FRAME: Efficacy and Safety of Romosozumab Treatment in Postmenopausal Women With Osteoporosis

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01575834
• Collaborator: (none)
• Enrollment: 7,180
• Locations: 218
• Arms: 2
• Actual Duration (Months): 57.5
• Patients Per Site: 32.9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if treatment with romosozumab is effective in preventing fractures in women with postmenopausal osteoporosis

Condition or Disease	Intervention/Treatment	Phase
Postmenopausal Osteoporosis	Drug: Romosozumab; Drug: Placebo; Drug: Denosumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 7180 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, International, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Assess the Efficacy and Safety of Romosozumab Treatment in Postmenopausal Women With Osteoporosis
• Actual Study Start Date: Mar 15, 2012
• Actual Primary Completion Date: Dec 14, 2015
• Actual Study Completion Date: Dec 28, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Romosozumab Participants received 210 mg romosozumab subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Drug: Romosozumab; Administered by subcutaneous injection once a month (QM); Other Names: AMG 785 EVENITY™ ; Drug: Denosumab; Administered by subcutaneous injection once every 6 months (Q6M); Other Names: Prolia®
Placebo Comparator: Placebo Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Drug: Placebo; Administered by subcutaneous injection once a month (QM); Drug: Denosumab; Administered by subcutaneous injection once every 6 months (Q6M); Other Names: Prolia®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With New Vertebral Fracture Through Month 12 [12 Months]

   New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant semiquantitative scoring method. The Genant semiquantitative scoring method was based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height.

2. Percentage of Participants With New Vertebral Fracture Through Month 24 [24 months]

   New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant semiquantitative scoring method. The Genant semiquantitative scoring method was based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height.

Secondary Outcome Measures

1. Percentage of Participants With a Clinical Fracture Through Month 12 [12 Months]

   Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.

2. Percentage of Participants With a Nonvertebral Fracture Through Month 12 [12 Months]

   A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.

3. Percentage of Participants With a Nonvertebral Fracture Through Month 24 [24 Months]

   A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date as recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.

4. Percentage of Participants With a Clinical Fracture Through Month 24 [24 Months]

   Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.

5. Percentage of Participants With a Major Nonvertebral Fracture Through Month 12 [12 Months]

   A major nonvertebral fracture was a subset of nonvertebral fractures including pelvis, distal femur (ie, femur excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus (ie, humerus excluding elbow), forearm, and hip.

6. Percentage of Participants With a Major Nonvertebral Fracture Through Month 24 [24 Months]

   A major nonvertebral fracture was a subset of nonvertebral fractures including pelvis, distal femur (ie, femur excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus (ie, humerus excluding elbow), forearm, and hip.

7. Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 12 [12 Months]

   A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4.

8. Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 24 [24 Months]

   A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4.

9. Percentage of Participants With a Hip Fracture Through Month 12 [12 Months]

   Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.

10. Percentage of Participants With a Hip Fracture Through Month 24 [24 Months]

    Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.

11. Percentage of Participants With a Major Osteoporotic Fracture Through Month 12 [12 Months]

    Major osteoporotic fractures included clinical vertebral fractures and fractures of the hip, forearm and humerus. Fractures associated with high trauma severity or pathologic fractures were excluded.

12. Percentage of Participants With a Major Osteoporotic Fracture Through Month 24 [24 Months]

    Major osteoporotic fractures included clinical vertebral fractures and fractures of the hip, forearm and humerus. Fractures associated with high trauma severity or pathologic fractures were excluded.

13. Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 12 [12 Months]

    A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4. A participant had multiple new or worsening vertebral fractures when there were ≥ 2 vertebrae from T4 to L4 with ≥ 1 grade increase from the previous grade. The multiple new or worsening vertebral fractures need not have occurred at the same visit.

14. Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 24 [24 Months]

    A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4. A participant had multiple new or worsening vertebral fractures when there were ≥ 2 vertebrae from T4 to L4 with ≥ 1 grade increase from the previous grade. The multiple new or worsening vertebral fractures need not have occurred at the same visit.

15. Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 12 [Baseline and Month 12]

    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

16. Percent Change From Baseline In Bone Mineral Density at the Lumbar Spine at Month 24 [Baseline and Month 24]

    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

17. Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 12 [Baseline and Month 12]

    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

18. Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 24 [Baseline and Month 24]

    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

19. Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 12 [Baseline and Month 12]

    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

20. Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 24 [Baseline and Month 24]

    Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 90 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Postmenopausal women with osteoporosis, defined as low bone mineral density (BMD T-score at the total hip or femoral neck of ≤ -2.50)

Exclusion Criteria:

• BMD T-score of ≤ -3.50 at the total hip or femoral neck

• History of hip fracture

• Any severe or more than 2 moderate vertebral fractures, as assessed by the central imaging based on lateral spine x-rays

• Use of agents affecting bone metabolism

• History of metabolic or bone disease (except osteoporosis)

• Vitamin D insufficiency (vitamin D repletion and rescreening is permitted)

• Current hyper- or hypocalcemia

• Current, uncontrolled hyper- or hypothyroidism

• Current, uncontrolled hyper- or hypoparathyroidism

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Tucson	Arizona	United States	85704
2	Research Site	Laguna Hills	California	United States	92653
3	Research Site	Los Angeles	California	United States	90057
4	Research Site	Sacramento	California	United States	95817
5	Research Site	Santa Maria	California	United States	93454
6	Research Site	Walnut Creek	California	United States	94598
7	Research Site	Lakewood	Colorado	United States	80227
8	Research Site	Leesburg	Florida	United States	34748
9	Research Site	Palm Harbor	Florida	United States	34684
10	Research Site	Plantation	Florida	United States	33324
11	Research Site	Tampa	Florida	United States	33614
12	Research Site	Gainesville	Georgia	United States	30501
13	Research Site	New Orleans	Louisiana	United States	70121
14	Research Site	Bethesda	Maryland	United States	20817
15	Research Site	Boston	Massachusetts	United States	02114
16	Research Site	Detroit	Michigan	United States	48236
17	Research Site	Albuquerque	New Mexico	United States	87106
18	Research Site	Asheville	North Carolina	United States	28803
19	Research Site	Fargo	North Dakota	United States	58104
20	Research Site	Cincinnati	Ohio	United States	45236
21	Research Site	Mayfield	Ohio	United States	44143
22	Research Site	Duncansville	Pennsylvania	United States	16635
23	Research Site	Denton	Texas	United States	76210-8625
24	Research Site	Richmond	Virginia	United States	23294
25	Research Site	Madison	Wisconsin	United States	53705
26	Research Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1012AAR
27	Research Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1015ABO
28	Research Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1128AAF
29	Research Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1430CKE
30	Research Site	Mar del Plata	Buenos Aires	Argentina	B7600DHK
31	Research Site	Cordoba	Córdoba	Argentina	X5000BNB
32	Research Site	Buenos Aires		Argentina	1425
33	Research Site	Buenos Aires		Argentina	C1425ACG
34	Research Site	Maroubra	New South Wales	Australia	2035
35	Research Site	St Leonards	New South Wales	Australia	2065
36	Research Site	Herston	Queensland	Australia	4029
37	Research Site	Keswick	South Australia	Australia	5035
38	Research Site	Footscray	Victoria	Australia	3011
39	Research Site	Geelong	Victoria	Australia	3220
40	Research Site	Heidelberg West	Victoria	Australia	3081
41	Research Site	Nedlands	Western Australia	Australia	6009
42	Research Site	Bruxelles		Belgium	1000
43	Research Site	Genk		Belgium	3600
44	Research Site	Ghent		Belgium	9000
45	Research Site	Leuven		Belgium	3000
46	Research Site	Liège		Belgium	4020
47	Research Site	Lommel		Belgium	3920
48	Research Site	Yvoir		Belgium	5530
49	Research Site	Curitiba	Paraná	Brazil	80030-110
50	Research Site	Sao Paulo	São Paulo	Brazil	04063-001
51	Research Site	São Paulo		Brazil	04266-010
52	Research Site	São Paulo		Brazil	05403-000
53	Research Site	São Paulo		Brazil	05437-010
54	Research Site	Calgary	Alberta	Canada	T2N 4Z6
55	Research Site	Vancouver	British Columbia	Canada	V5Z 4E1
56	Research Site	Hamilton	Ontario	Canada	L8N 1Y2
57	Research Site	Oakville	Ontario	Canada	L6M 1M1
58	Research Site	Lachine	Quebec	Canada	H8S 2E4
59	Research Site	Quebec		Canada	G1V 3M7
60	Research Site	Medellin	Antioquia	Colombia	050021
61	Research Site	Barranquilla	Atlántico	Colombia	08001000
62	Research Site	Bogota	Cundinamarca	Colombia	11001000
63	Research Site	Bogota	Cundinamarca	Colombia	110221
64	Research Site	Bogota	Cundinamarca	Colombia	1
65	Research Site	Bogota	Cundinamarca	Colombia
66	Research Site	Bogota		Colombia	11001000
67	Research Site	Brno		Czechia	602 00
68	Research Site	Ceske Budejovice		Czechia	370 87
69	Research Site	Havlickuv Brod		Czechia	580 22
70	Research Site	Klatovy		Czechia	339 38
71	Research Site	Ostrava-Trebovice		Czechia	722 00
72	Research Site	Pardubice		Czechia	530 02
73	Research Site	Plzen		Czechia	305 99
74	Research Site	Praha 11 - Chodov		Czechia	148 00
75	Research Site	Praha 2		Czechia	128 50
76	Research Site	Praha 3		Czechia	130 00
77	Research Site	Uherske Hradiste		Czechia	686 01
78	Research Site	Zlin		Czechia	760 01
79	Research Site	Aalborg		Denmark	9000
80	Research Site	Ballerup		Denmark	2750
81	Research Site	Glostrup		Denmark	2600
82	Research Site	Hvidovre		Denmark	2650
83	Research Site	Odense		Denmark	5000
84	Research Site	Vejle		Denmark	7100
85	Research Site	Århus C		Denmark	8000
86	Research Site	Santo Domingo	Distrito Nacional	Dominican Republic	10124
87	Research Site	Santo Domingo	Distrito Nacional	Dominican Republic	10514
88	Research Site	Santo Domingo		Dominican Republic	10605
89	Research Site	Pärnu		Estonia	80013
90	Research Site	Tallinn		Estonia	10128
91	Research Site	Tartu		Estonia	50410
92	Research Site	Berlin (Hellersdorf)		Germany	12627
93	Research Site	Berlin		Germany	12200
94	Research Site	Bochum		Germany	44787
95	Research Site	Dresden		Germany	01067
96	Research Site	Dresden		Germany	01307
97	Research Site	Frankfurt am Main		Germany	60313
98	Research Site	Frankfurt am Main		Germany	60528
99	Research Site	Görlitz		Germany	02826
100	Research Site	Hamburg		Germany	20354
101	Research Site	Hannover		Germany	30167
102	Research Site	Heinsberg		Germany	52525
103	Research Site	Leipzig		Germany	04103
104	Research Site	Magdeburg		Germany	39120
105	Research Site	Marburg		Germany	35043
106	Research Site	Schkeuditz		Germany	04435
107	Research Site	Bekescsaba		Hungary	5600
108	Research Site	Budapest		Hungary	1027
109	Research Site	Budapest		Hungary	1036
110	Research Site	Budapest		Hungary	1083
111	Research Site	Debrecen		Hungary	4032
112	Research Site	Gyor		Hungary	9023
113	Research Site	Heviz		Hungary	8380
114	Research Site	Szeged		Hungary	6720
115	Research Site	Zalaegerszeg		Hungary	8900
116	Research Site	Bangalore	Karnataka	India	560 054
117	Research Site	Mumbai	Maharashtra	India	400 012
118	Research Site	Pune	Maharashtra	India	411 005
119	Research Site	Jaipur	Rajasthan	India	302 019
120	Research Site	Chennai	Tamil Nadu	India	600 020
121	Research Site	Vellore	Tamil Nadu	India	632 004
122	Research Site	Anjyo-shi	Aichi	Japan	446-0063
123	Research Site	Urayasu-shi	Chiba	Japan	279-0004
124	Research Site	Fukui-shi	Fukui	Japan	910-0005
125	Research Site	Fukui-shi	Fukui	Japan	910-0067
126	Research Site	Fukui-shi	Fukui	Japan	918-8057
127	Research Site	Fukui-shi	Fukui	Japan	918-8236
128	Research Site	Fukuoka-shi	Fukuoka	Japan	814-0111
129	Research Site	Fukutsu-shi	Fukuoka	Japan	811-3217
130	Research Site	Kitakyushu-shi	Fukuoka	Japan	806-0026
131	Research Site	Kurume-shi	Fukuoka	Japan	830-0053
132	Research Site	Kurume-shi	Fukuoka	Japan	839-0832
133	Research Site	Hiroshima-shi	Hiroshima	Japan	733-0032
134	Research Site	Chitose-shi	Hokkaido	Japan	066-0062
135	Research Site	Ishikari-shi	Hokkaido	Japan	061-3203
136	Research Site	Sunagawa-shi	Hokkaido	Japan	073-0196
137	Research Site	Akashi-shi	Hyogo	Japan	674-0051
138	Research Site	Kako-gun	Hyogo	Japan	675-1115
139	Research Site	Toride-shi	Ibaraki	Japan	302-0022
140	Research Site	Morioka-shi	Iwate	Japan	020-0015
141	Research Site	Takamatsu-shi	Kagawa	Japan	760-8538
142	Research Site	Kirishima-shi	Kagoshima	Japan	899-5102
143	Research Site	Minamikyusyu-shi	Kagoshima	Japan	897-0215
144	Research Site	Atugi-shi	Kanagawa	Japan	243-0122
145	Research Site	Sagamihara-shi	Kanagawa	Japan	252-5225
146	Research Site	Yokohama-shi	Kanagawa	Japan	223-0059
147	Research Site	Yokohama-shi	Kanagawa	Japan	223-0062
148	Research Site	Yokohama-shi	Kanagawa	Japan	227-0064
149	Research Site	Yokohama-shi	Kanagawa	Japan	231-0023
150	Research Site	Yokohama-shi	Kanagawa	Japan	231-0861
151	Research Site	Kumamoto-shi	Kumamoto	Japan	860-0066
152	Research Site	Sendai-shi	Miyagi	Japan	981-3213
153	Research Site	Chiisagata-gun	Nagano	Japan	386-0603
154	Research Site	Matsumoto-shi	Nagano	Japan	390-1401
155	Research Site	Matsumoto-shi	Nagano	Japan	390-8601
156	Research Site	Ueda-shi	Nagano	Japan	386-0151
157	Research Site	Ueda-shi	Nagano	Japan	386-0405
158	Research Site	Bungoono-shi	Oita	Japan	879-7125
159	Research Site	Osaka-shi	Osaka	Japan	559-0011
160	Research Site	Takatsuki-shi	Osaka	Japan	569-1123
161	Research Site	Saga-shi	Saga	Japan	840-0027
162	Research Site	Fujimi-shi	Saitama	Japan	354-0021
163	Research Site	Matsue-shi	Shimane	Japan	699-0293
164	Research Site	Fujinomiya-shi	Shizuoka	Japan	418-0026
165	Research Site	Kikugawa-shi	Shizuoka	Japan	439-0012
166	Research Site	Tokushima-Shi	Tokushima	Japan	770-8503
167	Research Site	Hachioji-shi	Tokyo	Japan	192-0046
168	Research Site	Kiyose-shi	Tokyo	Japan	204-0021
169	Research Site	Minato-ku	Tokyo	Japan	108-0075
170	Research Site	Ota-ku	Tokyo	Japan	143-0015
171	Research Site	Setagaya-ku	Tokyo	Japan	157-0073
172	Research Site	Shinagawa-ku	Tokyo	Japan	140-0001
173	Research Site	Shinagawa-ku	Tokyo	Japan	140-0014
174	Research Site	Suginami-ku	Tokyo	Japan	166-0001
175	Research Site	Suginami-ku	Tokyo	Japan	166-0003
176	Research Site	Toshima-ku	Tokyo	Japan	171-0033
177	Research Site	Kofu-shi	Yamanashi	Japan	400-0831
178	Research Site	Liepaja		Latvia	3401
179	Research Site	Riga		Latvia	1012
180	Research Site	Riga		Latvia	1038
181	Research Site	Kaunas		Lithuania	49287
182	Research Site	Kaunas		Lithuania	49456
183	Research Site	Klaipeda		Lithuania	94231
184	Research Site	Vilnius		Lithuania	09310
185	Research Site	Vilnius		Lithuania	10323
186	Research Site	Mexico	Distrito Federal	Mexico	06100
187	Research Site	Monterrey	Nuevo León	Mexico	64460
188	Research Site	Ciudad Obregon	Sonora	Mexico	85000
189	Research Site	Christchurch		New Zealand	8022
190	Research Site	Grafton, Auckland		New Zealand	1023
191	Research Site	Dabrowka Dopiewo		Poland	62-069
192	Research Site	Elblag		Poland	82-300
193	Research Site	Krakow		Poland	30-510
194	Research Site	Lodz		Poland	90-368
195	Research Site	Swidnik		Poland	21-040
196	Research Site	Warszawa		Poland	02-341
197	Research Site	Wroclaw		Poland	51-124
198	Research Site	Bucharest		Romania	011172
199	Research Site	Bucuresti		Romania	020125
200	Research Site	Timisoara		Romania	300736
201	Research Site	Barcelona	Cataluña	Spain	08041
202	Research Site	Valencia	Comunidad Valenciana	Spain	46026
203	Research Site	Pozuelo de Alarcon	Madrid	Spain	28223
204	Research Site	Madrid		Spain	28009
205	Research Site	Madrid		Spain	28041
206	Research Site	Bern		Switzerland	3010
207	Research Site	Fribourg		Switzerland	1708
208	Research Site	Genève 14		Switzerland	1211
209	Research Site	Lausanne		Switzerland	1011
210	Research Site	Zurich		Switzerland	8063
211	Research Site	Zurich		Switzerland	8091
212	Research Site	Chorley		United Kingdom	PR7 7NA
213	Research Site	Glasgow		United Kingdom	G20 0SP
214	Research Site	Liverpool		United Kingdom	L22 0LG
215	Research Site	London		United Kingdom	DA14 6LT
216	Research Site	Manchester		United Kingdom	M15 6SX
217	Research Site	Northwood		United Kingdom	HA6 2RN
218	Research Site	Reading		United Kingdom	RG2 0TF

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Chavassieux P, Chapurlat R, Portero-Muzy N, Roux JP, Garcia P, Brown JP, Libanati C, Boyce RW, Wang A, Grauer A. Bone-Forming and Antiresorptive Effects of Romosozumab in Postmenopausal Women With Osteoporosis: Bone Histomorphometry and Microcomputed Tomography Analysis After 2 and 12 Months of Treatment. J Bone Miner Res. 2019 Sep;34(9):1597-1608. doi: 10.1002/jbmr.3735. Epub 2019 Jun 24.
• Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, Hofbauer LC, Lau E, Lewiecki EM, Miyauchi A, Zerbini CA, Milmont CE, Chen L, Maddox J, Meisner PD, Libanati C, Grauer A. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med. 2016 Oct 20;375(16):1532-1543. Epub 2016 Sep 18.
• Cosman F, Crittenden DB, Ferrari S, Khan A, Lane NE, Lippuner K, Matsumoto T, Milmont CE, Libanati C, Grauer A. FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab. J Bone Miner Res. 2018 Jul;33(7):1219-1226. doi: 10.1002/jbmr.3427. Epub 2018 May 17.
• Cosman F, Crittenden DB, Ferrari S, Lewiecki EM, Jaller-Raad J, Zerbini C, Milmont CE, Meisner PD, Libanati C, Grauer A. Romosozumab FRAME Study: A Post Hoc Analysis of the Role of Regional Background Fracture Risk on Nonvertebral Fracture Outcome. J Bone Miner Res. 2018 Aug;33(8):1407-1416. doi: 10.1002/jbmr.3439. Epub 2018 May 11.
• Lewiecki EM, Dinavahi RV, Lazaretti-Castro M, Ebeling PR, Adachi JD, Miyauchi A, Gielen E, Milmont CE, Libanati C, Grauer A. One Year of Romosozumab Followed by Two Years of Denosumab Maintains Fracture Risk Reductions: Results of the FRAME Extension Study. J Bone Miner Res. 2019 Mar;34(3):419-428. doi: 10.1002/jbmr.3622. Epub 2018 Dec 3.
• Miyauchi A, Dinavahi RV, Crittenden DB, Yang W, Maddox JC, Hamaya E, Nakamura Y, Libanati C, Grauer A, Shimauchi J. Increased bone mineral density for 1 year of romosozumab, vs placebo, followed by 2 years of denosumab in the Japanese subgroup of the pivotal FRAME trial and extension. Arch Osteoporos. 2019 Jun 5;14(1):59. doi: 10.1007/s11657-019-0608-z.
• Miyauchi A, Hamaya E, Yang W, Nishi K, Libanati C, Tolman C, Shimauchi J. Romosozumab followed by denosumab in Japanese women with high fracture risk in the FRAME trial. J Bone Miner Metab. 2021 Mar;39(2):278-288. doi: 10.1007/s00774-020-01147-5. Epub 2020 Oct 15.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01575834
• Other Study ID Numbers: 20070337; 2011-001456-11
• First Posted: Apr 12, 2012
• Last Update Posted: Dec 22, 2020
• Last Verified: Dec 1, 2020

• Keywords provided by Amgen: Osteoporosis, Osteoporosis-Postmenopausal, Bone Diseases-Metabolic, Bone Diseases, Musculoskeletal Diseases
• Additional relevant MeSH terms: Osteoporosis; Osteoporosis, Postmenopausal; Denosumab

Study Results

Participant Flow

Recruitment Details	This study was conducted at 222 centers in Europe, Central/Latin America, Asia, North America, and Australia/New Zealand. The first participant enrolled on 15 March 2012 and the last participant enrolled on 06 December 2013.
Pre-assignment Detail	Participants were randomized 1:1 to receive either romosozumab 210 mg or matched placebo for the 12-month, double-blind, placebo-controlled period. Randomization was stratified by age (< 75 years, ≥ 75 years) and prevalent vertebral fracture (yes, no), as determined by site staff at randomization based on local reading of the spine X-ray.

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Period Title: Overall Study
STARTED	3591	3589
Received Double-blind Treatment	3582	3575
Completed Double-blind Period	3205	3185
Completed 24-month Study Period	3032	2994
COMPLETED	2892	2851
NOT COMPLETED	699	738

Baseline Characteristics

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab	Total
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Total of all reporting groups
Overall Participants	3591	3589	7180
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.8 (6.9)	70.9 (7.0)	70.9 (7.0)
Age, Customized (Count of Participants)
< 65 years	757 21.1%	768 21.4%	1525 21.2%
≥ 65 years	2834 78.9%	2821 78.6%	5655 78.8%
Sex: Female, Male (Count of Participants)
Female	3591 100%	3589 100%	7180 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1416 39.4%	1427 39.8%	2843 39.6%
Not Hispanic or Latino	2175 60.6%	2162 60.2%	4337 60.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	2052 57.1%	2063 57.5%	4115 57.3%
Asian	441 12.3%	425 11.8%	866 12.1%
Black or African American	74 2.1%	77 2.1%	151 2.1%
American Indian/Alaska Native	63 1.8%	64 1.8%	127 1.8%
Native Hawaiian/Other Pacific Islander	1 0%	0 0%	1 0%
Multiple	59 1.6%	60 1.7%	119 1.7%
Other	901 25.1%	900 25.1%	1801 25.1%
Prevalent Vertebral Fracture Strata per Randomization (Count of Participants)
Yes	205 5.7%	204 5.7%	409 5.7%
No	3386 94.3%	3385 94.3%	6771 94.3%
Age Strata per Randomization (Count of Participants)
< 75 years	2471 68.8%	2470 68.8%	4941 68.8%
≥ 75 years	1120 31.2%	1119 31.2%	2239 31.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With New Vertebral Fracture Through Month 12
Description	New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant semiquantitative scoring method. The Genant semiquantitative scoring method was based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 12 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3322	3321
Number [percentage of participants]	1.8 0.1%	0.5 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Regression, Logistic
	Comments	Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.27
	Confidence Interval	(2-Sided) 95%; 0.15 to 0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < 1 for odds ratio favor romosozumab.

2. Primary Outcome

Title	Percentage of Participants With New Vertebral Fracture Through Month 24
Description	New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant semiquantitative scoring method. The Genant semiquantitative scoring method was based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used.

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	3327	3325
Number [percentage of participants]	2.5 0.1%	0.6 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Regression, Logistic
	Comments	Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; 0.15 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < 1 for odds ratio favor romosozumab.

3. Secondary Outcome

Title	Percentage of Participants With a Clinical Fracture Through Month 12
Description	Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Full analysis set; Last observation carried forward imputation (LOCF) was used.

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3591	3589
Number [percentage of participants]	2.5 0.1%	1.6 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.46 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab.

4. Secondary Outcome

Title	Percentage of Participants With a Nonvertebral Fracture Through Month 12
Description	A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3591	3589
Number [percentage of participants]	2.1 0.1%	1.6 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab.

5. Secondary Outcome

Title	Percentage of Participants With a Nonvertebral Fracture Through Month 24
Description	A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date as recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	3591	3589
Number [percentage of participants]	3.6 0.1%	2.7 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.057
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.57 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab.

6. Secondary Outcome

Title	Percentage of Participants With a Clinical Fracture Through Month 24
Description	Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Full analysis set; LOCF imputation was used

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	3591	3589
Number [percentage of participants]	4.1 0.1%	2.8 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab.

7. Secondary Outcome

Title	Percentage of Participants With a Major Nonvertebral Fracture Through Month 12
Description	A major nonvertebral fracture was a subset of nonvertebral fractures including pelvis, distal femur (ie, femur excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus (ie, humerus excluding elbow), forearm, and hip.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3591	3589
Number [percentage of participants]	1.5 0%	1.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.44 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab.

8. Secondary Outcome

Title	Percentage of Participants With a Major Nonvertebral Fracture Through Month 24
Description	A major nonvertebral fracture was a subset of nonvertebral fractures including pelvis, distal femur (ie, femur excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus (ie, humerus excluding elbow), forearm, and hip.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	3591	3589
Number [percentage of participants]	2.8 0.1%	1.9 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab

9. Secondary Outcome

Title	Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 12
Description	A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. LOCF imputation was used

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3322	3321
Number [percentage of participants]	1.8 0.1%	0.5 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Regression, Logistic
	Comments	Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < 1 for odds ratio favor romosozumab.

10. Secondary Outcome

Title	Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 24
Description	A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. LOCF imputation was used.

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	3327	3325
Number [percentage of participants]	2.5 0.1%	0.7 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Regression, Logistic
	Comments	Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; 0.16 to 0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < 1 for odds ratio favor romosozumab.

11. Secondary Outcome

Title	Percentage of Participants With a Hip Fracture Through Month 12
Description	Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3591	3589
Number [percentage of participants]	0.4 0%	0.2 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.22 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab.

12. Secondary Outcome

Title	Percentage of Participants With a Hip Fracture Through Month 24
Description	Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	3591	3589
Number [percentage of participants]	0.6 0%	0.3 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments	A fixed-sequence testing procedure was used for multiplicity adjustment of the coprimary and a subset of secondary efficacy endpoints to maintain the overall significance level at 0.05.
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.24 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab.

13. Secondary Outcome

Title	Percentage of Participants With a Major Osteoporotic Fracture Through Month 12
Description	Major osteoporotic fractures included clinical vertebral fractures and fractures of the hip, forearm and humerus. Fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3591	3589
Number [percentage of participants]	1.8 0.1%	1.1 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.40 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab.

14. Secondary Outcome

Title	Percentage of Participants With a Major Osteoporotic Fracture Through Month 24
Description	Major osteoporotic fractures included clinical vertebral fractures and fractures of the hip, forearm and humerus. Fractures associated with high trauma severity or pathologic fractures were excluded.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	3591	3589
Number [percentage of participants]	3.1 0.1%	1.9 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Cox proportional hazards
	Comments	Cox proportional hazards model adjusting for age and prevalent vertebral fracture stratification variables.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.46 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio < 1 favors romosozumab.

15. Secondary Outcome

Title	Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 12
Description	A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4. A participant had multiple new or worsening vertebral fractures when there were ≥ 2 vertebrae from T4 to L4 with ≥ 1 grade increase from the previous grade. The multiple new or worsening vertebral fractures need not have occurred at the same visit.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. LOCF imputation was used.

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3322	3321
Number [percentage of participants]	0.3 0%	0.03 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Regression, Logistic
	Comments	Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < 1 for odds ratio favor romosozumab.

16. Secondary Outcome

Title	Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 24
Description	A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4. A participant had multiple new or worsening vertebral fractures when there were ≥ 2 vertebrae from T4 to L4 with ≥ 1 grade increase from the previous grade. The multiple new or worsening vertebral fractures need not have occurred at the same visit.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set includes all participants who had a baseline and ≥ 1 postbaseline evaluation of vertebral fracture during the 24 months, including participants with missing baseline Genant scores whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. LOCF imputation was used.

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	3327	3325
Number [percentage of participants]	0.5 0%	0.03 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Regression, Logistic
	Comments	Based on logistic regression model adjusted for age and prevalent vertebral fracture stratification variables; p-value based on score test.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < 1 for odds ratio favor romosozumab.

17. Secondary Outcome

Title	Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 12
Description	Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3148	3151
Least Squares Mean (Standard Error) [percent change]	0.4 (0.1)	13.1 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments	The treatment comparison of BMD at the lumbar spine was analyzed using an analysis of covariance (ANCOVA) model which included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	12.7
	Confidence Interval	(2-Sided) 95%; 12.4 to 12.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

18. Secondary Outcome

Title	Percent Change From Baseline In Bone Mineral Density at the Lumbar Spine at Month 24
Description	Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	2877	2861
Least Squares Mean (Standard Error) [percent change]	5.5 (0.1)	16.6 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments	The treatment comparison of BMD at the lumbar spine was analyzed using an analysis of covariance (ANCOVA) model which included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	11.1
	Confidence Interval	(2-Sided) 95%; 10.8 to 11.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

19. Secondary Outcome

Title	Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 12
Description	Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3210	3197
Least Squares Mean (Standard Error) [percent change]	0.3 (0.1)	6.0 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments	The treatment comparison of BMD at the total hip was analyzed using an ANCOVA model which included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	5.8
	Confidence Interval	(2-Sided) 95%; 5.6 to 6.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

20. Secondary Outcome

Title	Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 24
Description	Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	2918	2903
Least Squares Mean (Standard Error) [percent change]	3.2 (0.1)	8.5 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments	The treatment comparison of BMD at the total hip was analyzed using an ANCOVA model which included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	5.3
	Confidence Interval	(2-Sided) 95%; 5.1 to 5.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

21. Secondary Outcome

Title	Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 12
Description	Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.

Arm/Group Title	Placebo	Romosozumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.
Measure Participants	3210	3197
Least Squares Mean (Standard Error) [percent change]	0.3 (0.1)	5.5 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments	The treatment comparison of BMD at the femoral neck was analyzed using an ANCOVA model which included included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	5.2
	Confidence Interval	(2-Sided) 95%; 4.9 to 5.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

22. Secondary Outcome

Title	Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 24
Description	Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

Primary efficacy analysis set for BMD includes all randomized participants who had a baseline and ≥ 1 post-baseline evaluation at or before the time point under consideration in the study period; LOCF imputation was used.

Arm/Group Title	Placebo/Denosumab	Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.	Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
Measure Participants	2918	2903
Least Squares Mean (Standard Error) [percent change]	2.3 (0.1)	7.3 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Romosozumab
	Comments	The treatment comparison of BMD at the femoral neck was analyzed using an ANCOVA model which included included treatment, age and prevalent vertebral fracture stratification variables, and baseline value of the endpoint, machine type and machine type-by-baseline value interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	4.9
	Confidence Interval	(2-Sided) 95%; 4.7 to 5.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

Adverse Events

Time Frame	Double-blind treatment period: 12 months; Overall study: 36 months
Adverse Event Reporting Description	Six participants randomized to placebo received a dose of romosozumab in error during the double-blind period. Therefore, these 6 participants were included in the romosozumab group (ie, as treated) for safety analyses. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	12-Month Double-blind Period: Placebo		12-Month Double-blind Period: Romosozumab		36-Month Study Period: Placebo/Denosumab		36-Month Study Period: Romosozumab/Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once a month for 12 months		Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months.		Participants received placebo subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.		Participants received romosozumab 210 mg subcutaneous injections once a month for 12 months, followed by 60 mg denosumab subcutaneously once every 6 months for 24 months.
All Cause Mortality
	12-Month Double-blind Period: Placebo		12-Month Double-blind Period: Romosozumab		36-Month Study Period: Placebo/Denosumab		36-Month Study Period: Romosozumab/Denosumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	12-Month Double-blind Period: Placebo		12-Month Double-blind Period: Romosozumab		36-Month Study Period: Placebo/Denosumab		36-Month Study Period: Romosozumab/Denosumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	314/3576 (8.8%)		344/3581 (9.6%)		733/3576 (20.5%)		728/3581 (20.3%)
Blood and lymphatic system disorders
Agranulocytosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Anaemia	4/3576 (0.1%)		2/3581 (0.1%)		9/3576 (0.3%)		4/3581 (0.1%)
Anaemia of chronic disease	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Aplastic anaemia	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Autoimmune haemolytic anaemia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Coagulopathy	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hypocoagulable state	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Iron deficiency anaemia	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		4/3581 (0.1%)
Lymphadenitis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Lymphadenopathy	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Neutropenia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pancytopenia	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Pernicious anaemia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Thrombocytopenia	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Cardiac disorders
Acute coronary syndrome	3/3576 (0.1%)		0/3581 (0%)		5/3576 (0.1%)		2/3581 (0.1%)
Acute myocardial infarction	4/3576 (0.1%)		6/3581 (0.2%)		10/3576 (0.3%)		16/3581 (0.4%)
Adams-Stokes syndrome	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Angina pectoris	3/3576 (0.1%)		3/3581 (0.1%)		5/3576 (0.1%)		7/3581 (0.2%)
Angina unstable	3/3576 (0.1%)		6/3581 (0.2%)		9/3576 (0.3%)		10/3581 (0.3%)
Aortic valve disease mixed	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Aortic valve stenosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Arrhythmia	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Arrhythmia supraventricular	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Arteriosclerosis coronary artery	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Atrial fibrillation	4/3576 (0.1%)		6/3581 (0.2%)		18/3576 (0.5%)		17/3581 (0.5%)
Atrioventricular block	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Atrioventricular block complete	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Bradycardia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Cardiac arrest	1/3576 (0%)		1/3581 (0%)		3/3576 (0.1%)		2/3581 (0.1%)
Cardiac failure	1/3576 (0%)		5/3581 (0.1%)		7/3576 (0.2%)		10/3581 (0.3%)
Cardiac failure acute	1/3576 (0%)		1/3581 (0%)		4/3576 (0.1%)		2/3581 (0.1%)
Cardiac failure chronic	1/3576 (0%)		0/3581 (0%)		5/3576 (0.1%)		3/3581 (0.1%)
Cardiac failure congestive	4/3576 (0.1%)		7/3581 (0.2%)		8/3576 (0.2%)		10/3581 (0.3%)
Cardio-respiratory arrest	0/3576 (0%)		2/3581 (0.1%)		5/3576 (0.1%)		4/3581 (0.1%)
Cardiogenic shock	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Cardiopulmonary failure	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Congestive cardiomyopathy	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Cor pulmonale	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Coronary artery disease	3/3576 (0.1%)		4/3581 (0.1%)		7/3576 (0.2%)		7/3581 (0.2%)
Coronary artery insufficiency	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Coronary artery stenosis	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Heart valve incompetence	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hypertensive heart disease	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Ischaemic cardiomyopathy	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Low cardiac output syndrome	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Mitral valve prolapse	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Mitral valve stenosis	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Myocardial infarction	2/3576 (0.1%)		2/3581 (0.1%)		9/3576 (0.3%)		8/3581 (0.2%)
Myocardial ischaemia	4/3576 (0.1%)		3/3581 (0.1%)		7/3576 (0.2%)		3/3581 (0.1%)
Palpitations	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Paroxysmal atrioventricular block	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Prinzmetal angina	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Sinus bradycardia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Sinus node dysfunction	2/3576 (0.1%)		1/3581 (0%)		2/3576 (0.1%)		4/3581 (0.1%)
Stress cardiomyopathy	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Supraventricular tachycardia	3/3576 (0.1%)		0/3581 (0%)		5/3576 (0.1%)		1/3581 (0%)
Ventricular tachycardia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Congenital, familial and genetic disorders
Dermoid cyst	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Ear and labyrinth disorders
Acute vestibular syndrome	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Deafness unilateral	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hypoacusis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Meniere's disease	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Vertigo	3/3576 (0.1%)		2/3581 (0.1%)		5/3576 (0.1%)		2/3581 (0.1%)
Vertigo positional	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Vestibular ataxia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Endocrine disorders
Goitre	1/3576 (0%)		2/3581 (0.1%)		3/3576 (0.1%)		5/3581 (0.1%)
Hyperthyroidism	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Primary hyperaldosteronism	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Eye disorders
Age-related macular degeneration	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Angle closure glaucoma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Blindness unilateral	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Cataract	5/3576 (0.1%)		4/3581 (0.1%)		14/3576 (0.4%)		13/3581 (0.4%)
Cystoid macular oedema	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Glaucoma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Lens disorder	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Posterior capsule rupture	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Retinal detachment	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Retinal disorder	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Uveitis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Gastrointestinal disorders
Abdominal adhesions	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Abdominal hernia	0/3576 (0%)		2/3581 (0.1%)		0/3576 (0%)		3/3581 (0.1%)
Abdominal incarcerated hernia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Abdominal pain	3/3576 (0.1%)		4/3581 (0.1%)		9/3576 (0.3%)		10/3581 (0.3%)
Abdominal pain upper	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		1/3581 (0%)
Acute abdomen	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Anal fissure	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Anal prolapse	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Chronic gastritis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Coeliac disease	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Colitis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Colitis ischaemic	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Constipation	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Diarrhoea	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Diverticular perforation	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Diverticulum	0/3576 (0%)		4/3581 (0.1%)		2/3576 (0.1%)		5/3581 (0.1%)
Diverticulum intestinal	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Duodenal ulcer haemorrhage	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Dyspepsia	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Dysphagia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Enteritis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Faecaloma	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Femoral hernia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Fistula of small intestine	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Functional gastrointestinal disorder	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Gastric haemorrhage	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Gastric polyps	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Gastric ulcer	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Gastric ulcer haemorrhage	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		0/3581 (0%)
Gastric ulcer perforation	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Gastritis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Gastrointestinal angiodysplasia	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Gastrointestinal haemorrhage	1/3576 (0%)		1/3581 (0%)		6/3576 (0.2%)		2/3581 (0.1%)
Gastrointestinal hypomotility	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Gastrointestinal necrosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Gastrooesophageal reflux disease	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		3/3581 (0.1%)
Haemorrhoidal haemorrhage	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Haemorrhoids	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Hernial eventration	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hiatus hernia	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Ileus	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Ileus paralytic	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Incarcerated inguinal hernia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Incarcerated umbilical hernia	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Inguinal hernia	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Intestinal ischaemia	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Intestinal obstruction	1/3576 (0%)		2/3581 (0.1%)		3/3576 (0.1%)		3/3581 (0.1%)
Intestinal perforation	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Irritable bowel syndrome	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Large intestinal ulcer	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Large intestine perforation	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Large intestine polyp	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Lower gastrointestinal haemorrhage	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		3/3581 (0.1%)
Mallory-Weiss syndrome	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Mechanical ileus	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Melaena	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Mesenteric artery thrombosis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Nausea	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Oesophageal varices haemorrhage	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pancreatic cyst	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pancreatic cyst rupture	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pancreatic fistula	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pancreatitis	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Pancreatitis acute	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		6/3581 (0.2%)
Pancreatitis chronic	2/3576 (0.1%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Peritoneal adhesions	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Rectal prolapse	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Reflux gastritis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Retroperitoneal haematoma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Small intestinal obstruction	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Small intestinal perforation	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Toothache	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Umbilical hernia	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Upper gastrointestinal haemorrhage	1/3576 (0%)		1/3581 (0%)		3/3576 (0.1%)		2/3581 (0.1%)
Vomiting	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		3/3581 (0.1%)
General disorders
Asthenia	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Chest pain	1/3576 (0%)		3/3581 (0.1%)		3/3576 (0.1%)		4/3581 (0.1%)
Complication associated with device	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Death	5/3576 (0.1%)		5/3581 (0.1%)		9/3576 (0.3%)		13/3581 (0.4%)
General physical health deterioration	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Malaise	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Medical device discomfort	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Mucosal dryness	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Multiple organ dysfunction syndrome	1/3576 (0%)		1/3581 (0%)		3/3576 (0.1%)		2/3581 (0.1%)
Non-cardiac chest pain	0/3576 (0%)		4/3581 (0.1%)		3/3576 (0.1%)		10/3581 (0.3%)
Oedema peripheral	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		0/3581 (0%)
Pyrexia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Sudden death	1/3576 (0%)		0/3581 (0%)		4/3576 (0.1%)		0/3581 (0%)
Hepatobiliary disorders
Autoimmune hepatitis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Bile duct stone	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Biliary colic	0/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Biliary dilatation	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Cholangitis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Cholangitis sclerosing	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Cholecystitis	0/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		2/3581 (0.1%)
Cholecystitis acute	1/3576 (0%)		3/3581 (0.1%)		6/3576 (0.2%)		5/3581 (0.1%)
Cholecystitis chronic	0/3576 (0%)		2/3581 (0.1%)		0/3576 (0%)		2/3581 (0.1%)
Cholelithiasis	8/3576 (0.2%)		5/3581 (0.1%)		11/3576 (0.3%)		12/3581 (0.3%)
Cholelithiasis obstructive	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Cholestasis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Drug-induced liver injury	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Hepatic cyst	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hepatic failure	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hepatic steatosis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hepatocellular injury	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Ischaemic hepatitis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Jaundice	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Jaundice cholestatic	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Liver disorder	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Liver injury	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Portal hypertension	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Portal vein thrombosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Sphincter of Oddi dysfunction	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Immune system disorders
Anaphylactic shock	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Drug hypersensitivity	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hypersensitivity	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Infections and infestations
Abdominal sepsis	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Abscess	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Abscess limb	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Amoebiasis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Amoebic colitis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Amoebic dysentery	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Appendicitis	2/3576 (0.1%)		1/3581 (0%)		7/3576 (0.2%)		4/3581 (0.1%)
Appendicitis perforated	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Arthritis bacterial	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Bacterial tracheitis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Bronchitis	1/3576 (0%)		4/3581 (0.1%)		3/3576 (0.1%)		9/3581 (0.3%)
Bronchitis bacterial	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Bronchitis viral	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Cellulitis	2/3576 (0.1%)		5/3581 (0.1%)		11/3576 (0.3%)		11/3581 (0.3%)
Chikungunya virus infection	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Chlamydial infection	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Chronic sinusitis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Clostridium colitis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Clostridium difficile colitis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		3/3581 (0.1%)
Cystitis	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Dengue fever	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Dermatitis infected	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Diverticulitis	3/3576 (0.1%)		1/3581 (0%)		6/3576 (0.2%)		3/3581 (0.1%)
Empyema	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Encephalitis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Enterobacter bacteraemia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Erysipelas	1/3576 (0%)		2/3581 (0.1%)		3/3576 (0.1%)		3/3581 (0.1%)
Escherichia sepsis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Escherichia urinary tract infection	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		0/3581 (0%)
Eye infection	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Gangrene	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Gastroenteritis	0/3576 (0%)		1/3581 (0%)		3/3576 (0.1%)		6/3581 (0.2%)
Gastroenteritis bacterial	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Gastroenteritis viral	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Hepatitis B	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hepatitis C	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hepatitis viral	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Herpes zoster	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Infected dermal cyst	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Infected skin ulcer	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Infective exacerbation of bronchiectasis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Infective exacerbation of chronic obstructive airways disease	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Influenza	2/3576 (0.1%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Intestinal gangrene	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Labyrinthitis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Liver abscess	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Lower respiratory tract infection	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Lyme disease	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Lymphangitis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Medical device site joint infection	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Meningitis pneumococcal	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Mycobacterium avium complex infection	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Osteomyelitis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Osteomyelitis chronic	2/3576 (0.1%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Otitis media acute	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Perichondritis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Perineal abscess	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Perirectal abscess	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Peritonitis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Peritonitis bacterial	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pharyngitis bacterial	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Phlebitis infective	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pneumococcal sepsis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pneumonia	10/3576 (0.3%)		19/3581 (0.5%)		37/3576 (1%)		44/3581 (1.2%)
Pneumonia bacterial	2/3576 (0.1%)		2/3581 (0.1%)		4/3576 (0.1%)		2/3581 (0.1%)
Pneumonia cryptococcal	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pneumonia haemophilus	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pneumonia mycoplasmal	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Postoperative wound infection	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Pulmonary sepsis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pulmonary tuberculosis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pyelocystitis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pyelonephritis	0/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		1/3581 (0%)
Pyelonephritis acute	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pyometra	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pyonephrosis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Salmonellosis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Sepsis	1/3576 (0%)		4/3581 (0.1%)		3/3576 (0.1%)		7/3581 (0.2%)
Septic shock	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		4/3581 (0.1%)
Sinusitis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Skin infection	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Staphylococcal infection	0/3576 (0%)		2/3581 (0.1%)		0/3576 (0%)		2/3581 (0.1%)
Streptococcal sepsis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Tick-borne viral encephalitis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Upper respiratory tract infection	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Ureteritis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Urinary tract infection	7/3576 (0.2%)		4/3581 (0.1%)		14/3576 (0.4%)		17/3581 (0.5%)
Urinary tract infection bacterial	3/3576 (0.1%)		3/3581 (0.1%)		4/3576 (0.1%)		4/3581 (0.1%)
Urosepsis	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Vaginitis bacterial	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Vestibular neuronitis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Wound abscess	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Accidental overdose	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Acetabulum fracture	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Animal bite	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Brain contusion	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Cataract operation complication	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Concussion	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		1/3581 (0%)
Contusion	2/3576 (0.1%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Craniocerebral injury	3/3576 (0.1%)		1/3581 (0%)		4/3576 (0.1%)		2/3581 (0.1%)
Eye injury	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Eyelid injury	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Face injury	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Facial bones fracture	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Fall	1/3576 (0%)		0/3581 (0%)		6/3576 (0.2%)		7/3581 (0.2%)
Femoral neck fracture	8/3576 (0.2%)		3/3581 (0.1%)		14/3576 (0.4%)		11/3581 (0.3%)
Femur fracture	7/3576 (0.2%)		4/3581 (0.1%)		19/3576 (0.5%)		9/3581 (0.3%)
Fibula fracture	4/3576 (0.1%)		4/3581 (0.1%)		8/3576 (0.2%)		7/3581 (0.2%)
Foot fracture	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Foreign body	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Fractured sacrum	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Gastrointestinal stoma complication	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hand fracture	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Head injury	1/3576 (0%)		2/3581 (0.1%)		3/3576 (0.1%)		6/3581 (0.2%)
Humerus fracture	0/3576 (0%)		1/3581 (0%)		8/3576 (0.2%)		8/3581 (0.2%)
Incisional hernia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Injury	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Internal injury	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Joint dislocation	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Joint injury	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Ligament sprain	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Limb injury	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Lumbar vertebral fracture	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Meniscus injury	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Multiple injuries	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Muscle rupture	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Muscle strain	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Overdose	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Patella fracture	1/3576 (0%)		0/3581 (0%)		4/3576 (0.1%)		2/3581 (0.1%)
Pneumothorax traumatic	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Post concussion syndrome	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Post procedural complication	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Post procedural haemorrhage	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Postoperative adhesion	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Postoperative delirium	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Procedural complication	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Procedural hypotension	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Procedural pain	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pubis fracture	0/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Radial head dislocation	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Radius fracture	5/3576 (0.1%)		3/3581 (0.1%)		17/3576 (0.5%)		14/3581 (0.4%)
Rib fracture	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		3/3581 (0.1%)
Road traffic accident	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Spinal fracture	0/3576 (0%)		1/3581 (0%)		3/3576 (0.1%)		2/3581 (0.1%)
Sternal fracture	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Stoma site ischaemia	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Subarachnoid haemorrhage	0/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Subdural haematoma	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Tendon rupture	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Thoracic vertebral fracture	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Tibia fracture	4/3576 (0.1%)		4/3581 (0.1%)		7/3576 (0.2%)		7/3581 (0.2%)
Toxicity to various agents	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Ulna fracture	4/3576 (0.1%)		2/3581 (0.1%)		12/3576 (0.3%)		8/3581 (0.2%)
Uterine dehiscence	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Wound	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Wound complication	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Wound evisceration	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Wound haemorrhage	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Wound necrosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Investigations
Blood lactic acid increased	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Blood pressure decreased	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Blood pressure increased	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Body mass index increased	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Fibrin D dimer increased	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Gastric pH decreased	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
General physical condition abnormal	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Haemoglobin decreased	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hepatic enzyme increased	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Influenza B virus test positive	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Liver function test increased	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Transaminases increased	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Metabolism and nutrition disorders
Decreased appetite	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Dehydration	0/3576 (0%)		2/3581 (0.1%)		1/3576 (0%)		7/3581 (0.2%)
Diabetes mellitus	0/3576 (0%)		1/3581 (0%)		3/3576 (0.1%)		4/3581 (0.1%)
Diabetes mellitus inadequate control	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Diabetic ketoacidosis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		3/3581 (0.1%)
Diabetic metabolic decompensation	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Electrolyte imbalance	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Folate deficiency	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hypercalcaemia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hyperglycaemia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hyperkalaemia	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Hypernatraemia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hypocalcaemia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hypochloraemia	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hypoglycaemia	2/3576 (0.1%)		0/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Hypokalaemia	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Hyponatraemia	0/3576 (0%)		3/3581 (0.1%)		5/3576 (0.1%)		4/3581 (0.1%)
Hyponatraemic syndrome	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hypoosmolar state	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Malnutrition	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Mineral metabolism disorder	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Type 2 diabetes mellitus	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Vitamin B12 deficiency	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/3576 (0%)		0/3581 (0%)		4/3576 (0.1%)		0/3581 (0%)
Arthritis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Arthropathy	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Back pain	1/3576 (0%)		2/3581 (0.1%)		5/3576 (0.1%)		5/3581 (0.1%)
Bursitis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Chondrocalcinosis pyrophosphate	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Coccydynia	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Costochondritis	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Foot deformity	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Fracture pain	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Haemarthrosis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Intervertebral disc compression	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Intervertebral disc degeneration	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Intervertebral disc disorder	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Intervertebral disc protrusion	2/3576 (0.1%)		0/3581 (0%)		4/3576 (0.1%)		4/3581 (0.1%)
Lumbar spinal stenosis	2/3576 (0.1%)		0/3581 (0%)		5/3576 (0.1%)		3/3581 (0.1%)
Meniscal degeneration	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Muscle haemorrhage	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Myalgia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Osteitis deformans	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Osteoarthritis	15/3576 (0.4%)		6/3581 (0.2%)		27/3576 (0.8%)		21/3581 (0.6%)
Osteonecrosis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Osteonecrosis of jaw	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pain in extremity	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Pain in jaw	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Polymyalgia rheumatica	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Psoriatic arthropathy	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Rotator cuff syndrome	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Scoliosis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Spinal column stenosis	3/3576 (0.1%)		1/3581 (0%)		5/3576 (0.1%)		4/3581 (0.1%)
Spinal osteoarthritis	2/3576 (0.1%)		0/3581 (0%)		10/3576 (0.3%)		1/3581 (0%)
Spinal pain	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Spondylolisthesis	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Synovial cyst	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Systemic lupus erythematosus	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Trigger finger	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acral lentiginous melanoma	0/3576 (0%)		2/3581 (0.1%)		0/3576 (0%)		2/3581 (0.1%)
Acute myeloid leukaemia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Adenocarcinoma gastric	2/3576 (0.1%)		1/3581 (0%)		8/3576 (0.2%)		2/3581 (0.1%)
Adenocarcinoma of colon	2/3576 (0.1%)		0/3581 (0%)		4/3576 (0.1%)		2/3581 (0.1%)
Adenocarcinoma pancreas	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Adrenal adenoma	2/3576 (0.1%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Adrenal neoplasm	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Anal cancer	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Angiocentric lymphoma	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Basal cell carcinoma	5/3576 (0.1%)		2/3581 (0.1%)		6/3576 (0.2%)		7/3581 (0.2%)
Basosquamous carcinoma	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Benign breast neoplasm	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Benign gastric neoplasm	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Benign neoplasm of adrenal gland	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Benign neoplasm of bladder	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Benign neoplasm of spinal cord	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Benign ovarian tumour	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Benign pleural neoplasm	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Benign salivary gland neoplasm	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Benign soft tissue neoplasm	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Bladder cancer	1/3576 (0%)		0/3581 (0%)		4/3576 (0.1%)		0/3581 (0%)
Bladder transitional cell carcinoma	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Bowen's disease	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Brain neoplasm malignant	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Breast cancer	3/3576 (0.1%)		1/3581 (0%)		11/3576 (0.3%)		8/3581 (0.2%)
Breast cancer female	2/3576 (0.1%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Breast cancer in situ	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Breast cancer recurrent	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Breast cancer stage II	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Breast cancer stage III	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Bronchial carcinoma	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Cervix carcinoma	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Cervix carcinoma stage II	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Choroid melanoma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Colon adenoma	0/3576 (0%)		3/3581 (0.1%)		0/3576 (0%)		3/3581 (0.1%)
Colon cancer	0/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		1/3581 (0%)
Colon cancer metastatic	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Colon neoplasm	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Colorectal adenocarcinoma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Colorectal cancer	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Diffuse large B-cell lymphoma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Endometrial adenocarcinoma	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Fibrous histiocytoma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Gallbladder cancer	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Gastric cancer	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Glioblastoma multiforme	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Granular cell tumour	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Haemangioma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hepatic cancer	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hepatocellular carcinoma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Intraductal proliferative breast lesion	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Intraocular melanoma	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Invasive ductal breast carcinoma	0/3576 (0%)		3/3581 (0.1%)		1/3576 (0%)		4/3581 (0.1%)
Large intestine benign neoplasm	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Laryngeal squamous cell carcinoma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Lentigo maligna	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Lung adenocarcinoma	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		1/3581 (0%)
Lung adenocarcinoma metastatic	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Lung neoplasm malignant	6/3576 (0.2%)		7/3581 (0.2%)		10/3576 (0.3%)		13/3581 (0.4%)
Lymphoma	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Malignant melanoma in situ	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Malignant neoplasm of conjunctiva	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Mantle cell lymphoma	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Meningioma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Meningioma benign	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Metastases to bone	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Metastases to liver	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		3/3581 (0.1%)
Metastases to lymph nodes	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Metastases to pleura	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Metastatic bronchial carcinoma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Metastatic malignant melanoma	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Nasopharyngeal cancer	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Neoplasm of appendix	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Neuroendocrine carcinoma of the skin	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Neurofibroma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Non-Hodgkin's lymphoma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Oesophageal carcinoma	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Oesophageal squamous cell carcinoma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Oesophageal squamous cell carcinoma recurrent	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Ovarian adenoma	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Ovarian cancer	1/3576 (0%)		1/3581 (0%)		3/3576 (0.1%)		3/3581 (0.1%)
Ovarian cancer metastatic	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Paget's disease of nipple	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pancoast's tumour	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pancreatic carcinoma	0/3576 (0%)		2/3581 (0.1%)		0/3576 (0%)		3/3581 (0.1%)
Pancreatic neuroendocrine tumour	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Papillary thyroid cancer	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Paranasal sinus benign neoplasm	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Phaeochromocytoma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pituitary tumour benign	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Plasma cell myeloma	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Pyogenic granuloma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Rectal adenocarcinoma	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Rectal cancer	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Rectal cancer stage II	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Rectosigmoid cancer	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Renal adenoma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Renal cancer	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Renal cell carcinoma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Skin cancer	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Small cell lung cancer	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Small intestine adenocarcinoma	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Small intestine carcinoma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Squamous cell carcinoma	2/3576 (0.1%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Squamous cell carcinoma of lung	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Squamous cell carcinoma of pharynx	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Squamous cell carcinoma of skin	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		1/3581 (0%)
Squamous cell carcinoma of the hypopharynx	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Tracheal cancer	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Uterine leiomyoma	0/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Nervous system disorders
Amyotrophic lateral sclerosis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Arachnoid cyst	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Basal ganglia stroke	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Brain oedema	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Brain stem ischaemia	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Carotid arteriosclerosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Carotid artery occlusion	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Carotid artery stenosis	1/3576 (0%)		0/3581 (0%)		4/3576 (0.1%)		0/3581 (0%)
Cerebellar ischaemia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Cerebral haematoma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Cerebral haemorrhage	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		3/3581 (0.1%)
Cerebral infarction	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Cerebral ischaemia	2/3576 (0.1%)		1/3581 (0%)		2/3576 (0.1%)		3/3581 (0.1%)
Cerebrovascular accident	7/3576 (0.2%)		4/3581 (0.1%)		9/3576 (0.3%)		14/3581 (0.4%)
Cerebrovascular disorder	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Cervical myelopathy	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Cervical radiculopathy	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Cervicobrachial syndrome	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Cervicogenic headache	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Cognitive disorder	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Dementia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Dementia Alzheimer's type	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Depressed level of consciousness	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Diabetic coma	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Dizziness	0/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Embolic cerebral infarction	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Epilepsy	0/3576 (0%)		3/3581 (0.1%)		1/3576 (0%)		5/3581 (0.1%)
Facial paralysis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Facial paresis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Haemorrhage intracranial	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Haemorrhagic cerebral infarction	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Haemorrhagic stroke	0/3576 (0%)		2/3581 (0.1%)		3/3576 (0.1%)		3/3581 (0.1%)
Haemorrhagic transformation stroke	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Headache	3/3576 (0.1%)		0/3581 (0%)		4/3576 (0.1%)		1/3581 (0%)
Hemiparesis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hemiplegia	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hepatic encephalopathy	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hydrocephalus	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Hypotonia	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Internal carotid artery kinking	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Intracranial aneurysm	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Ischaemic cerebral infarction	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Ischaemic stroke	1/3576 (0%)		0/3581 (0%)		9/3576 (0.3%)		13/3581 (0.4%)
Lacunar infarction	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Loss of consciousness	0/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Lumbosacral radiculopathy	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Meralgia paraesthetica	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Migraine	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Motor dysfunction	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Multiple sclerosis relapse	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Nerve compression	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Nerve root compression	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Neuropathy peripheral	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Normal pressure hydrocephalus	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Nystagmus	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Paraesthesia	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Paralysis recurrent laryngeal nerve	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Paresis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Parkinson's disease	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Polyneuropathy	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Post herpetic neuralgia	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Post-traumatic headache	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Ruptured cerebral aneurysm	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Sciatica	0/3576 (0%)		0/3581 (0%)		5/3576 (0.1%)		1/3581 (0%)
Seizure	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		3/3581 (0.1%)
Somnolence	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Stupor	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Syncope	3/3576 (0.1%)		4/3581 (0.1%)		7/3576 (0.2%)		9/3581 (0.3%)
Tension headache	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Transient ischaemic attack	1/3576 (0%)		4/3581 (0.1%)		6/3576 (0.2%)		13/3581 (0.4%)
Tremor	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Trigeminal neuralgia	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Vascular encephalopathy	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Vertebrobasilar insufficiency	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Product Issues
Device dislocation	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Device malfunction	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Psychiatric disorders
Affective disorder	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Alcohol withdrawal syndrome	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Alcoholism	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Anxiety	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Anxiety disorder	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Bipolar I disorder	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Bipolar disorder	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Confusional state	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Delirium	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Depression	4/3576 (0.1%)		1/3581 (0%)		6/3576 (0.2%)		3/3581 (0.1%)
Hallucination	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Major depression	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Mental status changes	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Personality change due to a general medical condition	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Pseudodementia	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Psychotic disorder	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Schizophreniform disorder	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Suicide attempt	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Transient psychosis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Renal and urinary disorders
Acute kidney injury	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		5/3581 (0.1%)
Acute prerenal failure	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Calculus urinary	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Chronic kidney disease	2/3576 (0.1%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Cystitis haemorrhagic	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Haematuria	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Hydrocalyx	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hydronephrosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Nephrolithiasis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Renal failure	0/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Renal impairment	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Renal infarct	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Renal injury	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Stress urinary incontinence	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Ureteric perforation	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Ureterolithiasis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Urinary incontinence	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		0/3581 (0%)
Urinary retention	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Urinary tract inflammation	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Reproductive system and breast disorders
Cervical dysplasia	2/3576 (0.1%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Cervical polyp	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Cystocele	0/3576 (0%)		2/3581 (0.1%)		0/3576 (0%)		3/3581 (0.1%)
Dysfunctional uterine bleeding	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Endometrial hyperplasia	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Endometrial hypertrophy	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Female genital tract fistula	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Fibrocystic breast disease	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Ovarian cyst	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Pelvic haematoma	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Pelvic prolapse	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Rectocele	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Urogenital prolapse	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Uterine polyp	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		1/3581 (0%)
Uterine prolapse	0/3576 (0%)		5/3581 (0.1%)		2/3576 (0.1%)		7/3581 (0.2%)
Uterovaginal prolapse	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Vaginal haematoma	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Vaginal polyp	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Vaginal prolapse	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Acute respiratory distress syndrome	1/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Acute respiratory failure	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Alveolitis allergic	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Asthma	2/3576 (0.1%)		3/3581 (0.1%)		3/3576 (0.1%)		8/3581 (0.2%)
Asthmatic crisis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Bronchial hyperreactivity	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Bronchiectasis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Bronchitis chronic	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Choking sensation	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Chronic obstructive pulmonary disease	15/3576 (0.4%)		6/3581 (0.2%)		28/3576 (0.8%)		22/3581 (0.6%)
Dyspnoea exertional	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Epistaxis	1/3576 (0%)		1/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Haemoptysis	2/3576 (0.1%)		1/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Pleural effusion	2/3576 (0.1%)		0/3581 (0%)		3/3576 (0.1%)		0/3581 (0%)
Pneumonia aspiration	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Pneumothorax	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		2/3581 (0.1%)
Pulmonary embolism	0/3576 (0%)		0/3581 (0%)		6/3576 (0.2%)		9/3581 (0.3%)
Pulmonary mass	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		1/3581 (0%)
Pulmonary oedema	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Respiratory distress	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Respiratory failure	0/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		3/3581 (0.1%)
Sinus polyp	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Vocal cord cyst	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Decubitus ulcer	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Dermatitis	0/3576 (0%)		1/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Dermatitis allergic	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Dermatitis exfoliative	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Granuloma annulare	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Ingrowing nail	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Lichen sclerosus	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Psoriasis	0/3576 (0%)		2/3581 (0.1%)		0/3576 (0%)		2/3581 (0.1%)
Rash	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Rash macular	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Skin disorder	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Skin necrosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Skin ulcer	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Social circumstances
Activities of daily living impaired	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Immobile	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Surgical and medical procedures
Cardiac pacemaker replacement	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Cataract operation	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Hysterectomy	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Knee arthroplasty	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Osteosynthesis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Pulmonary resection	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Rehabilitation therapy	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Scar excision	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Vascular disorders
Aortic aneurysm	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Aortic thrombosis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Arterial occlusive disease	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Arterial stenosis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Arteriosclerosis	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		2/3581 (0.1%)
Circulatory collapse	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		3/3581 (0.1%)
Deep vein thrombosis	2/3576 (0.1%)		2/3581 (0.1%)		3/3576 (0.1%)		5/3581 (0.1%)
Dry gangrene	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Extremity necrosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Hypertension	5/3576 (0.1%)		8/3581 (0.2%)		12/3576 (0.3%)		15/3581 (0.4%)
Hypertensive crisis	0/3576 (0%)		2/3581 (0.1%)		2/3576 (0.1%)		6/3581 (0.2%)
Hypertensive emergency	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Hypotension	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		2/3581 (0.1%)
Hypovolaemic shock	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		0/3581 (0%)
Pelvic venous thrombosis	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Peripheral arterial occlusive disease	1/3576 (0%)		0/3581 (0%)		4/3576 (0.1%)		3/3581 (0.1%)
Peripheral artery occlusion	0/3576 (0%)		1/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Peripheral artery stenosis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Peripheral artery thrombosis	0/3576 (0%)		2/3581 (0.1%)		0/3576 (0%)		2/3581 (0.1%)
Peripheral ischaemia	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Shock haemorrhagic	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Thrombophlebitis	1/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Thrombophlebitis superficial	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Varicose ulceration	1/3576 (0%)		0/3581 (0%)		2/3576 (0.1%)		1/3581 (0%)
Varicose vein	1/3576 (0%)		0/3581 (0%)		3/3576 (0.1%)		1/3581 (0%)
Vascular insufficiency	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		0/3581 (0%)
Vasculitis	0/3576 (0%)		0/3581 (0%)		0/3576 (0%)		1/3581 (0%)
Venous thrombosis limb	0/3576 (0%)		0/3581 (0%)		1/3576 (0%)		1/3581 (0%)
Other (Not Including Serious) Adverse Events
	12-Month Double-blind Period: Placebo		12-Month Double-blind Period: Romosozumab		36-Month Study Period: Placebo/Denosumab		36-Month Study Period: Romosozumab/Denosumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2059/3576 (57.6%)		2019/3581 (56.4%)		2434/3576 (68.1%)		2463/3581 (68.8%)
Gastrointestinal disorders
Constipation	162/3576 (4.5%)		138/3581 (3.9%)		210/3576 (5.9%)		189/3581 (5.3%)
Diarrhoea	133/3576 (3.7%)		111/3581 (3.1%)		191/3576 (5.3%)		182/3581 (5.1%)
Infections and infestations
Influenza	180/3576 (5%)		169/3581 (4.7%)		240/3576 (6.7%)		237/3581 (6.6%)
Nasopharyngitis	439/3576 (12.3%)		460/3581 (12.8%)		622/3576 (17.4%)		651/3581 (18.2%)
Upper respiratory tract infection	172/3576 (4.8%)		161/3581 (4.5%)		255/3576 (7.1%)		236/3581 (6.6%)
Urinary tract infection	142/3576 (4%)		130/3581 (3.6%)		263/3576 (7.4%)		244/3581 (6.8%)
Viral upper respiratory tract infection	227/3576 (6.3%)		206/3581 (5.8%)		263/3576 (7.4%)		230/3581 (6.4%)
Injury, poisoning and procedural complications
Contusion	122/3576 (3.4%)		102/3581 (2.8%)		204/3576 (5.7%)		179/3581 (5%)
Fall	319/3576 (8.9%)		255/3581 (7.1%)		539/3576 (15.1%)		484/3581 (13.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	434/3576 (12.1%)		468/3581 (13.1%)		663/3576 (18.5%)		668/3581 (18.7%)
Back pain	380/3576 (10.6%)		373/3581 (10.4%)		573/3576 (16%)		518/3581 (14.5%)
Muscle spasms	140/3576 (3.9%)		163/3581 (4.6%)		201/3576 (5.6%)		211/3581 (5.9%)
Musculoskeletal pain	172/3576 (4.8%)		168/3581 (4.7%)		260/3576 (7.3%)		263/3581 (7.3%)
Osteoarthritis	210/3576 (5.9%)		184/3581 (5.1%)		329/3576 (9.2%)		321/3581 (9%)
Pain in extremity	299/3576 (8.4%)		278/3581 (7.8%)		407/3576 (11.4%)		417/3581 (11.6%)
Nervous system disorders
Dizziness	158/3576 (4.4%)		154/3581 (4.3%)		216/3576 (6%)		228/3581 (6.4%)
Headache	206/3576 (5.8%)		235/3581 (6.6%)		270/3576 (7.6%)		293/3581 (8.2%)
Respiratory, thoracic and mediastinal disorders
Cough	117/3576 (3.3%)		130/3581 (3.6%)		179/3576 (5%)		189/3581 (5.3%)
Vascular disorders
Hypertension	260/3576 (7.3%)		219/3581 (6.1%)		411/3576 (11.5%)		384/3581 (10.7%)

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.