Study of Denosumab as Adjuvant Treatment for Women With High Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE)

• Sponsor: Amgen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01077154
• Collaborator: Daiichi Sankyo, Inc. (Industry)
• Enrollment: 4,509
• Locations: 459
• Arms: 2
• Actual Duration (Months): 93.8
• Patients Per Site: 9.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized phase 3 trial is studying the effect of denosumab to see if it can prevent disease recurrence in the bone or in any other part of the body, when it is given as adjuvant therapy for women with early-stage breast cancer, who are at high risk of disease recurrence.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Placebo; Drug: Denosumab	Phase 3

Detailed Description

Eligible participants were randomized in a 1:1 ratio to receive denosumab 120 mg or placebo subcutaneously (SC) for up to 5 years. Randomization was stratified based on:

1. Breast cancer therapy/lymph node (LN) status: neoadjuvant therapy/any LN status versus adjuvant therapy/LN negative (based on axillary LN dissection, or based on sentinel node status) versus adjuvant therapy/LN positive

2. Hormone receptor (estrogen receptor [ER]/progesterone receptor [PR]) status: ER and/or PR positive versus ER and PR negative

3. Human epidermal growth factor receptor 2 (HER-2) status: HER-2 positive versus HER-2 negative

4. Age: < 50 years versus ≥ 50 years

5. Geographic Region: Japan versus Other regions.

The primary analysis was conducted after all enrolled participants had the opportunity to complete 5 years of treatment from study day 1.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4509 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study of Denosumab as Adjuvant Treatment for Women With Early-Stage Breast Cancer at High Risk of Recurrence (D-CARE)
• Actual Study Start Date: Jun 2, 2010
• Actual Primary Completion Date: Aug 31, 2017
• Actual Study Completion Date: Mar 26, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo subcutaneous injections once every 4 weeks for 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Drug: Placebo; Administered subcutaneously for up to 5 years
Experimental: Denosumab Participants received denosumab 120 mg subcutaneous injections once every 4 weeks for 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.	Drug: Denosumab; Administered subcutaneously for up to 5 years; Other Names: XGEVA®

Outcome Measures

Primary Outcome Measures

1. Bone Metastasis-free Survival (BMFS) [From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.]

   BMFS time was defined as the time interval from the randomization date to the first occurrence of bone metastasis or death from any cause, whichever came first. Participants last known to be alive with no bone metastasis were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first occurrence of bone metastasis before randomization were censored at their randomization date. Bone metastasis must have been confirmed by central imaging analysis or by biopsy, Evidence of disseminated tumor cells in bone marrow was not sufficient for determination of disease recurrence. Development of new primary malignancy in bone was not considered as bone metastasis. Since the median BMSF time could not be estimated due to low number of events, the percentage of participants with an event (i.e., bone metastasis or death) is reported.

Secondary Outcome Measures

1. Disease-free Survival (DFS) [From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.]

   DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.

2. Disease-free Survival (DFS) in the Postmenopausal Subset [From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.]

   DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time in the postmenopausal subset could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.

3. Overall Survival [From randomization until the end of study; median (minimum, maximum) time on study was 72.7 (0, 92) and 72.3 (0, 92) months in each treatment group respectively.]

   Overall survival (OS) time was defined as the time interval from the randomization date to the date of death from any cause. Participants last known to be alive were censored at their last contact date. Since the median time to overall survival could not be estimated at the time of the final analysis due to low numbers of events, the percentage of participants with an event (i.e., death) is reported.

4. Distant Recurrence-free Survival [From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.]

   Distant recurrence-free survival (DRFS) was defined as the time interval from the randomization date to the date of first observation of distant disease recurrence or death from any cause, whichever came first. Participants last known to be alive, who had not experienced distant disease recurrence, were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first distant recurrence before randomization were censored at their randomization date. Distant disease recurrence includes confirmed bone metastasis and extraosseous disease other than local-regional disease recurrence. Development of non-breast cancer new primary malignancy was not considered as distant disease recurrence. Since the median time to DRFS could not be estimated due to the low number of events, the percentage of participants with an event (i.e., distant recurrence or death) is reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed, American Joint Committee on Cancer (AJCC) stage II or III breast cancer

• High risk of breast cancer recurrence, defined as documented evidence of one or more of the following criteria:

1. Biopsy evidence of breast cancer in regional lymph node(s) (LN) (node-positive disease); Nodal micrometastases only are not considered node positive ii) Tumor size > 5 cm (T3) or locally advanced disease (T4)

• Documented pathological evaluation of the breast cancer for hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) status and HER-2 status

• Subjects must be receiving or be scheduled to receive standard of care systemic adjuvant or neoadjuvant chemotherapy and/or endocrine therapy and/or HER-2 targeted therapy

• For subjects receiving adjuvant therapy only:

• subjects must have undergone complete resection of the primary tumor with clean surgical margins, or subjects must have undergone resection of the primary tumor and be scheduled for further treatment of the primary tumor with curative intent. Definitive treatment must be planned to be completed within approximately 9 months of randomization

• Time between definitive surgery and randomization must be ≤ 12 weeks. Definitive surgery may include secondary interventions (e.g. to clear inadequate surgical margins)

• Subjects with node positive disease must have undergone treatment of axillary LN with curative intent, or subjects must be scheduled for further treatment of regional lymph nodes with curative intent. Definitive treatment must be planned to be completed within approximately 9 months of randomization

• Subjects must not have received prior neoadjuvant treatment. Endocrine treatment for less than 30 days prior to surgery is not considered prior neoadjuvant treatment

• For subjects receiving neoadjuvant therapy only:

• Time between start of neoadjuvant treatment and randomization must be ≤ 8 weeks and subjects must be scheduled to undergo definitive treatment (including surgery and/or radiotherapy) with curative intent within approximately 9 months of starting neoadjuvant treatment

• Female subjects with age ≥ 18 years

• Subjects with reproductive potential must have a negative pregnancy test within 14 days before randomization

• Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Written informed consent before any study-specific procedure is performed

Exclusion Criteria:

• Prior or current evidence of any metastatic involvement of any distant site

• History of breast cancer (other than ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS]) prior to the current diagnosis

• Osteoporosis requiring treatment at the time of randomization or treatment considered likely to become necessary within the subsequent six months

• Any prior or synchronous malignancy (other than breast cancer), except i) Malignancy treated with curative intent and with no evidence of disease for ≥ 5 years prior to enrollment and considered to be at low risk for recurrence by the treating physician

1. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease

• Active infection with Hepatitis B virus or Hepatitis C virus

• Known infection with human immunodeficiency virus (HIV)

• Prior history or current evidence of osteomyelitis/osteonecrosis of the jaw

• Active dental or jaw condition which requires oral surgery

• Planned invasive dental procedure for the course of the study

• Non-healed dental or oral surgery

• Use of oral bisphosphonates within the past 1 year

• Prior or current IV bisphosphonate administration

• Prior administration of denosumab

• Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or investigational drug study(s), or subject is receiving other investigational agent(s)

• Subject is pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment.

• Subject is of child bearing potential and is not willing to use, in combination with her partner, 2 highly effective methods of contraception or abstinence during treatment and for 5 months after the end of treatment

• Subject has known sensitivity to any of the products to be administered during the study (e.g., mammalian derived products, calcium, or vitamin D)

• Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures.

• Any major medical or psychiatric disorder that in the opinion of the investigator prevent the subject from completing the study or interfere with the interpretation of the study results

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35205
2	Research Site	Tucson	Arizona	United States	85724
3	Research Site	Jonesboro	Arkansas	United States	72401
4	Research Site	Alhambra	California	United States	91801
5	Research Site	Anaheim	California	United States	92801
6	Research Site	Beverly Hills	California	United States	90211
7	Research Site	Campbell	California	United States	95008
8	Research Site	Fresno	California	United States	93720
9	Research Site	Fullerton	California	United States	92835
10	Research Site	La Verne	California	United States	91750
11	Research Site	Lancaster	California	United States	93534
12	Research Site	Long Beach	California	United States	90813
13	Research Site	Los Angeles	California	United States	90024
14	Research Site	Los Angeles	California	United States	90025
15	Research Site	Los Angeles	California	United States	90095-1772
16	Research Site	Northridge	California	United States	91328
17	Research Site	Redondo Beach	California	United States	90277
18	Research Site	Santa Barbara	California	United States	93105
19	Research Site	Santa Maria	California	United States	93454
20	Research Site	Torrance	California	United States	90502
21	Research Site	Denver	Colorado	United States	80220
22	Research Site	Grand Junction	Colorado	United States	81501
23	Research Site	New Haven	Connecticut	United States	06510
24	Research Site	Boynton Beach	Florida	United States	33435
25	Research Site	Coral Springs	Florida	United States	33065
26	Research Site	Fort Lauderdale	Florida	United States	33316
27	Research Site	Hollywood	Florida	United States	33021
28	Research Site	Jacksonville	Florida	United States	32256
29	Research Site	Melbourne	Florida	United States	32901
30	Research Site	Athens	Georgia	United States	30607
31	Research Site	Niles	Illinois	United States	60714
32	Research Site	Indianapolis	Indiana	United States	46260
33	Research Site	Cedar Rapids	Iowa	United States	52402
34	Research Site	Hutchinson	Kansas	United States	67502
35	Research Site	Wichita	Kansas	United States	67214
36	Research Site	Paducah	Kentucky	United States	42003
37	Research Site	Annapolis	Maryland	United States	21401
38	Research Site	Baltimore	Maryland	United States	21201
39	Research Site	Bethesda	Maryland	United States	20817
40	Research Site	Columbia	Maryland	United States	21044
41	Research Site	Boston	Massachusetts	United States	02114
42	Research Site	Danvers	Massachusetts	United States	01923
43	Research Site	Ann Arbor	Michigan	United States	48109
44	Research Site	Detroit	Michigan	United States	48201
45	Research Site	Edina	Minnesota	United States	55435
46	Research Site	Minneapolis	Minnesota	United States	55407
47	Research Site	Saint Louis Park	Minnesota	United States	55426
48	Research Site	Jackson	Mississippi	United States	39202
49	Research Site	Jefferson City	Missouri	United States	65109
50	Research Site	Lincoln	Nebraska	United States	68510
51	Research Site	Henderson	Nevada	United States	89052
52	Research Site	Lebanon	New Hampshire	United States	03756-0001
53	Research Site	Denville	New Jersey	United States	07834
54	Research Site	Hackensack	New Jersey	United States	07601
55	Research Site	East Setauket	New York	United States	11733
56	Research Site	New York	New York	United States	10003
57	Research Site	New York	New York	United States	10029
58	Research Site	New York	New York	United States	10032
59	Research Site	Nyack	New York	United States	10960
60	Research Site	Asheville	North Carolina	United States	28806
61	Research Site	High Point	North Carolina	United States	27262
62	Research Site	Cincinnati	Ohio	United States	45242
63	Research Site	Columbus	Ohio	United States	43210
64	Research Site	Tulsa	Oklahoma	United States	74136
65	Research Site	Hershey	Pennsylvania	United States	17033
66	Research Site	Pittsburgh	Pennsylvania	United States	15213
67	Research Site	Pawtucket	Rhode Island	United States	02860
68	Research Site	Charleston	South Carolina	United States	29414
69	Research Site	Columbia	South Carolina	United States	29210
70	Research Site	Hilton Head Island	South Carolina	United States	29926
71	Research Site	Sioux Falls	South Dakota	United States	57105
72	Research Site	Chattanooga	Tennessee	United States	37404
73	Research Site	Germantown	Tennessee	United States	38138
74	Research Site	Nashville	Tennessee	United States	37203
75	Research Site	Abilene	Texas	United States	79606-5208
76	Research Site	Corpus Christi	Texas	United States	78463
77	Research Site	Dallas	Texas	United States	75230-2510
78	Research Site	Dallas	Texas	United States	75246
79	Research Site	Dallas	Texas	United States	75390
80	Research Site	El Paso	Texas	United States	79902
81	Research Site	Garland	Texas	United States	75042
82	Research Site	Houston	Texas	United States	77024
83	Research Site	Houston	Texas	United States	77030
84	Research Site	Plano	Texas	United States	75075
85	Research Site	San Antonio	Texas	United States	78217
86	Research Site	San Antonio	Texas	United States	78229
87	Research Site	Tyler	Texas	United States	75702
88	Research Site	Richlands	Virginia	United States	24641
89	Research Site	Richmond	Virginia	United States	23230
90	Research Site	Roanoke	Virginia	United States	24014
91	Research Site	Seattle	Washington	United States	98109-1023
92	Research Site	Seattle	Washington	United States	98133
93	Research Site	Tacoma	Washington	United States	98405
94	Research Site	Quilmes	Buenos Aires	Argentina	B1878DVB
95	Research Site	Quilmes	Buenos Aires	Argentina	B1878GEG
96	Research Site	San Martin	Buenos Aires	Argentina	B1650BOB
97	Research Site	Neuquen	Neuquén	Argentina	Q8300HDH
98	Research Site	Provincia De Santa Fe	Santa Fe	Argentina	S3000FFV
99	Research Site	San Miguel de Tucuman	Tucuman	Argentina	T4000GTB
100	Research Site	Camperdown	New South Wales	Australia	2050
101	Research Site	Caringbah	New South Wales	Australia	2229
102	Research Site	Kogarah	New South Wales	Australia	2217
103	Research Site	Tweed Heads	New South Wales	Australia	2485
104	Research Site	Wahroonga	New South Wales	Australia	2076
105	Research Site	Bedford Park	South Australia	Australia	5042
106	Research Site	Bentleigh East	Victoria	Australia	3165
107	Research Site	East Melbourne	Victoria	Australia	3002
108	Research Site	Fitzroy	Victoria	Australia	3065
109	Research Site	Footscray	Victoria	Australia	3011
110	Research Site	Frankston	Victoria	Australia	3199
111	Research Site	Heidelberg	Victoria	Australia	3084
112	Research Site	Malvern	Victoria	Australia	3144
113	Research Site	Parkville	Victoria	Australia	3050
114	Research Site	Richmond	Victoria	Australia	3121
115	Research Site	Ringwood East	Victoria	Australia	3135
116	Research Site	Warrnambool	Victoria	Australia	3280
117	Research Site	Wodonga	Victoria	Australia	3690
118	Research Site	Perth	Western Australia	Australia	6000
119	Research Site	Subiaco	Western Australia	Australia	6008
120	Research Site	Antwerpen		Belgium	2020
121	Research Site	Bonheiden		Belgium	2820
122	Research Site	Brugge		Belgium	8000
123	Research Site	Brussel		Belgium	1090
124	Research Site	Bruxelles		Belgium	1020
125	Research Site	Bruxelles		Belgium	1200
126	Research Site	Edegem		Belgium	2650
127	Research Site	Gent		Belgium	9000
128	Research Site	Hasselt		Belgium	3500
129	Research Site	Kortrijk		Belgium	8500
130	Research Site	Leuven		Belgium	3000
131	Research Site	Libramont		Belgium	6800
132	Research Site	Liège		Belgium	4000
133	Research Site	Namur		Belgium	5000
134	Research Site	Oostende		Belgium	8400
135	Research Site	Ottignies		Belgium	1340
136	Research Site	Sint-Niklaas		Belgium	9100
137	Research Site	Tournai		Belgium	7500
138	Research Site	Wilrijk		Belgium	2610
139	Research Site	Yvoir		Belgium	5530
140	Research Site	Salvador	Bahia	Brazil	40950-640
141	Research Site	Salvador	Bahia	Brazil	41820-021
142	Research Site	Curitiba	Paraná	Brazil	81520-060
143	Research Site	Londrina	Paraná	Brazil	86050-190
144	Research Site	Porto Alegre	Rio Grande Do Sul	Brazil	90035-003
145	Research Site	Porto Alegre	Rio Grande Do Sul	Brazil	90050-170
146	Research Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
147	Research Site	ItajaÃ-	Santa Catarina	Brazil	88301-220
148	Research Site	Barretos	São Paulo	Brazil	14784-400
149	Research Site	Santo Andre	São Paulo	Brazil	09080-110
150	Research Site	Sao Paulo	São Paulo	Brazil	04038-034
151	Research Site	São Paulo		Brazil	01246-000
152	Research Site	São Paulo		Brazil	01317-000
153	Research Site	Plovdiv		Bulgaria	4004
154	Research Site	Rousse		Bulgaria	7002
155	Research Site	Sofia		Bulgaria	1756
156	Research Site	Sofia		Bulgaria	1784
157	Research Site	Stara Zagora		Bulgaria	6003
158	Research Site	Varna		Bulgaria	9000
159	Research Site	Veliko Tarnovo		Bulgaria	5000
160	Research Site	Calgary	Alberta	Canada	T2N 4N2
161	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
162	Research Site	Kelowna	British Columbia	Canada	V1Y 5L3
163	Research Site	Victoria	British Columbia	Canada	V8R 6V5
164	Research Site	Moncton	New Brunswick	Canada	E1C 6Z8
165	Research Site	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
166	Research Site	Sydney	Nova Scotia	Canada	B1P 1P3
167	Research Site	Barrie	Ontario	Canada	L4M 6M2
168	Research Site	Brampton	Ontario	Canada	L6R 3J7
169	Research Site	Kingston	Ontario	Canada	K7L 5P9
170	Research Site	Kitchener	Ontario	Canada	N2G 1G3
171	Research Site	Ottawa	Ontario	Canada	K1H 8L6
172	Research Site	Sault Ste. Marie	Ontario	Canada	P6B 0A8
173	Research Site	Sudbury	Ontario	Canada	P3E 5J1
174	Research Site	Toronto	Ontario	Canada	M4C 3E7
175	Research Site	Toronto	Ontario	Canada	M9N 1N8
176	Research Site	Greenfield Park	Quebec	Canada	J4V 2H1
177	Research Site	Montreal	Quebec	Canada	H1T 2M4
178	Research Site	Montreal	Quebec	Canada	H2W 1T8
179	Research Site	Montreal	Quebec	Canada	H3T 1E2
180	Research Site	Sherbrooke	Quebec	Canada	J1H 5N4
181	Research Site	Quebec		Canada	G1S 4L8
182	Research Site	Temuco	CautÃ-n	Chile	4810469
183	Research Site	Vina del Mar	ValparaÃ-so	Chile	2520612
184	Research Site	Santiago		Chile	8380455
185	Research Site	Brno		Czechia	625 00
186	Research Site	Brno		Czechia	656 53
187	Research Site	Chomutov		Czechia	430 12
188	Research Site	Horovice		Czechia	268 31
189	Research Site	Hradec Kralove		Czechia	500 05
190	Research Site	Olomouc		Czechia	775 20
191	Research Site	Praha 10		Czechia	100 00
192	Research Site	Praha 10		Czechia	100 34
193	Research Site	Praha 4		Czechia	140 44
194	Research Site	Praha 5		Czechia	150 06
195	Research Site	Praha 8		Czechia	180 81
196	Research Site	Herning		Denmark	7400
197	Research Site	Vejle		Denmark	7100
198	Research Site	Viborg		Denmark	8800
199	Research Site	Ã…rhus C		Denmark	8000
200	Research Site	Angers		France	49933
201	Research Site	Bordeaux Cedex		France	33030
202	Research Site	Dijon		France	21079
203	Research Site	Grenoble		France	38000
204	Research Site	Hyères		France	83400
205	Research Site	Le Mans		France	72000
206	Research Site	Lille		France	59000
207	Research Site	Monaco		France	98012
208	Research Site	Nantes Cedex 2		France	44202
209	Research Site	Paris		France	75012
210	Research Site	Pierre-Benite		France	69495
211	Research Site	Saint Priest en Jarez Cedex		France	42270
212	Research Site	Strasbourg cedex		France	67091
213	Research Site	Villejuif cedex		France	94805
214	Research Site	Berlin		Germany	10117
215	Research Site	Berlin		Germany	10713
216	Research Site	Bonn		Germany	53111
217	Research Site	Bottrop		Germany	46236
218	Research Site	Erlangen		Germany	91054
219	Research Site	Frankfurt		Germany	60590
220	Research Site	Kiel		Germany	24105
221	Research Site	Koblenz		Germany	56068
222	Research Site	Mannheim		Germany	68161
223	Research Site	München		Germany	80335
224	Research Site	München		Germany	80638
225	Research Site	München		Germany	81675
226	Research Site	Recklinghausen		Germany	45657
227	Research Site	Rostock		Germany	18059
228	Research Site	Trier		Germany	54290
229	Research Site	Tübingen		Germany	72076
230	Research Site	Athens		Greece	11522
231	Research Site	Athens		Greece	11528
232	Research Site	Heraklion		Greece	71110
233	Research Site	Patra		Greece	26500
234	Research Site	Thessaloniki		Greece	54636
235	Research Site	Thessaloniki		Greece	56429
236	Research Site	Hong Kong		Hong Kong
237	Research Site	New Territories		Hong Kong
238	Research Site	Budapest		Hungary	1032
239	Research Site	Budapest		Hungary	1062
240	Research Site	Budapest		Hungary	1082
241	Research Site	Budapest		Hungary	1122
242	Research Site	Budapest		Hungary	1125
243	Research Site	Budapest		Hungary	1145
244	Research Site	Debrecen		Hungary	4012
245	Research Site	Gyor		Hungary	9023
246	Research Site	Nyiregyhaza		Hungary	4400
247	Research Site	Pecs		Hungary	7624
248	Research Site	Szeged		Hungary	6725
249	Research Site	Szekesfehervar		Hungary	8000
250	Research Site	Szolnok		Hungary	5004
251	Research Site	Zalaegerszeg		Hungary	8900
252	Research Site	Hyderabad	Andhra Pradesh	India	500 024
253	Research Site	Bangalore	Karnataka	India	560 054
254	Research Site	Ahmednagar	Maharashtra	India	413 736
255	Research Site	Aurangabad	Maharashtra	India	431 001
256	Research Site	Miraj	Maharashtra	India	416 410
257	Research Site	Mumbai	Maharashtra	India	400 012
258	Research Site	Mumbai	Maharashtra	India	400 016
259	Research Site	Nashik	Maharashtra	India	422 004
260	Research Site	Nashik	Maharashtra	India	422 005
261	Research Site	Pune	Maharashtra	India	411 001
262	Research Site	Jaipur	Rajasthan	India	302 013
263	Research Site	Chennai	Tamil Nadu	India	600 018
264	Research Site	Madurai	Tamil Nadu	India	625 107
265	Research Site	Cork		Ireland
266	Research Site	Dublin		Ireland	4
267	Research Site	Dublin		Ireland	8
268	Research Site	Dublin		Ireland	9
269	Research Site	Limerick		Ireland
270	Research Site	Waterford		Ireland
271	Research Site	Ashkelon		Israel	78278
272	Research Site	Haifa		Israel	31096
273	Research Site	Jerusalem		Israel	91031
274	Research Site	Kfar Sava		Israel	44281
275	Research Site	Petah Tikva		Israel	49100
276	Research Site	Poria Eylit		Israel	15208
277	Research Site	Rehovot		Israel	76100
278	Research Site	Tel Aviv		Israel	64239
279	Research Site	Tel Aviv		Israel	69710
280	Research Site	Ancona		Italy	60131
281	Research Site	Bari		Italy	70124
282	Research Site	Brescia		Italy	25123
283	Research Site	Meldola FC		Italy	47014
284	Research Site	Milano		Italy	20142
285	Research Site	Monza (MB)		Italy	20900
286	Research Site	Palermo		Italy	90100
287	Research Site	Parma		Italy	43100
288	Research Site	San Giovanni Rotondo FG		Italy	71013
289	Research Site	Treviglio (BG)		Italy	24047
290	Research Site	Varese		Italy	21100
291	Research Site	Nagoya-shi	Aichi	Japan	464-8681
292	Research Site	Nagoya-shi	Aichi	Japan	467-8602
293	Research Site	Matsuyama-shi	Ehime	Japan	791-0280
294	Research Site	Fukuoka-shi	Fukuoka	Japan	811-1395
295	Research Site	Kitakyushu-shi	Fukuoka	Japan	802-0077
296	Research Site	Kurume-shi	Fukuoka	Japan	830-0013
297	Research Site	Kure-shi	Hiroshima	Japan	737-0023
298	Research Site	Akashi-shi	Hyogo	Japan	673-8558
299	Research Site	Kagoshima-shi	Kagoshima	Japan	892-0833
300	Research Site	Isehara-shi	Kanagawa	Japan	259-1193
301	Research Site	Kumamoto-shi	Kumamoto	Japan	860-8556
302	Research Site	Kyoto-shi	Kyoto	Japan	606-8507
303	Research Site	Miyazaki-shi	Miyazaki	Japan	880-0052
304	Research Site	Niigata-shi	Niigata	Japan	951-8566
305	Research Site	Kurashiki-shi	Okayama	Japan	701-0192
306	Research Site	Osaka-shi	Osaka	Japan	537-8511
307	Research Site	Osaka-shi	Osaka	Japan	540-0006
308	Research Site	Suita-shi	Osaka	Japan	565-0871
309	Research Site	Hidaka-Shi	Saitama	Japan	350-1298
310	Research Site	Kitaadachi-gun	Saitama	Japan	362-0806
311	Research Site	Suntou-gun	Shizuoka	Japan	411-8777
312	Research Site	Shimotsuke-shi	Tochigi	Japan	329-0498
313	Research Site	Utsunomiya-shi	Tochigi	Japan	320-0834
314	Research Site	Chuo-ku	Tokyo	Japan	104-0045
315	Research Site	Tokyo		Japan	135-8550
316	Research Site	Tokyo		Japan	142-8666
317	Research Site	Tokyo		Japan	160-0023
318	Research Site	Tokyo		Japan	173-0003
319	Research Site	Goyang-si, Gyeonggi-do		Korea, Republic of	410-769
320	Research Site	Incheon		Korea, Republic of	405-835
321	Research Site	Seoul		Korea, Republic of	110-744
322	Research Site	Seoul		Korea, Republic of	120-752
323	Research Site	Seoul		Korea, Republic of	135-710
324	Research Site	Daugavpils		Latvia	5417
325	Research Site	Liepaja		Latvia	3401
326	Research Site	Riga		Latvia	1079
327	Research Site	Kota Bharu	Kelantan	Malaysia	16150
328	Research Site	Subang Jaya	Selangor (incl. Putrajaya)	Malaysia	47500
329	Research Site	Kuala Lumpur	Wilayah Persekutuan	Malaysia	50703
330	Research Site	Kuala Lumpur	Wilayah Persekutuan	Malaysia	56000
331	Research Site	Mexico City	Distrito Federal	Mexico	06726
332	Research Site	Mexico City	Distrito Federal	Mexico	07760
333	Research Site	Mexico	Distrito Federal	Mexico	01120
334	Research Site	Leon	Guanajuato	Mexico	37670
335	Research Site	Pachuca de Soto	Hidalgo	Mexico	42084
336	Research Site	Monterrey	Nuevo León	Mexico	64000
337	Research Site	Queretaro	Querétaro	Mexico	76178
338	Research Site	San Luis Potosi	San Luis PotosÃ-	Mexico	78200
339	Research Site	Colima		Mexico	28030
340	Research Site	Distrito Federal		Mexico	11000
341	Research Site	Durango		Mexico	34000
342	Research Site	Toluca		Mexico	50180
343	Research Site	Amsterdam		Netherlands	1066 CX
344	Research Site	Bergen op Zoom		Netherlands	4624 VT
345	Research Site	Breda		Netherlands	4819 EV
346	Research Site	Capelle aan den ijssel		Netherlands	2906 ZC
347	Research Site	Den Haag		Netherlands	2545 CH
348	Research Site	Dordrecht		Netherlands	3318 AT
349	Research Site	Hoofddorp		Netherlands	2134 TM
350	Research Site	Leiden		Netherlands	2333 ZA
351	Research Site	Nieuwegein		Netherlands	3435 CM
352	Research Site	Rotterdam		Netherlands	3045 PM
353	Research Site	Rotterdam		Netherlands	3075 EA
354	Research Site	Schiedam		Netherlands	3118 JH
355	Research Site	Sittard-Geleen		Netherlands	6162 BG
356	Research Site	Tiel		Netherlands	4002 WP
357	Research Site	Tilburg		Netherlands	5022 GC
358	Research Site	Venlo		Netherlands	5912 BL
359	Research Site	Lima		Peru	Lima 11
360	Research Site	Lima		Peru	Lima 18
361	Research Site	Lima		Peru	Lima 27
362	Research Site	Cebu City		Philippines	6000
363	Research Site	Manila		Philippines	1000
364	Research Site	Manila		Philippines	1008
365	Research Site	Metro Manila		Philippines	1100
366	Research Site	Quezon City		Philippines	1102
367	Research Site	Gdansk		Poland	80-219
368	Research Site	Gdansk		Poland	80-952
369	Research Site	Krakow		Poland	31-108
370	Research Site	Olsztyn		Poland	10-228
371	Research Site	Poznan		Poland	61-485
372	Research Site	Rzeszow		Poland	35-021
373	Research Site	Szczecin		Poland	71-730
374	Research Site	Lisboa		Portugal	1099-023
375	Research Site	Lisboa		Portugal	1500-650
376	Research Site	Porto		Portugal	4200-072
377	Research Site	Porto		Portugal	4200-319
378	Research Site	Santa Maria da Feira		Portugal	4520-211
379	Research Site	Bucharest		Romania	022328
380	Research Site	Craiova		Romania	200385
381	Research Site	Sibiu		Romania	550245
382	Research Site	Suceava		Romania	720237
383	Research Site	Timisoara		Romania	300239
384	Research Site	Barnaul		Russian Federation	656049
385	Research Site	Chelyabinsk		Russian Federation	454076
386	Research Site	Ivanovo		Russian Federation	153013
387	Research Site	Kazan		Russian Federation	420029
388	Research Site	Moscow		Russian Federation	115478
389	Research Site	Saint Petersburg		Russian Federation	195271
390	Research Site	Saint Petersburg		Russian Federation	197022
391	Research Site	Belgrade		Serbia	11000
392	Research Site	Nis		Serbia	18000
393	Research Site	Bardejov		Slovakia	085 01
394	Research Site	Kosice		Slovakia	041 91
395	Research Site	Michalovce		Slovakia	071 01
396	Research Site	Poprad		Slovakia	058 01
397	Research Site	Presov		Slovakia	080 01
398	Research Site	Spisska Nova Ves		Slovakia	052 01
399	Research Site	Trebisov		Slovakia	075 01
400	Research Site	Ljublijana		Slovenia	1525
401	Research Site	Maribor		Slovenia	2000
402	Research Site	Groenkloof	Gauteng	South Africa	0181
403	Research Site	Johannesburg	Gauteng	South Africa	2196
404	Research Site	Cape Town		South Africa	7925
405	Research Site	Pietermaritzburg		South Africa	3201
406	Research Site	Port Elizabeth		South Africa	6045
407	Research Site	Pretoria		South Africa	0002
408	Research Site	Pretoria		South Africa	0081
409	Research Site	Cádiz	AndalucÃ-a	Spain	11009
410	Research Site	Córdoba	AndalucÃ-a	Spain	14004
411	Research Site	Jaén	AndalucÃ-a	Spain	23007
412	Research Site	Málaga	AndalucÃ-a	Spain	29010
413	Research Site	Sevilla	AndalucÃ-a	Spain	41013
414	Research Site	Zaragoza	Aragón	Spain	50009
415	Research Site	Santander	Cantabria	Spain	39008
416	Research Site	Badalona	Cataluña	Spain	08916
417	Research Site	Barcelona	Cataluña	Spain	08003
418	Research Site	Barcelona	Cataluña	Spain	08035
419	Research Site	Barcelona	Cataluña	Spain	08036
420	Research Site	Barcelona	Cataluña	Spain	08041
421	Research Site	Girona	Cataluña	Spain	17007
422	Research Site	Lleida	Cataluña	Spain	25198
423	Research Site	Sabadell	Cataluña	Spain	08208
424	Research Site	Elche	Comunidad Valenciana	Spain	03203
425	Research Site	Valencia	Comunidad Valenciana	Spain	46009
426	Research Site	Valencia	Comunidad Valenciana	Spain	46010
427	Research Site	A Coruña	Galicia	Spain	15006
428	Research Site	A Coruña	Galicia	Spain	15009
429	Research Site	Alcorcón	Madrid	Spain	28922
430	Research Site	Madrid		Spain	28009
431	Research Site	Madrid		Spain	28040
432	Research Site	Madrid		Spain	28050
433	Research Site	Putzu City	Chiayi	Taiwan	61363
434	Research Site	Keelung City	Keelung	Taiwan	20401
435	Research Site	Tainan		Taiwan	704
436	Research Site	Taipei		Taiwan	10002
437	Research Site	Ankara		Turkey	06100
438	Research Site	Ankara		Turkey	06500
439	Research Site	Bornova-Izmir		Turkey	35100
440	Research Site	Ä°zmir		Turkey	35340
441	Research Site	Bebington		United Kingdom	CH63 4JY
442	Research Site	Birmingham		United Kingdom	B15 2TT
443	Research Site	Brighton		United Kingdom	BN2 5BE
444	Research Site	Bristol		United Kingdom	BS2 8ED
445	Research Site	Cambridge		United Kingdom	CB2 0QQ
446	Research Site	Dorset		United Kingdom	BH7 7DW
447	Research Site	Guildford		United Kingdom	GU2 7XX
448	Research Site	Leeds		United Kingdom	LS9 7TF
449	Research Site	London		United Kingdom	SW3 6JJ
450	Research Site	London		United Kingdom	W2 1NY
451	Research Site	Manchester		United Kingdom	M20 4BX
452	Research Site	Manchester		United Kingdom	M23 9LT
453	Research Site	Newcastle		United Kingdom	NE4 6BE
454	Research Site	Peterborough		United Kingdom	PE3 9GZ
455	Research Site	Plymouth		United Kingdom	PL6 8DH
456	Research Site	Poole		United Kingdom	BH15 2JB
457	Research Site	Portsmouth		United Kingdom	PO6 3LY
458	Research Site	Sheffield		United Kingdom	S10 2SJ
459	Research Site	Truro		United Kingdom	TR1 3LJ

Sponsors and Collaborators

• Amgen
• Daiichi Sankyo, Inc.

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Oct 17, 2016
• Statistical Analysis Plan: SAP 3.0 - Nov 15, 2017
• Statistical Analysis Plan: SAP 3.0 Addendum - Mar 26, 2018

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, Glaspy J, Periañez AM, Tonkin K, Deleu I, Sohn J, Crown J, Delaloge S, Dai T, Zhou Y, Jandial D, Chan A. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):60-72. doi: 10.1016/S1470-2045(19)30687-4. Epub 2019 Dec 2.
• Coleman R, Zhou Y, Jandial D, Cadieux B, Chan A. Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer. Adv Ther. 2021 Aug;38(8):4569-4580. doi: 10.1007/s12325-021-01812-9. Epub 2021 Jun 29.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01077154
• Other Study ID Numbers: 20060359; 2009-011299-32
• First Posted: Feb 26, 2010
• Last Update Posted: Sep 28, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by Amgen: Early Stage Breast Cancer; Bone Metastasis; Adjuvant treatment; Neoadjuvant treatment; Denosumab; Stage II breast cancer; Stage III breast cancer; Stage IIA breast cancer; Stage IIB breast cancer; Stage IIIA breast cancer; Stage IIIB breast cancer; Stage IIIC breast cancer; Early breast cancer; Breast Tumors; Breast Neoplasms
• Additional relevant MeSH terms: Breast Neoplasms; Denosumab

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 407 centers in Australia, Western Europe, Eastern Europe, Israel, North America, Asia, South America, South Africa, and Turkey from 02 June 2010 to 24 August 2012.
Pre-assignment Detail	Participants were randomized in a 1:1 ratio to 1 of 2 groups. Randomization was stratified based on breast cancer therapy/lymph node (LN) status, hormone receptor status, human epidermal growth factor receptor 2 (HER-2) status, age, and geographic region.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Period Title: Overall Study
STARTED	2253	2256
Received Study Drug	2229	2230
COMPLETED	27	28
NOT COMPLETED	2226	2228

Baseline Characteristics

Arm/Group Title	Placebo	Denosumab	Total
Arm/Group Description	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.	Total of all reporting groups
Overall Participants	2253	2256	4509
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.6 (10.6)	51.4 (10.7)	51.5 (10.7)
Age, Customized (Count of Participants)
18 - 64 years	1960 87%	1959 86.8%	3919 86.9%
65 - 74 years	259 11.5%	260 11.5%	519 11.5%
75 - 84 years	33 1.5%	36 1.6%	69 1.5%
≥ 85 years	1 0%	1 0%	2 0%
Sex: Female, Male (Count of Participants)
Female	2253 100%	2256 100%	4509 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	1692 75.1%	1676 74.3%	3368 74.7%
Asian	222 9.9%	213 9.4%	435 9.6%
Japanese	134 5.9%	135 6%	269 6%
Hispanic/Latino	112 5%	135 6%	247 5.5%
Black	70 3.1%	74 3.3%	144 3.2%
Native Hawaiian or Other Pacific Islander	4 0.2%	3 0.1%	7 0.2%
American Indian or Alaska Native	1 0%	0 0%	1 0%
Other	18 0.8%	20 0.9%	38 0.8%
Menopausal Status (Count of Participants)
Premenopausal	1165 51.7%	1195 53%	2360 52.3%
Postmenopausal	1088 48.3%	1061 47%	2149 47.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0 (Fully active)	1913 84.9%	1922 85.2%	3835 85.1%
1 (Restricted but ambulatory)	340 15.1%	329 14.6%	669 14.8%
2 (Ambulatory, unable to work)	0 0%	3 0.1%	3 0.1%
Missing	0 0%	2 0.1%	2 0%
Breast Cancer Therapy / Lymph Node Status (Strata per Randomization) (Count of Participants)
Neo-adjuvant therapy / any lymph node status	550 24.4%	552 24.5%	1102 24.4%
Adjuvant therapy / lymph node negative	68 3%	65 2.9%	133 2.9%
Adjuvant therapy / lymph node positive	1635 72.6%	1639 72.7%	3274 72.6%
Hormone Receptor Status (Strata per Randomization) (Count of Participants)
ER and/or PR positive	1740 77.2%	1747 77.4%	3487 77.3%
ER and PR negative	513 22.8%	509 22.6%	1022 22.7%
Human Epidermal Growth Factor Receptor 2 (HER-2) Status (Strata per Randomization) (Count of Participants)
HER-2 positive	490 21.7%	492 21.8%	982 21.8%
HER-2 negative	1763 78.3%	1764 78.2%	3527 78.2%
Age (Strata per Randomization) (Count of Participants)
< 50 years	1026 45.5%	1029 45.6%	2055 45.6%
≥ 50 years	1227 54.5%	1227 54.4%	2454 54.4%
Geographic Region (Strata per Randomization) (Count of Participants)
Japan	131 5.8%	131 5.8%	262 5.8%
Other	2122 94.2%	2125 94.2%	4247 94.2%
Molecular Subtypes of Breast Cancer (Count of Participants)
HR positive and HER-2 positive	288 12.8%	286 12.7%	574 12.7%
HR positive and HER-2 negative	1460 64.8%	1458 64.6%	2918 64.7%
HR negative and HER-2 positive	163 7.2%	168 7.4%	331 7.3%
HR negative and HER-2 negative	341 15.1%	343 15.2%	684 15.2%
Missing	1 0%	1 0%	2 0%
Lymph Node Status (Count of Participants)
N0	130 5.8%	131 5.8%	261 5.8%
N1	1369 60.8%	1381 61.2%	2750 61%
N2	506 22.5%	505 22.4%	1011 22.4%
N3	230 10.2%	224 9.9%	454 10.1%
Nx	18 0.8%	15 0.7%	33 0.7%
Breast Cancer Histopathologic Grade (Count of Participants)
Grade 1 = Low	222 9.9%	209 9.3%	431 9.6%
Grade 2 = Intermediate	1015 45.1%	1079 47.8%	2094 46.4%
Grade 3 = High	938 41.6%	906 40.2%	1844 40.9%
Not Evaluable/Missing	78 3.5%	62 2.7%	140 3.1%

Outcome Measures

1. Primary Outcome

Title	Bone Metastasis-free Survival (BMFS)
Description	BMFS time was defined as the time interval from the randomization date to the first occurrence of bone metastasis or death from any cause, whichever came first. Participants last known to be alive with no bone metastasis were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first occurrence of bone metastasis before randomization were censored at their randomization date. Bone metastasis must have been confirmed by central imaging analysis or by biopsy, Evidence of disseminated tumor cells in bone marrow was not sufficient for determination of disease recurrence. Development of new primary malignancy in bone was not considered as bone metastasis. Since the median BMSF time could not be estimated due to low number of events, the percentage of participants with an event (i.e., bone metastasis or death) is reported.
Time Frame	From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Measure Participants	2253	2256
Number (95% Confidence Interval) [percentage of participants]	13.5 0.6%	12.9 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.

2. Secondary Outcome

Title	Disease-free Survival (DFS)
Description	DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
Time Frame	From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Measure Participants	2253	2256
Number (95% Confidence Interval) [percentage of participants]	19.2 0.9%	19.6 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hzard ratio < 1 favors denosumab.

3. Secondary Outcome

Title	Disease-free Survival (DFS) in the Postmenopausal Subset
Description	DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time in the postmenopausal subset could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
Time Frame	From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

Randomized participants postmenopausal at enrollment, defined as: Undergone bilateral oophorectomy Age ≥ 60 years Age 45 to 59 years with 1 of the criteria, ie, either amenorrhea > 12 months with an intact uterus and ≥ 1 intact ovary; or amenorrhea for ≤ 12 months and follicle-stimulating hormone and estradiol in postmenopausal range.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Measure Participants	1088	1061
Number (95% Confidence Interval) [percentage of participants]	18.6 0.8%	20.3 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) time was defined as the time interval from the randomization date to the date of death from any cause. Participants last known to be alive were censored at their last contact date. Since the median time to overall survival could not be estimated at the time of the final analysis due to low numbers of events, the percentage of participants with an event (i.e., death) is reported.
Time Frame	From randomization until the end of study; median (minimum, maximum) time on study was 72.7 (0, 92) and 72.3 (0, 92) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Measure Participants	2253	2256
Number (95% Confidence Interval) [percentage of participants]	9.5 0.4%	9.5 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.

5. Secondary Outcome

Title	Distant Recurrence-free Survival
Description	Distant recurrence-free survival (DRFS) was defined as the time interval from the randomization date to the date of first observation of distant disease recurrence or death from any cause, whichever came first. Participants last known to be alive, who had not experienced distant disease recurrence, were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first distant recurrence before randomization were censored at their randomization date. Distant disease recurrence includes confirmed bone metastasis and extraosseous disease other than local-regional disease recurrence. Development of non-breast cancer new primary malignancy was not considered as distant disease recurrence. Since the median time to DRFS could not be estimated due to the low number of events, the percentage of participants with an event (i.e., distant recurrence or death) is reported.
Time Frame	From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Measure Participants	2253	2256
Number (95% Confidence Interval) [percentage of participants]	18.0 0.8%	18.7 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.41
	Comments
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.

Adverse Events

Time Frame	All-cause mortality includes deaths from first dose of study drug to the end of study date; median (min, max) time on study was 72.7 (0, 92) and 72.3 (0, 92) months for Placebo/Denosumab respectively. Adverse Events are from first dose of study drug to 30 days after last dose; median (min, max) time on treatment was 59.4 (0.7, 67) and 59.3 (0.7, 67) months for Placebo/Denosumab respectively.
Adverse Event Reporting Description	Eleven participants randomized to the placebo group received at least 1 dose of denosumab during the study and are counted in the denosumab group for safety analyses. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo		Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.		Participants received denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
All Cause Mortality
	Placebo		Denosumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	215/2218 (9.7%)		215/2241 (9.6%)
Serious Adverse Events
	Placebo		Denosumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	675/2218 (30.4%)		702/2241 (31.3%)
Blood and lymphatic system disorders
Agranulocytosis	1/2218 (0%)		1/2241 (0%)
Anaemia	12/2218 (0.5%)		17/2241 (0.8%)
Anaemia megaloblastic	1/2218 (0%)		0/2241 (0%)
Bone marrow failure	1/2218 (0%)		0/2241 (0%)
Febrile neutropenia	114/2218 (5.1%)		83/2241 (3.7%)
Immune thrombocytopenic purpura	0/2218 (0%)		1/2241 (0%)
Leukocytosis	3/2218 (0.1%)		0/2241 (0%)
Leukopenia	5/2218 (0.2%)		2/2241 (0.1%)
Neutropenia	36/2218 (1.6%)		35/2241 (1.6%)
Pancytopenia	4/2218 (0.2%)		3/2241 (0.1%)
Thrombocytopenia	5/2218 (0.2%)		6/2241 (0.3%)
Cardiac disorders
Acute myocardial infarction	3/2218 (0.1%)		2/2241 (0.1%)
Angina pectoris	0/2218 (0%)		1/2241 (0%)
Angina unstable	1/2218 (0%)		0/2241 (0%)
Arteriospasm coronary	1/2218 (0%)		0/2241 (0%)
Atrial fibrillation	6/2218 (0.3%)		1/2241 (0%)
Atrial flutter	1/2218 (0%)		1/2241 (0%)
Atrial thrombosis	0/2218 (0%)		1/2241 (0%)
Bradycardia	1/2218 (0%)		0/2241 (0%)
Cardiac aneurysm	1/2218 (0%)		0/2241 (0%)
Cardiac arrest	1/2218 (0%)		0/2241 (0%)
Cardiac failure chronic	1/2218 (0%)		0/2241 (0%)
Cardiac failure congestive	4/2218 (0.2%)		4/2241 (0.2%)
Cardio-respiratory arrest	0/2218 (0%)		2/2241 (0.1%)
Cardiogenic shock	1/2218 (0%)		1/2241 (0%)
Cardiopulmonary failure	1/2218 (0%)		0/2241 (0%)
Coronary artery disease	0/2218 (0%)		2/2241 (0.1%)
Coronary artery occlusion	1/2218 (0%)		0/2241 (0%)
Coronary artery stenosis	1/2218 (0%)		0/2241 (0%)
Left ventricular dysfunction	1/2218 (0%)		1/2241 (0%)
Metabolic cardiomyopathy	0/2218 (0%)		1/2241 (0%)
Myocardial infarction	4/2218 (0.2%)		2/2241 (0.1%)
Palpitations	1/2218 (0%)		2/2241 (0.1%)
Pericardial effusion	1/2218 (0%)		0/2241 (0%)
Pericarditis constrictive	0/2218 (0%)		1/2241 (0%)
Sinus tachycardia	0/2218 (0%)		2/2241 (0.1%)
Supraventricular tachycardia	2/2218 (0.1%)		0/2241 (0%)
Tachyarrhythmia	1/2218 (0%)		0/2241 (0%)
Tachycardia	5/2218 (0.2%)		0/2241 (0%)
Ventricular tachycardia	2/2218 (0.1%)		0/2241 (0%)
Ear and labyrinth disorders
Deafness	1/2218 (0%)		0/2241 (0%)
Ear pain	0/2218 (0%)		1/2241 (0%)
External ear disorder	0/2218 (0%)		1/2241 (0%)
Tinnitus	1/2218 (0%)		0/2241 (0%)
Vertigo	0/2218 (0%)		5/2241 (0.2%)
Vertigo positional	1/2218 (0%)		0/2241 (0%)
Endocrine disorders
Hypothyroidism	0/2218 (0%)		1/2241 (0%)
Thyroiditis acute	1/2218 (0%)		0/2241 (0%)
Eye disorders
Angle closure glaucoma	0/2218 (0%)		1/2241 (0%)
Blindness	1/2218 (0%)		0/2241 (0%)
Cataract	5/2218 (0.2%)		5/2241 (0.2%)
Diplopia	1/2218 (0%)		0/2241 (0%)
Macular hole	0/2218 (0%)		1/2241 (0%)
Retinal artery occlusion	0/2218 (0%)		1/2241 (0%)
Retinal detachment	0/2218 (0%)		2/2241 (0.1%)
Retinopathy proliferative	0/2218 (0%)		1/2241 (0%)
Vision blurred	1/2218 (0%)		0/2241 (0%)
Vitreous haematoma	0/2218 (0%)		1/2241 (0%)
Vitreous haemorrhage	1/2218 (0%)		0/2241 (0%)
Gastrointestinal disorders
Abdominal hernia	0/2218 (0%)		1/2241 (0%)
Abdominal incarcerated hernia	0/2218 (0%)		1/2241 (0%)
Abdominal pain	2/2218 (0.1%)		6/2241 (0.3%)
Abdominal pain lower	3/2218 (0.1%)		0/2241 (0%)
Abdominal pain upper	0/2218 (0%)		2/2241 (0.1%)
Anal fissure	1/2218 (0%)		1/2241 (0%)
Anal fistula	1/2218 (0%)		1/2241 (0%)
Anal prolapse	0/2218 (0%)		1/2241 (0%)
Ascites	0/2218 (0%)		2/2241 (0.1%)
Chronic gastritis	1/2218 (0%)		0/2241 (0%)
Colitis	1/2218 (0%)		2/2241 (0.1%)
Colitis ischaemic	0/2218 (0%)		1/2241 (0%)
Colitis ulcerative	1/2218 (0%)		0/2241 (0%)
Constipation	2/2218 (0.1%)		4/2241 (0.2%)
Crohn's disease	0/2218 (0%)		1/2241 (0%)
Dental caries	1/2218 (0%)		0/2241 (0%)
Diarrhoea	24/2218 (1.1%)		15/2241 (0.7%)
Diverticular perforation	1/2218 (0%)		0/2241 (0%)
Diverticulum intestinal	1/2218 (0%)		0/2241 (0%)
Duodenal obstruction	1/2218 (0%)		0/2241 (0%)
Duodenal ulcer	0/2218 (0%)		1/2241 (0%)
Dyspepsia	1/2218 (0%)		0/2241 (0%)
Enteritis	1/2218 (0%)		1/2241 (0%)
Enterocolitis	1/2218 (0%)		1/2241 (0%)
Enterocolitis haemorrhagic	2/2218 (0.1%)		0/2241 (0%)
Femoral hernia	1/2218 (0%)		0/2241 (0%)
Gastric disorder	0/2218 (0%)		1/2241 (0%)
Gastric polyps	0/2218 (0%)		1/2241 (0%)
Gastric ulcer	0/2218 (0%)		2/2241 (0.1%)
Gastritis	2/2218 (0.1%)		3/2241 (0.1%)
Gastrointestinal disorder	0/2218 (0%)		1/2241 (0%)
Gastrointestinal haemorrhage	0/2218 (0%)		1/2241 (0%)
Gastrooesophageal reflux disease	1/2218 (0%)		2/2241 (0.1%)
Gingival pain	0/2218 (0%)		1/2241 (0%)
Haemorrhoidal haemorrhage	0/2218 (0%)		1/2241 (0%)
Haemorrhoids thrombosed	1/2218 (0%)		0/2241 (0%)
Hiatus hernia	0/2218 (0%)		1/2241 (0%)
Inguinal hernia	1/2218 (0%)		1/2241 (0%)
Intestinal haemorrhage	1/2218 (0%)		1/2241 (0%)
Intestinal obstruction	0/2218 (0%)		1/2241 (0%)
Large intestinal haemorrhage	1/2218 (0%)		0/2241 (0%)
Large intestine perforation	1/2218 (0%)		1/2241 (0%)
Large intestine polyp	1/2218 (0%)		1/2241 (0%)
Lower gastrointestinal haemorrhage	0/2218 (0%)		1/2241 (0%)
Mouth ulceration	0/2218 (0%)		2/2241 (0.1%)
Nausea	10/2218 (0.5%)		18/2241 (0.8%)
Necrotising colitis	1/2218 (0%)		0/2241 (0%)
Obstructive pancreatitis	0/2218 (0%)		1/2241 (0%)
Oesophageal spasm	0/2218 (0%)		1/2241 (0%)
Oesophageal stenosis	0/2218 (0%)		1/2241 (0%)
Oesophagitis	1/2218 (0%)		0/2241 (0%)
Pancreatitis acute	1/2218 (0%)		3/2241 (0.1%)
Pancreatitis chronic	1/2218 (0%)		0/2241 (0%)
Rectal haemorrhage	0/2218 (0%)		1/2241 (0%)
Rectal prolapse	1/2218 (0%)		0/2241 (0%)
Small intestinal obstruction	2/2218 (0.1%)		1/2241 (0%)
Stomatitis	1/2218 (0%)		2/2241 (0.1%)
Umbilical hernia	1/2218 (0%)		1/2241 (0%)
Upper gastrointestinal haemorrhage	1/2218 (0%)		0/2241 (0%)
Vomiting	13/2218 (0.6%)		24/2241 (1.1%)
General disorders
Adverse drug reaction	1/2218 (0%)		0/2241 (0%)
Application site pain	1/2218 (0%)		0/2241 (0%)
Asthenia	3/2218 (0.1%)		3/2241 (0.1%)
BRCA2 gene mutation	0/2218 (0%)		1/2241 (0%)
Breast complication associated with device	1/2218 (0%)		0/2241 (0%)
Capsular contracture associated with breast implant	0/2218 (0%)		1/2241 (0%)
Catheter site haematoma	0/2218 (0%)		1/2241 (0%)
Chest discomfort	1/2218 (0%)		2/2241 (0.1%)
Chest pain	6/2218 (0.3%)		5/2241 (0.2%)
Chills	2/2218 (0.1%)		0/2241 (0%)
Complication associated with device	1/2218 (0%)		1/2241 (0%)
Death	1/2218 (0%)		0/2241 (0%)
Disease progression	1/2218 (0%)		0/2241 (0%)
Drug intolerance	1/2218 (0%)		0/2241 (0%)
Extravasation	0/2218 (0%)		1/2241 (0%)
Fatigue	4/2218 (0.2%)		4/2241 (0.2%)
General physical health deterioration	3/2218 (0.1%)		3/2241 (0.1%)
Generalised oedema	0/2218 (0%)		1/2241 (0%)
Granuloma	0/2218 (0%)		1/2241 (0%)
Idiosyncratic drug reaction	0/2218 (0%)		1/2241 (0%)
Impaired healing	3/2218 (0.1%)		0/2241 (0%)
Incarcerated hernia	1/2218 (0%)		0/2241 (0%)
Inflammation	1/2218 (0%)		0/2241 (0%)
Influenza like illness	0/2218 (0%)		2/2241 (0.1%)
Infusion site extravasation	1/2218 (0%)		1/2241 (0%)
Malaise	1/2218 (0%)		7/2241 (0.3%)
Mucosal inflammation	4/2218 (0.2%)		2/2241 (0.1%)
Non-cardiac chest pain	4/2218 (0.2%)		6/2241 (0.3%)
Oedema peripheral	2/2218 (0.1%)		2/2241 (0.1%)
Pain	1/2218 (0%)		2/2241 (0.1%)
Peripheral swelling	0/2218 (0%)		1/2241 (0%)
Pseudocyst	0/2218 (0%)		1/2241 (0%)
Pyrexia	33/2218 (1.5%)		37/2241 (1.7%)
Hepatobiliary disorders
Bile duct stone	0/2218 (0%)		1/2241 (0%)
Biliary colic	2/2218 (0.1%)		2/2241 (0.1%)
Cholangitis	0/2218 (0%)		1/2241 (0%)
Cholecystitis	3/2218 (0.1%)		6/2241 (0.3%)
Cholecystitis acute	4/2218 (0.2%)		3/2241 (0.1%)
Cholecystitis chronic	0/2218 (0%)		1/2241 (0%)
Cholelithiasis	4/2218 (0.2%)		5/2241 (0.2%)
Cholestasis	1/2218 (0%)		0/2241 (0%)
Gallbladder non-functioning	1/2218 (0%)		0/2241 (0%)
Hepatic failure	2/2218 (0.1%)		1/2241 (0%)
Hepatic function abnormal	1/2218 (0%)		1/2241 (0%)
Hepatic steatosis	0/2218 (0%)		1/2241 (0%)
Hepatocellular injury	1/2218 (0%)		0/2241 (0%)
Hepatomegaly	1/2218 (0%)		0/2241 (0%)
Hyperbilirubinaemia	1/2218 (0%)		1/2241 (0%)
Hyperplastic cholecystopathy	1/2218 (0%)		0/2241 (0%)
Jaundice cholestatic	0/2218 (0%)		1/2241 (0%)
Immune system disorders
Allergy to vaccine	0/2218 (0%)		1/2241 (0%)
Drug hypersensitivity	3/2218 (0.1%)		2/2241 (0.1%)
Hypersensitivity	2/2218 (0.1%)		3/2241 (0.1%)
Reaction to preservatives	0/2218 (0%)		1/2241 (0%)
Infections and infestations
Abdominal abscess	1/2218 (0%)		0/2241 (0%)
Anal abscess	2/2218 (0.1%)		2/2241 (0.1%)
Appendiceal abscess	0/2218 (0%)		1/2241 (0%)
Appendicitis	3/2218 (0.1%)		7/2241 (0.3%)
Appendicitis perforated	0/2218 (0%)		2/2241 (0.1%)
Atypical pneumonia	1/2218 (0%)		0/2241 (0%)
Bacteraemia	1/2218 (0%)		2/2241 (0.1%)
Bacterial sepsis	1/2218 (0%)		2/2241 (0.1%)
Bartholinitis	0/2218 (0%)		1/2241 (0%)
Breast abscess	3/2218 (0.1%)		5/2241 (0.2%)
Breast cellulitis	18/2218 (0.8%)		20/2241 (0.9%)
Bronchitis	3/2218 (0.1%)		4/2241 (0.2%)
Bursitis infective	1/2218 (0%)		0/2241 (0%)
Campylobacter gastroenteritis	0/2218 (0%)		3/2241 (0.1%)
Catheter site infection	2/2218 (0.1%)		0/2241 (0%)
Cellulitis	30/2218 (1.4%)		34/2241 (1.5%)
Cellulitis staphylococcal	2/2218 (0.1%)		0/2241 (0%)
Cellulitis streptococcal	1/2218 (0%)		0/2241 (0%)
Chest wall abscess	1/2218 (0%)		1/2241 (0%)
Clostridial infection	1/2218 (0%)		0/2241 (0%)
Clostridium colitis	1/2218 (0%)		0/2241 (0%)
Clostridium difficile colitis	2/2218 (0.1%)		3/2241 (0.1%)
Clostridium difficile infection	2/2218 (0.1%)		0/2241 (0%)
Colonic abscess	1/2218 (0%)		0/2241 (0%)
Cystitis	2/2218 (0.1%)		1/2241 (0%)
Dengue fever	0/2218 (0%)		2/2241 (0.1%)
Device related infection	10/2218 (0.5%)		3/2241 (0.1%)
Device related sepsis	1/2218 (0%)		1/2241 (0%)
Diverticulitis	8/2218 (0.4%)		1/2241 (0%)
Erysipelas	4/2218 (0.2%)		14/2241 (0.6%)
Erysipelothrix infection	0/2218 (0%)		1/2241 (0%)
Escherichia bacteraemia	0/2218 (0%)		1/2241 (0%)
Escherichia sepsis	1/2218 (0%)		0/2241 (0%)
Escherichia urinary tract infection	2/2218 (0.1%)		4/2241 (0.2%)
Febrile infection	1/2218 (0%)		0/2241 (0%)
Fungal skin infection	0/2218 (0%)		1/2241 (0%)
Gastroenteritis	3/2218 (0.1%)		2/2241 (0.1%)
Gastroenteritis salmonella	1/2218 (0%)		0/2241 (0%)
Gastroenteritis viral	0/2218 (0%)		1/2241 (0%)
Genital herpes simplex	0/2218 (0%)		1/2241 (0%)
H1N1 influenza	1/2218 (0%)		1/2241 (0%)
Haemophilus infection	0/2218 (0%)		1/2241 (0%)
Hepatitis B	1/2218 (0%)		0/2241 (0%)
Hepatitis C	1/2218 (0%)		0/2241 (0%)
Herpes zoster	2/2218 (0.1%)		4/2241 (0.2%)
Infected fistula	1/2218 (0%)		0/2241 (0%)
Infected seroma	0/2218 (0%)		2/2241 (0.1%)
Infection	2/2218 (0.1%)		1/2241 (0%)
Infectious colitis	0/2218 (0%)		2/2241 (0.1%)
Influenza	5/2218 (0.2%)		1/2241 (0%)
Intervertebral discitis	0/2218 (0%)		2/2241 (0.1%)
Labyrinthitis	0/2218 (0%)		1/2241 (0%)
Localised infection	1/2218 (0%)		1/2241 (0%)
Lower respiratory tract infection	3/2218 (0.1%)		6/2241 (0.3%)
Lower respiratory tract infection bacterial	1/2218 (0%)		0/2241 (0%)
Lung infection	0/2218 (0%)		1/2241 (0%)
Lymphangitis	3/2218 (0.1%)		2/2241 (0.1%)
Mastitis	8/2218 (0.4%)		12/2241 (0.5%)
Mastitis bacterial	1/2218 (0%)		0/2241 (0%)
Meningitis aseptic	0/2218 (0%)		1/2241 (0%)
Mycobacterial infection	0/2218 (0%)		1/2241 (0%)
Necrotising fasciitis	0/2218 (0%)		1/2241 (0%)
Neutropenic infection	2/2218 (0.1%)		1/2241 (0%)
Neutropenic sepsis	14/2218 (0.6%)		15/2241 (0.7%)
Oesophageal candidiasis	0/2218 (0%)		1/2241 (0%)
Ophthalmic herpes zoster	1/2218 (0%)		0/2241 (0%)
Oral candidiasis	2/2218 (0.1%)		3/2241 (0.1%)
Osteomyelitis	0/2218 (0%)		1/2241 (0%)
Osteomyelitis chronic	0/2218 (0%)		1/2241 (0%)
Pelvic inflammatory disease	1/2218 (0%)		1/2241 (0%)
Pericoronitis	0/2218 (0%)		1/2241 (0%)
Perirectal abscess	0/2218 (0%)		1/2241 (0%)
Peritoneal abscess	1/2218 (0%)		0/2241 (0%)
Periumbilical abscess	0/2218 (0%)		1/2241 (0%)
Pharyngeal abscess	1/2218 (0%)		1/2241 (0%)
Pharyngitis	2/2218 (0.1%)		1/2241 (0%)
Pharyngitis streptococcal	1/2218 (0%)		0/2241 (0%)
Pneumonia	30/2218 (1.4%)		27/2241 (1.2%)
Pneumonia bacterial	0/2218 (0%)		2/2241 (0.1%)
Pneumonia haemophilus	0/2218 (0%)		1/2241 (0%)
Pneumonia klebsiella	1/2218 (0%)		0/2241 (0%)
Pneumonia pneumococcal	1/2218 (0%)		0/2241 (0%)
Pneumonia staphylococcal	0/2218 (0%)		1/2241 (0%)
Pneumonia streptococcal	1/2218 (0%)		0/2241 (0%)
Post procedural cellulitis	0/2218 (0%)		1/2241 (0%)
Post procedural infection	1/2218 (0%)		2/2241 (0.1%)
Postoperative abscess	0/2218 (0%)		1/2241 (0%)
Postoperative wound infection	9/2218 (0.4%)		7/2241 (0.3%)
Pseudomonal sepsis	1/2218 (0%)		0/2241 (0%)
Pyelonephritis	0/2218 (0%)		5/2241 (0.2%)
Pyelonephritis acute	1/2218 (0%)		4/2241 (0.2%)
Respiratory tract infection	1/2218 (0%)		3/2241 (0.1%)
Sebaceous gland infection	1/2218 (0%)		0/2241 (0%)
Sepsis	11/2218 (0.5%)		3/2241 (0.1%)
Septic shock	2/2218 (0.1%)		2/2241 (0.1%)
Sinusitis	1/2218 (0%)		3/2241 (0.1%)
Skin infection	2/2218 (0.1%)		1/2241 (0%)
Staphylococcal infection	2/2218 (0.1%)		4/2241 (0.2%)
Staphylococcal skin infection	1/2218 (0%)		0/2241 (0%)
Streptococcal sepsis	1/2218 (0%)		0/2241 (0%)
Subcutaneous abscess	1/2218 (0%)		0/2241 (0%)
Tooth abscess	1/2218 (0%)		2/2241 (0.1%)
Tooth infection	0/2218 (0%)		1/2241 (0%)
Tracheobronchitis	1/2218 (0%)		0/2241 (0%)
Upper respiratory tract infection	9/2218 (0.4%)		7/2241 (0.3%)
Upper respiratory tract infection bacterial	1/2218 (0%)		0/2241 (0%)
Urinary tract infection	13/2218 (0.6%)		6/2241 (0.3%)
Urinary tract infection bacterial	2/2218 (0.1%)		2/2241 (0.1%)
Urinary tract infection pseudomonal	0/2218 (0%)		1/2241 (0%)
Urosepsis	3/2218 (0.1%)		1/2241 (0%)
Vestibular neuronitis	0/2218 (0%)		1/2241 (0%)
Viral infection	2/2218 (0.1%)		0/2241 (0%)
Viral upper respiratory tract infection	3/2218 (0.1%)		1/2241 (0%)
Vulval abscess	0/2218 (0%)		1/2241 (0%)
Vulvovaginal candidiasis	0/2218 (0%)		1/2241 (0%)
Wound infection	2/2218 (0.1%)		1/2241 (0%)
Wound infection bacterial	3/2218 (0.1%)		6/2241 (0.3%)
Wound infection staphylococcal	3/2218 (0.1%)		1/2241 (0%)
Cystitis escherichia	0/2218 (0%)		1/2241 (0%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence	0/2218 (0%)		1/2241 (0%)
Accidental overdose	1/2218 (0%)		0/2241 (0%)
Acetabulum fracture	0/2218 (0%)		1/2241 (0%)
Alcohol poisoning	0/2218 (0%)		1/2241 (0%)
Ankle fracture	1/2218 (0%)		1/2241 (0%)
Cartilage injury	1/2218 (0%)		0/2241 (0%)
Concussion	2/2218 (0.1%)		2/2241 (0.1%)
Craniocerebral injury	0/2218 (0%)		1/2241 (0%)
Exposure to radiation	0/2218 (0%)		1/2241 (0%)
Facial bones fracture	1/2218 (0%)		0/2241 (0%)
Fall	2/2218 (0.1%)		1/2241 (0%)
Femoral neck fracture	3/2218 (0.1%)		0/2241 (0%)
Femur fracture	0/2218 (0%)		3/2241 (0.1%)
Fibula fracture	6/2218 (0.3%)		3/2241 (0.1%)
Foot fracture	0/2218 (0%)		3/2241 (0.1%)
Fracture	0/2218 (0%)		2/2241 (0.1%)
Graft complication	0/2218 (0%)		1/2241 (0%)
Hand fracture	1/2218 (0%)		0/2241 (0%)
Head injury	1/2218 (0%)		0/2241 (0%)
Humerus fracture	2/2218 (0.1%)		1/2241 (0%)
Incision site pain	0/2218 (0%)		1/2241 (0%)
Incisional hernia	1/2218 (0%)		0/2241 (0%)
Infusion related reaction	0/2218 (0%)		1/2241 (0%)
Intentional overdose	0/2218 (0%)		1/2241 (0%)
Joint dislocation	0/2218 (0%)		1/2241 (0%)
Laceration	1/2218 (0%)		1/2241 (0%)
Ligament sprain	2/2218 (0.1%)		0/2241 (0%)
Lumbar vertebral fracture	1/2218 (0%)		0/2241 (0%)
Meniscus injury	0/2218 (0%)		1/2241 (0%)
Muscle strain	1/2218 (0%)		0/2241 (0%)
Overdose	1/2218 (0%)		1/2241 (0%)
Pneumothorax traumatic	0/2218 (0%)		1/2241 (0%)
Poisoning	0/2218 (0%)		1/2241 (0%)
Post procedural complication	2/2218 (0.1%)		2/2241 (0.1%)
Post procedural haematoma	0/2218 (0%)		3/2241 (0.1%)
Post procedural inflammation	0/2218 (0%)		2/2241 (0.1%)
Postmastectomy lymphoedema syndrome	1/2218 (0%)		0/2241 (0%)
Postoperative renal failure	1/2218 (0%)		0/2241 (0%)
Postoperative thrombosis	1/2218 (0%)		0/2241 (0%)
Postoperative wound complication	0/2218 (0%)		1/2241 (0%)
Procedural complication	1/2218 (0%)		0/2241 (0%)
Procedural pain	0/2218 (0%)		1/2241 (0%)
Pubis fracture	1/2218 (0%)		0/2241 (0%)
Radiation injury	0/2218 (0%)		1/2241 (0%)
Radiation mastitis	1/2218 (0%)		0/2241 (0%)
Radiation pneumonitis	1/2218 (0%)		1/2241 (0%)
Radius fracture	6/2218 (0.3%)		0/2241 (0%)
Rib fracture	0/2218 (0%)		1/2241 (0%)
Road traffic accident	0/2218 (0%)		2/2241 (0.1%)
Scapula fracture	0/2218 (0%)		1/2241 (0%)
Seroma	6/2218 (0.3%)		5/2241 (0.2%)
Skin flap necrosis	0/2218 (0%)		1/2241 (0%)
Subarachnoid haemorrhage	0/2218 (0%)		1/2241 (0%)
Synovial rupture	1/2218 (0%)		0/2241 (0%)
Thermal burn	0/2218 (0%)		1/2241 (0%)
Tibia fracture	2/2218 (0.1%)		3/2241 (0.1%)
Ulna fracture	1/2218 (0%)		1/2241 (0%)
Wound dehiscence	1/2218 (0%)		2/2241 (0.1%)
Wrist fracture	4/2218 (0.2%)		1/2241 (0%)
Wrong drug administered	0/2218 (0%)		1/2241 (0%)
Investigations
Alanine aminotransferase increased	1/2218 (0%)		1/2241 (0%)
Aspartate aminotransferase increased	1/2218 (0%)		1/2241 (0%)
Body temperature increased	2/2218 (0.1%)		2/2241 (0.1%)
Bone scan abnormal	0/2218 (0%)		1/2241 (0%)
Cardiac murmur	0/2218 (0%)		1/2241 (0%)
Ejection fraction decreased	2/2218 (0.1%)		0/2241 (0%)
Fibrin D dimer increased	0/2218 (0%)		1/2241 (0%)
Haemoglobin decreased	2/2218 (0.1%)		0/2241 (0%)
International normalised ratio increased	0/2218 (0%)		2/2241 (0.1%)
Liver function test abnormal	0/2218 (0%)		2/2241 (0.1%)
Neutrophil count abnormal	1/2218 (0%)		0/2241 (0%)
Neutrophil count decreased	2/2218 (0.1%)		2/2241 (0.1%)
Oestradiol increased	1/2218 (0%)		0/2241 (0%)
Oxygen saturation decreased	1/2218 (0%)		0/2241 (0%)
Stroke volume increased	1/2218 (0%)		0/2241 (0%)
Transaminases increased	0/2218 (0%)		1/2241 (0%)
White blood cell count decreased	1/2218 (0%)		0/2241 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/2218 (0%)		3/2241 (0.1%)
Dehydration	8/2218 (0.4%)		16/2241 (0.7%)
Diabetes mellitus	1/2218 (0%)		2/2241 (0.1%)
Diabetes mellitus inadequate control	1/2218 (0%)		0/2241 (0%)
Electrolyte imbalance	0/2218 (0%)		1/2241 (0%)
Fluid overload	0/2218 (0%)		1/2241 (0%)
Hypercalcaemia	0/2218 (0%)		1/2241 (0%)
Hyperglycaemia	2/2218 (0.1%)		0/2241 (0%)
Hypocalcaemia	3/2218 (0.1%)		5/2241 (0.2%)
Hypoglycaemia	1/2218 (0%)		0/2241 (0%)
Hypokalaemia	1/2218 (0%)		6/2241 (0.3%)
Hyponatraemia	1/2218 (0%)		1/2241 (0%)
Hypophosphataemia	0/2218 (0%)		1/2241 (0%)
Hypovolaemia	0/2218 (0%)		1/2241 (0%)
Malnutrition	0/2218 (0%)		1/2241 (0%)
Type 2 diabetes mellitus	2/2218 (0.1%)		0/2241 (0%)
Vitamin D deficiency	0/2218 (0%)		1/2241 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/2218 (0%)		6/2241 (0.3%)
Arthritis	0/2218 (0%)		1/2241 (0%)
Back pain	6/2218 (0.3%)		3/2241 (0.1%)
Bone pain	1/2218 (0%)		1/2241 (0%)
Flank pain	0/2218 (0%)		1/2241 (0%)
Foot deformity	1/2218 (0%)		1/2241 (0%)
Intervertebral disc protrusion	2/2218 (0.1%)		6/2241 (0.3%)
Jaw disorder	0/2218 (0%)		1/2241 (0%)
Joint instability	0/2218 (0%)		1/2241 (0%)
Lumbar spinal stenosis	1/2218 (0%)		1/2241 (0%)
Muscle haemorrhage	0/2218 (0%)		1/2241 (0%)
Muscle spasms	0/2218 (0%)		1/2241 (0%)
Muscular weakness	1/2218 (0%)		3/2241 (0.1%)
Musculoskeletal pain	1/2218 (0%)		2/2241 (0.1%)
Myalgia	4/2218 (0.2%)		1/2241 (0%)
Neck pain	1/2218 (0%)		1/2241 (0%)
Osteitis	0/2218 (0%)		1/2241 (0%)
Osteoarthritis	4/2218 (0.2%)		6/2241 (0.3%)
Osteochondritis	0/2218 (0%)		1/2241 (0%)
Osteochondrosis	0/2218 (0%)		1/2241 (0%)
Osteonecrosis	1/2218 (0%)		1/2241 (0%)
Osteonecrosis of jaw	0/2218 (0%)		30/2241 (1.3%)
Pain in extremity	1/2218 (0%)		3/2241 (0.1%)
Pain in jaw	0/2218 (0%)		1/2241 (0%)
Periarthritis	0/2218 (0%)		1/2241 (0%)
Periostitis	0/2218 (0%)		1/2241 (0%)
Soft tissue necrosis	0/2218 (0%)		1/2241 (0%)
Synovial cyst	0/2218 (0%)		1/2241 (0%)
Synovitis	1/2218 (0%)		0/2241 (0%)
Tendon disorder	0/2218 (0%)		1/2241 (0%)
Tenosynovitis stenosans	0/2218 (0%)		1/2241 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon	1/2218 (0%)		0/2241 (0%)
Acute leukaemia	0/2218 (0%)		1/2241 (0%)
Acute myeloid leukaemia	1/2218 (0%)		1/2241 (0%)
Adenocarcinoma	1/2218 (0%)		0/2241 (0%)
Adenocarcinoma gastric	1/2218 (0%)		0/2241 (0%)
Adenocarcinoma of colon	2/2218 (0.1%)		0/2241 (0%)
Adenolipoma	1/2218 (0%)		0/2241 (0%)
Appendix cancer	0/2218 (0%)		1/2241 (0%)
B-cell lymphoma	1/2218 (0%)		0/2241 (0%)
B-cell small lymphocytic lymphoma	1/2218 (0%)		0/2241 (0%)
Basal cell carcinoma	0/2218 (0%)		4/2241 (0.2%)
Benign neoplasm of thymus	1/2218 (0%)		0/2241 (0%)
Benign neoplasm of thyroid gland	0/2218 (0%)		1/2241 (0%)
Bladder transitional cell carcinoma	1/2218 (0%)		0/2241 (0%)
Bladder transitional cell carcinoma stage III	0/2218 (0%)		1/2241 (0%)
Bone neoplasm	1/2218 (0%)		0/2241 (0%)
Bowen's disease	1/2218 (0%)		0/2241 (0%)
Brain cancer metastatic	1/2218 (0%)		1/2241 (0%)
Breast cancer	3/2218 (0.1%)		8/2241 (0.4%)
Breast cancer metastatic	3/2218 (0.1%)		4/2241 (0.2%)
Breast cancer recurrent	2/2218 (0.1%)		2/2241 (0.1%)
Cancer pain	0/2218 (0%)		2/2241 (0.1%)
Chest wall tumour	1/2218 (0%)		0/2241 (0%)
Chronic myeloid leukaemia	1/2218 (0%)		0/2241 (0%)
Colon cancer	5/2218 (0.2%)		1/2241 (0%)
Colorectal adenocarcinoma	0/2218 (0%)		1/2241 (0%)
Endometrial adenocarcinoma	1/2218 (0%)		1/2241 (0%)
Endometrial adenoma	1/2218 (0%)		0/2241 (0%)
Endometrial cancer	1/2218 (0%)		1/2241 (0%)
Endometrial cancer stage I	0/2218 (0%)		1/2241 (0%)
Endometrial stromal sarcoma	0/2218 (0%)		1/2241 (0%)
Extranodal marginal zone B-cell lymphoma (MALT type)	0/2218 (0%)		1/2241 (0%)
Fallopian tube cancer	1/2218 (0%)		0/2241 (0%)
Gastric cancer	1/2218 (0%)		0/2241 (0%)
Gastric neoplasm	1/2218 (0%)		0/2241 (0%)
Hepatic cancer	0/2218 (0%)		1/2241 (0%)
Hepatocellular carcinoma	1/2218 (0%)		0/2241 (0%)
Intestinal metastasis	1/2218 (0%)		0/2241 (0%)
Intraductal proliferative breast lesion	1/2218 (0%)		1/2241 (0%)
Invasive ductal breast carcinoma	0/2218 (0%)		1/2241 (0%)
Large intestine benign neoplasm	1/2218 (0%)		0/2241 (0%)
Leiomyoma	1/2218 (0%)		0/2241 (0%)
Leiomyosarcoma	0/2218 (0%)		1/2241 (0%)
Leiomyosarcoma metastatic	0/2218 (0%)		1/2241 (0%)
Lung adenocarcinoma	3/2218 (0.1%)		2/2241 (0.1%)
Lung adenocarcinoma stage IV	1/2218 (0%)		0/2241 (0%)
Lung cancer metastatic	1/2218 (0%)		0/2241 (0%)
Lung neoplasm malignant	1/2218 (0%)		0/2241 (0%)
Lymphangiosis carcinomatosa	2/2218 (0.1%)		1/2241 (0%)
Malignant melanoma	2/2218 (0.1%)		0/2241 (0%)
Malignant melanoma stage III	1/2218 (0%)		0/2241 (0%)
Malignant neoplasm of thorax	0/2218 (0%)		1/2241 (0%)
Malignant neoplasm progression	1/2218 (0%)		0/2241 (0%)
Malignant pleural effusion	3/2218 (0.1%)		0/2241 (0%)
Meningioma	1/2218 (0%)		1/2241 (0%)
Metastases to bone	0/2218 (0%)		1/2241 (0%)
Metastases to breast	0/2218 (0%)		1/2241 (0%)
Metastases to central nervous system	17/2218 (0.8%)		15/2241 (0.7%)
Metastases to liver	4/2218 (0.2%)		3/2241 (0.1%)
Metastases to lung	4/2218 (0.2%)		7/2241 (0.3%)
Metastases to lymph nodes	0/2218 (0%)		1/2241 (0%)
Metastases to meninges	3/2218 (0.1%)		0/2241 (0%)
Metastases to ovary	2/2218 (0.1%)		0/2241 (0%)
Metastases to peritoneum	1/2218 (0%)		0/2241 (0%)
Metastases to skin	1/2218 (0%)		0/2241 (0%)
Metastatic neoplasm	0/2218 (0%)		1/2241 (0%)
Neuroendocrine carcinoma	1/2218 (0%)		0/2241 (0%)
Non-small cell lung cancer stage I	1/2218 (0%)		0/2241 (0%)
Oesophageal neoplasm	0/2218 (0%)		1/2241 (0%)
Ovarian adenoma	1/2218 (0%)		0/2241 (0%)
Ovarian cancer	1/2218 (0%)		1/2241 (0%)
Ovarian cancer stage III	0/2218 (0%)		1/2241 (0%)
Ovarian epithelial cancer	1/2218 (0%)		0/2241 (0%)
Ovarian neoplasm	0/2218 (0%)		1/2241 (0%)
Paget's disease of the vulva	1/2218 (0%)		0/2241 (0%)
Papillary thyroid cancer	2/2218 (0.1%)		1/2241 (0%)
Paraneoplastic syndrome	1/2218 (0%)		0/2241 (0%)
Parathyroid tumour benign	0/2218 (0%)		1/2241 (0%)
Rectal adenocarcinoma	1/2218 (0%)		1/2241 (0%)
Rectal cancer	1/2218 (0%)		3/2241 (0.1%)
Renal cancer	0/2218 (0%)		1/2241 (0%)
Renal cancer stage I	1/2218 (0%)		0/2241 (0%)
Renal cell carcinoma	0/2218 (0%)		2/2241 (0.1%)
Retro-orbital neoplasm	1/2218 (0%)		0/2241 (0%)
Small intestine carcinoma	0/2218 (0%)		1/2241 (0%)
Squamous cell carcinoma of the cervix	0/2218 (0%)		1/2241 (0%)
Thymoma	0/2218 (0%)		1/2241 (0%)
Thyroid cancer	1/2218 (0%)		0/2241 (0%)
Thyroid neoplasm	0/2218 (0%)		1/2241 (0%)
Uterine leiomyoma	5/2218 (0.2%)		5/2241 (0.2%)
Astrocytoma	0/2218 (0%)		1/2241 (0%)
Papilloma	0/2218 (0%)		1/2241 (0%)
Nervous system disorders
Aphasia	0/2218 (0%)		1/2241 (0%)
Ataxia	0/2218 (0%)		1/2241 (0%)
Brain oedema	1/2218 (0%)		3/2241 (0.1%)
Carotid artery stenosis	1/2218 (0%)		0/2241 (0%)
Carpal tunnel syndrome	1/2218 (0%)		1/2241 (0%)
Cerebellar ataxia	0/2218 (0%)		1/2241 (0%)
Cerebellar infarction	1/2218 (0%)		0/2241 (0%)
Cerebral disorder	0/2218 (0%)		1/2241 (0%)
Cerebral haemorrhage	0/2218 (0%)		1/2241 (0%)
Cerebral infarction	1/2218 (0%)		0/2241 (0%)
Cerebral ischaemia	3/2218 (0.1%)		1/2241 (0%)
Cerebrospinal fistula	0/2218 (0%)		1/2241 (0%)
Cerebrovascular accident	6/2218 (0.3%)		5/2241 (0.2%)
Cervical radiculopathy	0/2218 (0%)		1/2241 (0%)
Coma hepatic	1/2218 (0%)		0/2241 (0%)
Dementia	0/2218 (0%)		1/2241 (0%)
Dementia with Lewy bodies	1/2218 (0%)		0/2241 (0%)
Depressed level of consciousness	1/2218 (0%)		2/2241 (0.1%)
Dizziness	4/2218 (0.2%)		3/2241 (0.1%)
Dystonia	1/2218 (0%)		0/2241 (0%)
Encephalopathy	1/2218 (0%)		0/2241 (0%)
Epilepsy	0/2218 (0%)		2/2241 (0.1%)
Facial neuralgia	0/2218 (0%)		1/2241 (0%)
Facial paralysis	2/2218 (0.1%)		1/2241 (0%)
Headache	3/2218 (0.1%)		10/2241 (0.4%)
Hemiparesis	0/2218 (0%)		2/2241 (0.1%)
Hydrocephalus	1/2218 (0%)		0/2241 (0%)
Intracranial aneurysm	0/2218 (0%)		1/2241 (0%)
Ischaemic stroke	0/2218 (0%)		3/2241 (0.1%)
Lethargy	0/2218 (0%)		1/2241 (0%)
Loss of consciousness	0/2218 (0%)		1/2241 (0%)
Migraine	1/2218 (0%)		1/2241 (0%)
Myoclonus	1/2218 (0%)		0/2241 (0%)
Neurological symptom	0/2218 (0%)		1/2241 (0%)
Neuropathy peripheral	1/2218 (0%)		0/2241 (0%)
Occipital neuralgia	0/2218 (0%)		1/2241 (0%)
Peripheral sensory neuropathy	1/2218 (0%)		0/2241 (0%)
Presyncope	1/2218 (0%)		1/2241 (0%)
Psychomotor hyperactivity	0/2218 (0%)		1/2241 (0%)
Ruptured cerebral aneurysm	0/2218 (0%)		1/2241 (0%)
Sciatica	1/2218 (0%)		1/2241 (0%)
Seizure	4/2218 (0.2%)		5/2241 (0.2%)
Somnolence	0/2218 (0%)		1/2241 (0%)
Status epilepticus	1/2218 (0%)		0/2241 (0%)
Superior sagittal sinus thrombosis	0/2218 (0%)		1/2241 (0%)
Syncope	9/2218 (0.4%)		2/2241 (0.1%)
Thrombotic stroke	1/2218 (0%)		0/2241 (0%)
Transient ischaemic attack	4/2218 (0.2%)		3/2241 (0.1%)
Trigeminal nerve disorder	0/2218 (0%)		1/2241 (0%)
Visual field defect	0/2218 (0%)		1/2241 (0%)
IIIrd nerve paralysis	1/2218 (0%)		0/2241 (0%)
Nerve root compression	0/2218 (0%)		1/2241 (0%)
Pregnancy, puerperium and perinatal conditions
Foetal death	0/2218 (0%)		1/2241 (0%)
Product Issues
Device expulsion	0/2218 (0%)		1/2241 (0%)
Device failure	0/2218 (0%)		1/2241 (0%)
Psychiatric disorders
Alcoholism	1/2218 (0%)		0/2241 (0%)
Anxiety	0/2218 (0%)		7/2241 (0.3%)
Anxiety disorder	0/2218 (0%)		1/2241 (0%)
Completed suicide	1/2218 (0%)		0/2241 (0%)
Confusional state	3/2218 (0.1%)		0/2241 (0%)
Delirium	1/2218 (0%)		0/2241 (0%)
Depressed mood	1/2218 (0%)		0/2241 (0%)
Depression	2/2218 (0.1%)		8/2241 (0.4%)
Hypomania	1/2218 (0%)		0/2241 (0%)
Insomnia	1/2218 (0%)		0/2241 (0%)
Major depression	1/2218 (0%)		0/2241 (0%)
Mania	0/2218 (0%)		1/2241 (0%)
Persistent depressive disorder	2/2218 (0.1%)		0/2241 (0%)
Psychomotor retardation	0/2218 (0%)		1/2241 (0%)
Psychotic disorder	1/2218 (0%)		1/2241 (0%)
Restlessness	0/2218 (0%)		1/2241 (0%)
Suicidal ideation	1/2218 (0%)		2/2241 (0.1%)
Renal and urinary disorders
Acute kidney injury	3/2218 (0.1%)		6/2241 (0.3%)
Bladder perforation	1/2218 (0%)		0/2241 (0%)
Calculus bladder	1/2218 (0%)		0/2241 (0%)
Dysuria	0/2218 (0%)		1/2241 (0%)
Haematuria	0/2218 (0%)		2/2241 (0.1%)
Hydronephrosis	1/2218 (0%)		0/2241 (0%)
Nephrocalcinosis	0/2218 (0%)		1/2241 (0%)
Renal failure	3/2218 (0.1%)		2/2241 (0.1%)
Renal impairment	1/2218 (0%)		1/2241 (0%)
Ureteric stenosis	0/2218 (0%)		1/2241 (0%)
Urinary incontinence	1/2218 (0%)		0/2241 (0%)
Urinary retention	0/2218 (0%)		1/2241 (0%)
Reproductive system and breast disorders
Bartholin's cyst	0/2218 (0%)		1/2241 (0%)
Breast haematoma	1/2218 (0%)		2/2241 (0.1%)
Breast inflammation	0/2218 (0%)		1/2241 (0%)
Breast mass	0/2218 (0%)		1/2241 (0%)
Breast necrosis	1/2218 (0%)		1/2241 (0%)
Breast pain	2/2218 (0.1%)		1/2241 (0%)
Cervical dysplasia	2/2218 (0.1%)		3/2241 (0.1%)
Cystocele	1/2218 (0%)		0/2241 (0%)
Dysfunctional uterine bleeding	0/2218 (0%)		1/2241 (0%)
Endometrial disorder	1/2218 (0%)		0/2241 (0%)
Endometrial hyperplasia	4/2218 (0.2%)		7/2241 (0.3%)
Endometriosis	1/2218 (0%)		0/2241 (0%)
Genital haemorrhage	0/2218 (0%)		1/2241 (0%)
Genital prolapse	1/2218 (0%)		0/2241 (0%)
Haemorrhagic ovarian cyst	0/2218 (0%)		1/2241 (0%)
Menometrorrhagia	1/2218 (0%)		0/2241 (0%)
Menopausal symptoms	1/2218 (0%)		0/2241 (0%)
Menorrhagia	2/2218 (0.1%)		1/2241 (0%)
Metrorrhagia	1/2218 (0%)		0/2241 (0%)
Ovarian cyst	7/2218 (0.3%)		3/2241 (0.1%)
Ovarian enlargement	1/2218 (0%)		0/2241 (0%)
Pelvic pain	1/2218 (0%)		0/2241 (0%)
Postmenopausal haemorrhage	1/2218 (0%)		0/2241 (0%)
Uterine polyp	2/2218 (0.1%)		3/2241 (0.1%)
Uterine prolapse	4/2218 (0.2%)		0/2241 (0%)
Vaginal haemorrhage	0/2218 (0%)		1/2241 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/2218 (0%)		1/2241 (0%)
Acute respiratory distress syndrome	3/2218 (0.1%)		0/2241 (0%)
Asthma	4/2218 (0.2%)		0/2241 (0%)
Atelectasis	0/2218 (0%)		2/2241 (0.1%)
Chronic obstructive pulmonary disease	0/2218 (0%)		3/2241 (0.1%)
Cough	1/2218 (0%)		2/2241 (0.1%)
Dyspnoea	10/2218 (0.5%)		13/2241 (0.6%)
Dyspnoea at rest	1/2218 (0%)		0/2241 (0%)
Dyspnoea exertional	2/2218 (0.1%)		0/2241 (0%)
Epistaxis	0/2218 (0%)		1/2241 (0%)
Hyperventilation	0/2218 (0%)		1/2241 (0%)
Hypoxia	2/2218 (0.1%)		1/2241 (0%)
Interstitial lung disease	0/2218 (0%)		1/2241 (0%)
Laryngospasm	0/2218 (0%)		1/2241 (0%)
Lung disorder	1/2218 (0%)		1/2241 (0%)
Lung infiltration	1/2218 (0%)		1/2241 (0%)
Obstructive airways disorder	1/2218 (0%)		0/2241 (0%)
Organising pneumonia	0/2218 (0%)		1/2241 (0%)
Oropharyngeal pain	1/2218 (0%)		1/2241 (0%)
Pleural effusion	5/2218 (0.2%)		4/2241 (0.2%)
Pleurisy	0/2218 (0%)		1/2241 (0%)
Pneumonia aspiration	0/2218 (0%)		1/2241 (0%)
Pneumonitis	2/2218 (0.1%)		6/2241 (0.3%)
Pneumothorax	2/2218 (0.1%)		3/2241 (0.1%)
Productive cough	1/2218 (0%)		0/2241 (0%)
Pulmonary embolism	20/2218 (0.9%)		17/2241 (0.8%)
Pulmonary mass	1/2218 (0%)		1/2241 (0%)
Respiratory arrest	0/2218 (0%)		1/2241 (0%)
Respiratory failure	7/2218 (0.3%)		2/2241 (0.1%)
Vocal cord polyp	0/2218 (0%)		1/2241 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/2218 (0%)		0/2241 (0%)
Dermatitis	1/2218 (0%)		0/2241 (0%)
Erythema	0/2218 (0%)		1/2241 (0%)
Lichen sclerosus	1/2218 (0%)		0/2241 (0%)
Onycholysis	1/2218 (0%)		0/2241 (0%)
Pain of skin	0/2218 (0%)		1/2241 (0%)
Rash	1/2218 (0%)		1/2241 (0%)
Rash papular	0/2218 (0%)		1/2241 (0%)
Segmented hyalinising vasculitis	1/2218 (0%)		0/2241 (0%)
Skin ulcer	0/2218 (0%)		2/2241 (0.1%)
Toxic skin eruption	0/2218 (0%)		1/2241 (0%)
Urticaria	1/2218 (0%)		0/2241 (0%)
Surgical and medical procedures
Ankle arthroplasty	0/2218 (0%)		1/2241 (0%)
Breast conserving surgery	1/2218 (0%)		0/2241 (0%)
Breast operation	1/2218 (0%)		0/2241 (0%)
Breast reconstruction	2/2218 (0.1%)		2/2241 (0.1%)
Cancer surgery	0/2218 (0%)		1/2241 (0%)
Catheter removal	1/2218 (0%)		0/2241 (0%)
Cervical polypectomy	1/2218 (0%)		0/2241 (0%)
Cholecystectomy	0/2218 (0%)		1/2241 (0%)
Hysterectomy	1/2218 (0%)		0/2241 (0%)
Incisional drainage	0/2218 (0%)		1/2241 (0%)
Mammoplasty	1/2218 (0%)		0/2241 (0%)
Oophorectomy bilateral	1/2218 (0%)		0/2241 (0%)
Salpingo-oophorectomy bilateral	1/2218 (0%)		0/2241 (0%)
Uterine dilation and curettage	0/2218 (0%)		1/2241 (0%)
Mastectomy	0/2218 (0%)		1/2241 (0%)
Vascular disorders
Aortic stenosis	1/2218 (0%)		0/2241 (0%)
Arteritis	1/2218 (0%)		0/2241 (0%)
Brachiocephalic vein thrombosis	0/2218 (0%)		1/2241 (0%)
Circulatory collapse	0/2218 (0%)		1/2241 (0%)
Deep vein thrombosis	12/2218 (0.5%)		9/2241 (0.4%)
Embolism	1/2218 (0%)		1/2241 (0%)
Embolism arterial	0/2218 (0%)		1/2241 (0%)
Embolism venous	0/2218 (0%)		1/2241 (0%)
Haematoma	1/2218 (0%)		0/2241 (0%)
Hypertension	3/2218 (0.1%)		3/2241 (0.1%)
Hypertensive crisis	1/2218 (0%)		0/2241 (0%)
Hypotension	6/2218 (0.3%)		7/2241 (0.3%)
Intermittent claudication	0/2218 (0%)		1/2241 (0%)
Lymphocele	0/2218 (0%)		1/2241 (0%)
Lymphoedema	2/2218 (0.1%)		5/2241 (0.2%)
Peripheral arterial occlusive disease	1/2218 (0%)		0/2241 (0%)
Peripheral artery stenosis	1/2218 (0%)		0/2241 (0%)
Peripheral artery thrombosis	1/2218 (0%)		0/2241 (0%)
Peripheral vascular disorder	0/2218 (0%)		1/2241 (0%)
Phlebitis	2/2218 (0.1%)		0/2241 (0%)
Shock	1/2218 (0%)		0/2241 (0%)
Subclavian artery thrombosis	1/2218 (0%)		0/2241 (0%)
Subclavian vein thrombosis	1/2218 (0%)		1/2241 (0%)
Superior vena cava syndrome	1/2218 (0%)		3/2241 (0.1%)
Thrombophlebitis	1/2218 (0%)		0/2241 (0%)
Thrombophlebitis superficial	3/2218 (0.1%)		0/2241 (0%)
Thrombosis	2/2218 (0.1%)		2/2241 (0.1%)
Varicose vein	1/2218 (0%)		2/2241 (0.1%)
Vena cava thrombosis	0/2218 (0%)		1/2241 (0%)
Venous thrombosis	0/2218 (0%)		1/2241 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Denosumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2123/2218 (95.7%)		2149/2241 (95.9%)
Blood and lymphatic system disorders
Anaemia	349/2218 (15.7%)		354/2241 (15.8%)
Leukopenia	154/2218 (6.9%)		145/2241 (6.5%)
Neutropenia	461/2218 (20.8%)		441/2241 (19.7%)
Eye disorders
Lacrimation increased	243/2218 (11%)		195/2241 (8.7%)
Gastrointestinal disorders
Abdominal pain	242/2218 (10.9%)		232/2241 (10.4%)
Abdominal pain upper	199/2218 (9%)		179/2241 (8%)
Constipation	635/2218 (28.6%)		626/2241 (27.9%)
Diarrhoea	638/2218 (28.8%)		660/2241 (29.5%)
Dyspepsia	245/2218 (11%)		273/2241 (12.2%)
Nausea	1095/2218 (49.4%)		1145/2241 (51.1%)
Stomatitis	398/2218 (17.9%)		399/2241 (17.8%)
Toothache	159/2218 (7.2%)		198/2241 (8.8%)
Vomiting	536/2218 (24.2%)		536/2241 (23.9%)
General disorders
Asthenia	404/2218 (18.2%)		407/2241 (18.2%)
Fatigue	893/2218 (40.3%)		901/2241 (40.2%)
Influenza like illness	145/2218 (6.5%)		154/2241 (6.9%)
Mucosal inflammation	278/2218 (12.5%)		281/2241 (12.5%)
Oedema	112/2218 (5%)		106/2241 (4.7%)
Oedema peripheral	397/2218 (17.9%)		380/2241 (17%)
Pain	178/2218 (8%)		156/2241 (7%)
Pyrexia	342/2218 (15.4%)		338/2241 (15.1%)
Infections and infestations
Bronchitis	112/2218 (5%)		86/2241 (3.8%)
Influenza	117/2218 (5.3%)		117/2241 (5.2%)
Nasopharyngitis	290/2218 (13.1%)		292/2241 (13%)
Sinusitis	101/2218 (4.6%)		113/2241 (5%)
Upper respiratory tract infection	195/2218 (8.8%)		206/2241 (9.2%)
Urinary tract infection	149/2218 (6.7%)		177/2241 (7.9%)
Injury, poisoning and procedural complications
Procedural pain	161/2218 (7.3%)		170/2241 (7.6%)
Radiation skin injury	351/2218 (15.8%)		361/2241 (16.1%)
Investigations
Weight increased	151/2218 (6.8%)		167/2241 (7.5%)
Metabolism and nutrition disorders
Decreased appetite	289/2218 (13%)		330/2241 (14.7%)
Hypocalcaemia	73/2218 (3.3%)		135/2241 (6%)
Musculoskeletal and connective tissue disorders
Arthralgia	974/2218 (43.9%)		973/2241 (43.4%)
Back pain	486/2218 (21.9%)		563/2241 (25.1%)
Bone pain	256/2218 (11.5%)		288/2241 (12.9%)
Muscle spasms	204/2218 (9.2%)		201/2241 (9%)
Musculoskeletal chest pain	143/2218 (6.4%)		129/2241 (5.8%)
Musculoskeletal pain	308/2218 (13.9%)		337/2241 (15%)
Myalgia	539/2218 (24.3%)		553/2241 (24.7%)
Neck pain	112/2218 (5%)		106/2241 (4.7%)
Pain in extremity	545/2218 (24.6%)		570/2241 (25.4%)
Pain in jaw	124/2218 (5.6%)		150/2241 (6.7%)
Nervous system disorders
Dizziness	255/2218 (11.5%)		273/2241 (12.2%)
Dysgeusia	344/2218 (15.5%)		351/2241 (15.7%)
Headache	567/2218 (25.6%)		527/2241 (23.5%)
Hypoaesthesia	112/2218 (5%)		112/2241 (5%)
Neuropathy peripheral	421/2218 (19%)		417/2241 (18.6%)
Paraesthesia	197/2218 (8.9%)		216/2241 (9.6%)
Peripheral sensory neuropathy	177/2218 (8%)		198/2241 (8.8%)
Psychiatric disorders
Anxiety	207/2218 (9.3%)		220/2241 (9.8%)
Depression	202/2218 (9.1%)		195/2241 (8.7%)
Insomnia	432/2218 (19.5%)		429/2241 (19.1%)
Reproductive system and breast disorders
Breast pain	189/2218 (8.5%)		178/2241 (7.9%)
Respiratory, thoracic and mediastinal disorders
Cough	426/2218 (19.2%)		410/2241 (18.3%)
Dyspnoea	268/2218 (12.1%)		280/2241 (12.5%)
Epistaxis	151/2218 (6.8%)		168/2241 (7.5%)
Oropharyngeal pain	176/2218 (7.9%)		157/2241 (7%)
Skin and subcutaneous tissue disorders
Alopecia	923/2218 (41.6%)		938/2241 (41.9%)
Dermatitis	112/2218 (5%)		107/2241 (4.8%)
Dry skin	133/2218 (6%)		125/2241 (5.6%)
Erythema	226/2218 (10.2%)		260/2241 (11.6%)
Nail disorder	264/2218 (11.9%)		275/2241 (12.3%)
Palmar-plantar erythrodysaesthesia syndrome	114/2218 (5.1%)		138/2241 (6.2%)
Pruritus	181/2218 (8.2%)		144/2241 (6.4%)
Rash	372/2218 (16.8%)		392/2241 (17.5%)
Vascular disorders
Hot flush	645/2218 (29.1%)		669/2241 (29.9%)
Hypertension	209/2218 (9.4%)		195/2241 (8.7%)
Lymphoedema	350/2218 (15.8%)		392/2241 (17.5%)

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.