosing information in the All-IP period, and with non-missing data at each time point.

Arm/Group Title	Standard of Care	Evolocumab + Standard of Care
Arm/Group Description	Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period). At week 48, participants began treatment with evolocumab at a dose of either 140 mg every 2 weeks (Q2W) or 420 mg every month (QM), based on participant choice, for approximately 2 years during the all-investigational product [all-IP] period.	Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period) and for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.
Measure Participants	1152	2291
Week 48	0.4 (43.9)	-68.8 (46.6)
Week 104	-66.4 (50.1)	-67.2 (46.6)

Adverse Events

Time Frame	48 weeks in the SOC-controlled period and up to 2 years in the All-IP period.
Adverse Event Reporting Description	Adverse evens are reported for all randomized participants in the SOC-controlled period (year 1) and for all participants who entered the all-IP period (years 2-3). Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Year 1: Standard of Care		Year 1: Evolocumab + Standard of Care		Years 2-3: SOC / Evolocumab + SOC		Years 2-3: Evolocumab + SOC / Evolocumab + SOC		Years 2-3: Total
Arm/Group Description	Participants received standard of care (SOC) treatment for the first year of the study (SOC-controlled period).		Participants received subcutaneous evolocumab plus standard of care during the first year of the study (SOC-controlled period). Evolocumab was administered at a dose of 140 mg every 2 weeks (Q2W) or 420 mg every month (QM) based on participant choice.		At week 48, participants began treatment with evolocumab at a dose of either 140 mg Q2W or 420 mg QM, based on participant choice, plus SOC, for approximately 2 years during the all-IP period.		Participants continued to receive evolocumab plus SOC for approximately 2 years during the all-IP period. Evolocumab was administered at a dose of 140 mg Q2W or 420 mg QM based on participant choice.		All participants in the All-IP period who received evolocumab plus SOC for approximately 2 years. Evolocumab was administered at a dose of 140 mg Q2W or 420 mg QM based on participant choice.
All Cause Mortality
	Year 1: Standard of Care		Year 1: Evolocumab + Standard of Care		Years 2-3: SOC / Evolocumab + SOC		Years 2-3: Evolocumab + SOC / Evolocumab + SOC		Years 2-3: Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/1227 (0.4%)		5/2454 (0.2%)		5/1197 (0.4%)		16/2391 (0.7%)		21/3588 (0.6%)
Serious Adverse Events
	Year 1: Standard of Care		Year 1: Evolocumab + Standard of Care		Years 2-3: SOC / Evolocumab + SOC		Years 2-3: Evolocumab + SOC / Evolocumab + SOC		Years 2-3: Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	104/1227 (8.5%)		195/2454 (7.9%)		181/1197 (15.1%)		344/2391 (14.4%)		525/3588 (14.6%)
Blood and lymphatic system disorders
Anaemia	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Haemolysis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Haemorrhagic anaemia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Lymphadenopathy	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Thrombocytopenia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Thrombocytopenic purpura	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Cardiac disorders
Acute coronary syndrome	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Acute myocardial infarction	4/1227 (0.3%)		8/2454 (0.3%)		3/1197 (0.3%)		12/2391 (0.5%)		15/3588 (0.4%)
Angina pectoris	0/1227 (0%)		7/2454 (0.3%)		10/1197 (0.8%)		8/2391 (0.3%)		18/3588 (0.5%)
Angina unstable	6/1227 (0.5%)		7/2454 (0.3%)		4/1197 (0.3%)		11/2391 (0.5%)		15/3588 (0.4%)
Aortic valve disease	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Aortic valve incompetence	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Aortic valve sclerosis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Aortic valve stenosis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Arrhythmia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Arteriosclerosis coronary artery	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Atrial fibrillation	3/1227 (0.2%)		1/2454 (0%)		7/1197 (0.6%)		7/2391 (0.3%)		14/3588 (0.4%)
Atrial flutter	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		3/2391 (0.1%)		3/3588 (0.1%)
Atrioventricular block	1/1227 (0.1%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Bradycardia	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Cardiac arrest	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		4/2391 (0.2%)		4/3588 (0.1%)
Cardiac failure	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Cardiac failure acute	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Cardiac failure congestive	0/1227 (0%)		1/2454 (0%)		3/1197 (0.3%)		6/2391 (0.3%)		9/3588 (0.3%)
Cardio-respiratory arrest	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Coronary artery disease	4/1227 (0.3%)		3/2454 (0.1%)		2/1197 (0.2%)		7/2391 (0.3%)		9/3588 (0.3%)
Coronary artery occlusion	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Coronary artery stenosis	0/1227 (0%)		2/2454 (0.1%)		1/1197 (0.1%)		3/2391 (0.1%)		4/3588 (0.1%)
Left ventricular failure	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Mitral valve incompetence	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Myocardial infarction	2/1227 (0.2%)		5/2454 (0.2%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Myocardial ischaemia	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		4/2391 (0.2%)		5/3588 (0.1%)
Palpitations	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Pericardial effusion	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pericarditis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Rheumatic heart disease	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Sinus node dysfunction	1/1227 (0.1%)		0/2454 (0%)		2/1197 (0.2%)		1/2391 (0%)		3/3588 (0.1%)
Supraventricular tachycardia	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Tachycardia	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Tricuspid valve incompetence	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Ventricular extrasystoles	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Ventricular fibrillation	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Ventricular tachycardia	0/1227 (0%)		2/2454 (0.1%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Congenital, familial and genetic disorders
Adenomatous polyposis coli	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Ear and labyrinth disorders
Deafness neurosensory	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Tinnitus	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Vertigo	1/1227 (0.1%)		2/2454 (0.1%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Vertigo positional	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Endocrine disorders
Goitre	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Hyperparathyroidism primary	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hyperthyroidism	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hypothyroidism	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Eye disorders
Blindness transient	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Cataract	1/1227 (0.1%)		1/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Macular fibrosis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Retinal vein occlusion	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Gastrointestinal disorders
Abdominal hernia	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Abdominal pain	0/1227 (0%)		3/2454 (0.1%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Abdominal pain upper	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Anal skin tags	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Colitis ischaemic	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Constipation	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Diarrhoea	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Diverticulum intestinal	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Duodenal ulcer haemorrhage	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Duodenitis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Enterovesical fistula	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Gastric haemorrhage	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Gastric ulcer	0/1227 (0%)		0/2454 (0%)		2/1197 (0.2%)		2/2391 (0.1%)		4/3588 (0.1%)
Gastritis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Gastroduodenal ulcer	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Gastrointestinal haemorrhage	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Gastrooesophageal reflux disease	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		3/2391 (0.1%)		4/3588 (0.1%)
Haemorrhoids	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hiatus hernia	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Ileus	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Incarcerated inguinal hernia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Inguinal hernia	0/1227 (0%)		2/2454 (0.1%)		3/1197 (0.3%)		3/2391 (0.1%)		6/3588 (0.2%)
Intestinal obstruction	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Intestinal perforation	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Intra-abdominal haematoma	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Intussusception	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Large intestinal obstruction	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Large intestine perforation	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Large intestine polyp	1/1227 (0.1%)		1/2454 (0%)		1/1197 (0.1%)		3/2391 (0.1%)		4/3588 (0.1%)
Lower gastrointestinal haemorrhage	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Mechanical ileus	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Nausea	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Oesophageal ulcer	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Oesophageal ulcer haemorrhage	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Oesophagitis	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Pancreatitis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pancreatitis acute	1/1227 (0.1%)		1/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Salivary gland calculus	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Short-bowel syndrome	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Small intestinal obstruction	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Umbilical hernia	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Vomiting	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
General disorders
Asthenia	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Chest discomfort	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Chest pain	2/1227 (0.2%)		1/2454 (0%)		3/1197 (0.3%)		4/2391 (0.2%)		7/3588 (0.2%)
Complication associated with device	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Face oedema	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Fatigue	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Gait disturbance	0/1227 (0%)		2/2454 (0.1%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Impaired healing	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Injection site erythema	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Malaise	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Multiple organ dysfunction syndrome	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Non-cardiac chest pain	3/1227 (0.2%)		4/2454 (0.2%)		10/1197 (0.8%)		8/2391 (0.3%)		18/3588 (0.5%)
Oedema peripheral	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Pain	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Polyp	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pyrexia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Sudden death	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Vascular stent occlusion	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Vascular stent stenosis	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hepatobiliary disorders
Bile duct stenosis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Bile duct stone	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Cholangitis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Cholecystitis	0/1227 (0%)		0/2454 (0%)		3/1197 (0.3%)		3/2391 (0.1%)		6/3588 (0.2%)
Cholecystitis acute	0/1227 (0%)		0/2454 (0%)		3/1197 (0.3%)		3/2391 (0.1%)		6/3588 (0.2%)
Cholecystitis chronic	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Cholelithiasis	0/1227 (0%)		3/2454 (0.1%)		5/1197 (0.4%)		0/2391 (0%)		5/3588 (0.1%)
Gallbladder necrosis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Hepatic function abnormal	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Non-alcoholic fatty liver	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Sphincter of Oddi dysfunction	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Immune system disorders
Allergy to arthropod sting	0/1227 (0%)		2/2454 (0.1%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Anaphylactic reaction	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Contrast media allergy	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Drug hypersensitivity	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Hypersensitivity	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Infections and infestations
Abdominal abscess	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Abscess jaw	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Abscess neck	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Appendicitis	2/1227 (0.2%)		0/2454 (0%)		1/1197 (0.1%)		3/2391 (0.1%)		4/3588 (0.1%)
Appendicitis perforated	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Arthritis bacterial	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Bronchitis	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Bronchopulmonary aspergillosis	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Campylobacter infection	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Cellulitis	0/1227 (0%)		0/2454 (0%)		3/1197 (0.3%)		3/2391 (0.1%)		6/3588 (0.2%)
Clostridium difficile infection	1/1227 (0.1%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Cystitis	1/1227 (0.1%)		2/2454 (0.1%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Device related infection	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Diverticulitis	2/1227 (0.2%)		1/2454 (0%)		2/1197 (0.2%)		5/2391 (0.2%)		7/3588 (0.2%)
Endocarditis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Epididymitis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Gastroenteritis	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Gastroenteritis bacterial	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Gastroenteritis viral	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Haematoma infection	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Hepatitis B	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Herpes zoster	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Infected dermal cyst	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Infective exacerbation of chronic obstructive airways disease	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Influenza	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Intervertebral discitis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Liver abscess	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Localised infection	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Lower respiratory tract infection	0/1227 (0%)		2/2454 (0.1%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Meningitis viral	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Neurosyphilis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Osteomyelitis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Otitis externa	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Parotitis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Pelvic inflammatory disease	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Peritonitis	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pneumonia	1/1227 (0.1%)		0/2454 (0%)		4/1197 (0.3%)		12/2391 (0.5%)		16/3588 (0.4%)
Pneumonia pneumococcal	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pneumonia viral	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Post procedural infection	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Postoperative abscess	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Postoperative wound infection	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pyelitis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Pyelonephritis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Pyelonephritis acute	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Sepsis	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Septic shock	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Sinusitis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Staphylococcal infection	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Tonsillitis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Urinary tract infection	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Urosepsis	0/1227 (0%)		2/2454 (0.1%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Injury, poisoning and procedural complications
Accidental overdose	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Alcohol poisoning	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Anaemia postoperative	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Anastomotic complication	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Ankle fracture	1/1227 (0.1%)		2/2454 (0.1%)		2/1197 (0.2%)		2/2391 (0.1%)		4/3588 (0.1%)
Back injury	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Cartilage injury	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Clavicle fracture	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Comminuted fracture	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Concussion	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Contusion	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Craniocerebral injury	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Face injury	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Fall	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Femoral neck fracture	1/1227 (0.1%)		0/2454 (0%)		2/1197 (0.2%)		0/2391 (0%)		2/3588 (0.1%)
Femur fracture	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		3/2391 (0.1%)		3/3588 (0.1%)
Fibula fracture	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Foot fracture	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Fractured coccyx	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Gastroenteritis radiation	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hip fracture	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Humerus fracture	1/1227 (0.1%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Incision site haematoma	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Incisional hernia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Intestinal anastomosis complication	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Jaw fracture	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Joint dislocation	1/1227 (0.1%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Laceration	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Lower limb fracture	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Lumbar vertebral fracture	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Meniscus injury	0/1227 (0%)		2/2454 (0.1%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Multiple fractures	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Overdose	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Patella fracture	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pelvic fracture	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Post procedural fever	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Post procedural haemorrhage	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		4/2391 (0.2%)		4/3588 (0.1%)
Procedural pain	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Radius fracture	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Rib fracture	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Road traffic accident	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Spinal fracture	0/1227 (0%)		0/2454 (0%)		2/1197 (0.2%)		0/2391 (0%)		2/3588 (0.1%)
Subarachnoid haemorrhage	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Subdural haematoma	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Subdural haemorrhage	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Tendon rupture	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Thermal burn	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Tibia fracture	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Toxicity to various agents	0/1227 (0%)		0/2454 (0%)		2/1197 (0.2%)		0/2391 (0%)		2/3588 (0.1%)
Upper limb fracture	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
VIIIth nerve injury	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Vascular graft complication	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Vascular graft stenosis	2/1227 (0.2%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Wrist fracture	0/1227 (0%)		0/2454 (0%)		2/1197 (0.2%)		0/2391 (0%)		2/3588 (0.1%)
Investigations
Alanine aminotransferase increased	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Anticoagulation drug level below therapeutic	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Antimitochondrial antibody positive	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Antinuclear antibody	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Aspartate aminotransferase increased	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Blood immunoglobulin M increased	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Ejection fraction decreased	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Intraocular pressure increased	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Liver function test abnormal	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Red blood cell sedimentation rate increased	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Scan myocardial perfusion abnormal	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Metabolism and nutrition disorders
Dehydration	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Fluid overload	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Gout	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hyperglycaemia	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Hypocalcaemia	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Hypoglycaemia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Hyponatraemia	2/1227 (0.2%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Obesity	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Type 2 diabetes mellitus	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Arthritis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		5/2391 (0.2%)		5/3588 (0.1%)
Arthropathy	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Back pain	1/1227 (0.1%)		2/2454 (0.1%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Bursitis	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Cervical spinal stenosis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Diffuse idiopathic skeletal hyperostosis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Dupuytren's contracture	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Femoroacetabular impingement	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Fibromyalgia	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Foot deformity	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		3/2391 (0.1%)		3/3588 (0.1%)
Fracture nonunion	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Gouty arthritis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Intervertebral disc degeneration	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		3/2391 (0.1%)		3/3588 (0.1%)
Intervertebral disc protrusion	1/1227 (0.1%)		1/2454 (0%)		6/1197 (0.5%)		6/2391 (0.3%)		12/3588 (0.3%)
Joint effusion	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Knee deformity	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Lumbar spinal stenosis	0/1227 (0%)		0/2454 (0%)		2/1197 (0.2%)		4/2391 (0.2%)		6/3588 (0.2%)
Metatarsalgia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Muscle haemorrhage	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Musculoskeletal chest pain	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Musculoskeletal pain	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Myalgia	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Osteoarthritis	5/1227 (0.4%)		12/2454 (0.5%)		22/1197 (1.8%)		22/2391 (0.9%)		44/3588 (1.2%)
Osteonecrosis	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pain in extremity	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Polymyalgia rheumatica	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Rhabdomyolysis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Rotator cuff syndrome	0/1227 (0%)		0/2454 (0%)		2/1197 (0.2%)		2/2391 (0.1%)		4/3588 (0.1%)
Spinal column stenosis	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		4/2391 (0.2%)		5/3588 (0.1%)
Spinal deformity	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Spinal osteoarthritis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Spinal pain	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Tendon disorder	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Vertebral foraminal stenosis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Adenocarcinoma of colon	0/1227 (0%)		2/2454 (0.1%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Basal cell carcinoma	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Benign anorectal neoplasm	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Bladder cancer	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Bladder neoplasm	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Bladder transitional cell carcinoma	0/1227 (0%)		3/2454 (0.1%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Breast cancer	4/1227 (0.3%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Breast cancer metastatic	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Breast neoplasm	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Cancer pain	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Cervix carcinoma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Chronic lymphocytic leukaemia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Colon adenoma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Colon cancer	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Diffuse large B-cell lymphoma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Duodenal neoplasm	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Essential thrombocythaemia	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Intraductal proliferative breast lesion	1/1227 (0.1%)		1/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Invasive breast carcinoma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Invasive ductal breast carcinoma	0/1227 (0%)		0/2454 (0%)		2/1197 (0.2%)		2/2391 (0.1%)		4/3588 (0.1%)
Invasive papillary breast carcinoma	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Laryngeal squamous cell carcinoma	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Lipoma	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Lung adenocarcinoma	1/1227 (0.1%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Lung adenocarcinoma stage IV	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Lung neoplasm malignant	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Lymphoma	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Malignant melanoma	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Malignant melanoma in situ	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Meningioma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Metastases to bone	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Metastases to central nervous system	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Metastases to peritoneum	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Neoplasm of appendix	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Neuroendocrine carcinoma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Non-Hodgkin's lymphoma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Oral papilloma	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Pancreatic carcinoma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pancreatic carcinoma metastatic	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Papillary thyroid cancer	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Papillary tumour of renal pelvis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Penile neoplasm	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Prostate cancer	2/1227 (0.2%)		3/2454 (0.1%)		3/1197 (0.3%)		4/2391 (0.2%)		7/3588 (0.2%)
Rectal adenocarcinoma	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Rectal cancer	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Renal cancer	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Renal cell carcinoma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		3/2391 (0.1%)		3/3588 (0.1%)
Salivary gland adenoma	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Salivary gland cancer	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Squamous cell carcinoma	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Squamous cell carcinoma of lung	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Squamous cell carcinoma of the vulva	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Testicular seminoma (pure)	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Thyroid adenoma	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Thyroid cancer	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Thyroid neoplasm	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Tongue neoplasm malignant stage unspecified	1/1227 (0.1%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Uterine cancer	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Uterine leiomyoma	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Vulval cancer	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Nervous system disorders
Ataxia	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Carotid artery aneurysm	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Carotid artery stenosis	1/1227 (0.1%)		2/2454 (0.1%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Carpal tunnel syndrome	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Cerebellar haemorrhage	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Cerebral haemorrhage	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Cerebral ischaemia	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Cerebrovascular accident	1/1227 (0.1%)		1/2454 (0%)		1/1197 (0.1%)		7/2391 (0.3%)		8/3588 (0.2%)
Cervical radiculopathy	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Dizziness	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Dysaesthesia	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Epilepsy	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Haemorrhage intracranial	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Haemorrhagic stroke	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Headache	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Hydrocephalus	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Hypoaesthesia	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hypoglycaemic seizure	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Intracranial aneurysm	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Ischaemic stroke	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Lacunar infarction	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Lumbar radiculopathy	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Metabolic encephalopathy	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Migraine	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Myelopathy	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Nerve root compression	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Paresis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Polyneuropathy	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Presyncope	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		4/2391 (0.2%)		4/3588 (0.1%)
Sciatica	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Seizure	0/1227 (0%)		2/2454 (0.1%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Spinal cord haematoma	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Syncope	3/1227 (0.2%)		1/2454 (0%)		2/1197 (0.2%)		5/2391 (0.2%)		7/3588 (0.2%)
Transient global amnesia	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Transient ischaemic attack	3/1227 (0.2%)		0/2454 (0%)		3/1197 (0.3%)		5/2391 (0.2%)		8/3588 (0.2%)
Tremor	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Vertebrobasilar insufficiency	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Visual field defect	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Product Issues
Device leakage	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Psychiatric disorders
Adjustment disorder with depressed mood	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Agoraphobia	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Alcoholism	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Bipolar I disorder	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Bipolar disorder	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Completed suicide	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Confusional state	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Depression	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		4/2391 (0.2%)		4/3588 (0.1%)
Drug dependence	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Psychotic disorder	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Schizophrenia	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Suicidal ideation	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Suicide attempt	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Renal and urinary disorders
Acute kidney injury	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Bladder fibrosis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Calculus bladder	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Calculus urinary	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Chronic kidney disease	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Haematuria	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hydronephrosis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Nephrolithiasis	0/1227 (0%)		4/2454 (0.2%)		1/1197 (0.1%)		4/2391 (0.2%)		5/3588 (0.1%)
Renal artery stenosis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Renal cyst	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Renal failure	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Renal impairment	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Renal infarct	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Ureteral spasm	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Ureteric stenosis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Ureterolithiasis	0/1227 (0%)		3/2454 (0.1%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Urethral stenosis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Urinary incontinence	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/1227 (0.1%)		2/2454 (0.1%)		3/1197 (0.3%)		2/2391 (0.1%)		5/3588 (0.1%)
Cystocele	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Genital prolapse	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Mastoptosis	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Ovarian cyst	0/1227 (0%)		0/2454 (0%)		2/1197 (0.2%)		0/2391 (0%)		2/3588 (0.1%)
Prostatic obstruction	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Prostatism	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Prostatitis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Rectocele	1/1227 (0.1%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Uterine haemorrhage	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Uterine polyp	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Uterine prolapse	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Vaginal prolapse	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Respiratory, thoracic and mediastinal disorders
Acquired diaphragmatic eventration	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Acute pulmonary oedema	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Asthma	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Atelectasis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Bronchospasm	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Bronchostenosis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Chronic obstructive pulmonary disease	0/1227 (0%)		0/2454 (0%)		2/1197 (0.2%)		3/2391 (0.1%)		5/3588 (0.1%)
Diaphragmatic paralysis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Dyspnoea	2/1227 (0.2%)		1/2454 (0%)		0/1197 (0%)		4/2391 (0.2%)		4/3588 (0.1%)
Dyspnoea exertional	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Epistaxis	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Haemoptysis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Interstitial lung disease	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Nasal polyps	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Nasal septum deviation	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pleural effusion	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Pleurisy	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Pneumonia aspiration	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Pneumothorax	0/1227 (0%)		1/2454 (0%)		1/1197 (0.1%)		2/2391 (0.1%)		3/3588 (0.1%)
Pulmonary embolism	2/1227 (0.2%)		1/2454 (0%)		0/1197 (0%)		4/2391 (0.2%)		4/3588 (0.1%)
Pulmonary hypertension	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Pulmonary mass	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Respiratory failure	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Sleep apnoea syndrome	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Vocal cord polyp	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Dermatitis contact	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hyperhidrosis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Skin lesion	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Toxic skin eruption	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Vascular disorders
Accelerated hypertension	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Aortic aneurysm	0/1227 (0%)		2/2454 (0.1%)		1/1197 (0.1%)		1/2391 (0%)		2/3588 (0.1%)
Aortic dilatation	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Aortic dissection	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Aortic stenosis	0/1227 (0%)		1/2454 (0%)		4/1197 (0.3%)		0/2391 (0%)		4/3588 (0.1%)
Arteriosclerosis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Artery dissection	1/1227 (0.1%)		0/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Blood pressure fluctuation	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Deep vein thrombosis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Haematoma	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Hypertension	2/1227 (0.2%)		1/2454 (0%)		1/1197 (0.1%)		4/2391 (0.2%)		5/3588 (0.1%)
Hypertensive crisis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Hypertensive emergency	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Hypotension	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Labile blood pressure	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Malignant hypertension	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Microangiopathy	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Orthostatic hypotension	0/1227 (0%)		1/2454 (0%)		2/1197 (0.2%)		0/2391 (0%)		2/3588 (0.1%)
Pelvic venous thrombosis	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Peripheral arterial occlusive disease	0/1227 (0%)		2/2454 (0.1%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Peripheral artery aneurysm	0/1227 (0%)		1/2454 (0%)		0/1197 (0%)		0/2391 (0%)		0/3588 (0%)
Peripheral artery occlusion	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Peripheral ischaemia	1/1227 (0.1%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Peripheral vascular disorder	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Subclavian artery stenosis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Thrombophlebitis	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		1/2391 (0%)		1/3588 (0%)
Varicose vein	0/1227 (0%)		0/2454 (0%)		0/1197 (0%)		2/2391 (0.1%)		2/3588 (0.1%)
Venous thrombosis	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Venous thrombosis limb	0/1227 (0%)		0/2454 (0%)		1/1197 (0.1%)		0/2391 (0%)		1/3588 (0%)
Other (Not Including Serious) Adverse Events
	Year 1: Standard of Care		Year 1: Evolocumab + Standard of Care		Years 2-3: SOC / Evolocumab + SOC		Years 2-3: Evolocumab + SOC / Evolocumab + SOC		Years 2-3: Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	334/1227 (27.2%)		681/2454 (27.8%)		498/1197 (41.6%)		928/2391 (38.8%)		1426/3588 (39.7%)
Infections and infestations
Bronchitis	43/1227 (3.5%)		78/2454 (3.2%)		70/1197 (5.8%)		132/2391 (5.5%)		202/3588 (5.6%)
Influenza	28/1227 (2.3%)		66/2454 (2.7%)		60/1197 (5%)		115/2391 (4.8%)		175/3588 (4.9%)
Nasopharyngitis	108/1227 (8.8%)		201/2454 (8.2%)		151/1197 (12.6%)		253/2391 (10.6%)		404/3588 (11.3%)
Upper respiratory tract infection	55/1227 (4.5%)		104/2454 (4.2%)		99/1197 (8.3%)		178/2391 (7.4%)		277/3588 (7.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	38/1227 (3.1%)		106/2454 (4.3%)		80/1197 (6.7%)		162/2391 (6.8%)		242/3588 (6.7%)
Back pain	35/1227 (2.9%)		83/2454 (3.4%)		78/1197 (6.5%)		147/2391 (6.1%)		225/3588 (6.3%)
Myalgia	43/1227 (3.5%)		88/2454 (3.6%)		61/1197 (5.1%)		67/2391 (2.8%)		128/3588 (3.6%)
Vascular disorders
Hypertension	56/1227 (4.6%)		87/2454 (3.5%)		78/1197 (6.5%)		180/2391 (7.5%)		258/3588 (7.2%)

Limitations/Caveats

[Not Specified]

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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.