ARCH: Study to Determine the Efficacy and Safety of Romosozumab in the Treatment of Postmenopausal Women With Osteoporosis
Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT01631214
Collaborator
(none)
4,093
317
2
61.8
12.9
0.2
Study Details
Study Description
Brief Summary
The purpose of this study is to determine if treatment is effective in preventing fractures in women with postmenopausal osteoporosis.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
In this trial, women were randomly assigned in a 1:1 ratio to receive monthly subcutaneous romosozumab or weekly oral alendronate for 12 months. Randomization was stratified according to age (<75 vs. ≥75 years). After completion of the double-blind treatment period, all the participants were to receive open-label weekly oral alendronate until the end of the trial, with blinding to the initial treatment assignment maintained.
The primary analysis was performed when clinical fracture events had been confirmed in at least 330 participants and all the participants had completed the month 24 visit. The study was to continue in an event-driven manner until at least 440 participants experienced a nonvertebral fracture or if the superiority of romosozumab was proven for nonvertebral fractures at the primary analysis.
Study Design
Study Type:
Interventional
Actual Enrollment
:
4093 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Multicenter, International, Randomized, Double-blind, Alendronate-controlled Study to Determine the Efficacy and Safety of Romosozumab in the Treatment of Postmenopausal Women With Osteoporosis
Actual Study Start Date
:
May 4, 2012
Actual Primary Completion Date
:
Feb 27, 2017
Actual Study Completion Date
:
Jun 29, 2017
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Alendronate/Alendronate Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. |
Drug: Alendronate
Alendronate 70 mg tablet taken once a week
Other Names:
Drug: Placebo to Romosozumab
Administered by subcutaneous injection once a month during the double-blind treatment phase.
|
| Experimental: Romosozumab/Alendronate Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
Biological: Romosozumab
Romosozumab 210 mg administered by subcutaneous injection once a month during the double-blind treatment phase.
Other Names:
Drug: Alendronate
Alendronate 70 mg tablet taken once a week
Other Names:
Drug: Placebo to Alendronate
Matching placebo tablet taken once a week during the double-blind treatment phase.
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With New Vertebral Fractures Through Month 24 [24 months]
All fracture assessments were performed by blinded central imaging readers. New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader using the Semiquantitative method.
- Percentage of Participants With a Clinical Fracture at the Primary Analysis [The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).]
All fracture assessments were performed by blinded central imaging readers. Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.
Secondary Outcome Measures
- Percentage of Participants With a Nonvertebral Fracture at the Primary Analysis [The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).]
A nonvertebral fracture was defined as a documented fracture excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
- Percentage of Participants With Any Fracture at the Primary Analysis [The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).]
All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures.
- Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 24 [24 months]
A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4 according to the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader using the Semiquantitative method.
- Percentage of Participants With a Major Nonvertebral Fracture at the Primary Analysis [The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).]
Major nonvertebral fractures included a subset of nonvertebral fractures including pelvis, distal femur (ie, femur excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus (ie, humerus excluding elbow), forearm, and hip.
- Percentage of Participants With a Hip Fracture at the Primary Analysis [The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3).]
Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
- Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 24 [24 months]
A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4 according to the Genant Semiquantitative Scoring method. A participant had multiple new or worsening vertebral fractures when there were ≥ 2 vertebrae from T4 to L4 with ≥ 1 grade increase from the previous grade. The multiple new or worsening vertebral fractures need not have occurred at the same visit. Incident vertebral fractures were confirmed by a second independent reader.
- Percentage of Participants With a Clinical Fracture Through Month 24 [24 months]
Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.
- Percentage of Participants With a Nonvertebral Fracture Through Month 24 [24 months]
A nonvertebral fracture was defined as a documented fracture excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
- Percentage of Participants With a Hip Fracture Through Month 24 [24 months]
Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
- Percentage of Participants With a Clinical Vertebral Fracture Through Month 24 [24 months]
A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic.
- Percentage of Participants With a Clinical Fracture Through Month 12 [12 months]
Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded.
- Percentage of Participants With New Vertebral Fractures Through Month 12 [12 months]
New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader.
- Percentage of Participants With Any Fracture Through Month 12 [12 months]
All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures.
- Percentage of Participants With a Nonvertebral Fracture Through Month 12 [12 months]
A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded.
- Percentage of Participants With a Hip Fracture Through Month 12 [12 months]
Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter.
- Percentage of Participants With a Major Osteoporotic Fracture Through Month 12 [12 months]
Major osteoporotic fractures included clinical vertebral fractures and fractures of the hip, forearm and humerus. Fractures associated with high trauma severity or pathologic fractures were excluded.
- Percentage of Participants With a Clinical Vertebral Fracture Through Month 12 [12 months]
A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic.
- Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 24 [Baseline and month 24]
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
- Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 24 [Baseline and month 24]
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
- Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at at Month 24 [Baseline and month 24]
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
- Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 12 [Baseline and month 12]
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
- Percent Change From Baseline in Bone Mineral Density at the Total Hip at Month 12 [Baseline and month 12]
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
- Percent Change From Baseline in Bone Mineral Density at the Femoral Neck at Month 12 [Baseline and month 12]
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
- Percent Change From Baseline in Bone Mineral Density of the Lumbar Spine at Month 36 [Baseline and month 36]
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
- Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 36 [Baseline and month 36]
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
- Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 36 [Baseline and month 36]
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center.
Eligibility Criteria
Criteria
Ages Eligible for Study:
55 Years
to 90 Years
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
Inclusion Criteria:
Postmenopausal women who meet at least one of the following bone mineral density (BMD) and fracture criteria:
-
BMD T-score at the total hip or femoral neck of ≤ -2.50 and EITHER:
-
at least 1 moderate (semiquantitative grade [SQ]2) or severe (SQ3) vertebral fracture OR
-
at least 2 mild (SQ1) vertebral fractures OR
-
BMD T-score at the total hip or femoral neck of ≤ -2.00 and EITHER:
-
at least 2 moderate (SQ2) or severe (SQ3) vertebral fractures OR
-
a fracture of the proximal femur that occurred within 3 to 24 months prior to randomization.
Exclusion Criteria:
-
History of metabolic or bone disease (except osteoporosis)
-
Use of agents affecting bone metabolism
-
Vitamin D insufficiency
-
History of solid organ or bone marrow transplants
-
Hyper- or hypocalcemia
-
Hyper- or hypothyroidism
-
Hyper- or hypoparathyroidism
-
Possible signs of intolerance to alendronate
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Birmingham | Alabama | United States | 35294 |
| 2 | Research Site | Peoria | Arizona | United States | 85381 |
| 3 | Research Site | Phoenix | Arizona | United States | 85037 |
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| 7 | Research Site | Los Angeles | California | United States | 90057 |
| 8 | Research Site | South Lake Tahoe | California | United States | 96150 |
| 9 | Research Site | Tustin | California | United States | 92780 |
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| 98 | Research Site | Plzen | Czechia | 305 99 | |
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| 101 | Research Site | Uherske Hradiste | Czechia | 686 01 | |
| 102 | Research Site | Zlin | Czechia | 760 01 | |
| 103 | Research Site | Aalborg | Denmark | 9000 | |
| 104 | Research Site | Ballerup | Denmark | 2750 | |
| 105 | Research Site | Glostrup | Denmark | 2600 | |
| 106 | Research Site | Hvidovre | Denmark | 2650 | |
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| 113 | Research Site | Santiago | Dominican Republic | 51000 | |
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| 118 | Research Site | Jyväskylä | Finland | 40100 | |
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| 121 | Research Site | Bordeaux Cedex | France | 33076 | |
| 122 | Research Site | Cahors Cedex | France | 46005 | |
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| 129 | Research Site | Berlin (Hellersdorf) | Germany | 12627 | |
| 130 | Research Site | Berlin | Germany | 12200 | |
| 131 | Research Site | Bonn | Germany | 53105 | |
| 132 | Research Site | Dresden | Germany | 01307 | |
| 133 | Research Site | Frankfurt am Main | Germany | 60528 | |
| 134 | Research Site | Frankfurt am Main | Germany | 60596 | |
| 135 | Research Site | Freiburg | Germany | 79106 | |
| 136 | Research Site | Hamburg | Germany | 20354 | |
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| 141 | Research Site | Marburg | Germany | 35043 | |
| 142 | Research Site | München | Germany | 80336 | |
| 143 | Research Site | Würzburg | Germany | 97074 | |
| 144 | Research Site | Athens | Greece | 11525 | |
| 145 | Research Site | Athens | Greece | 11526 | |
| 146 | Research Site | Athens | Greece | 11527 | |
| 147 | Research Site | Athens | Greece | 14561 | |
| 148 | Research Site | Athens | Greece | 16673 | |
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| 150 | Research Site | Thessaloniki | Greece | 54636 | |
| 151 | Research Site | Thessaloniki | Greece | 56403 | |
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| 153 | Research Site | Antigua | Sacatepéquez | Guatemala | 03001 |
| 154 | Research Site | Guatemala | Guatemala | 01001 | |
| 155 | Research Site | Guatemala | Guatemala | 01007 | |
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| 158 | Research Site | Guatemala | Guatemala | 01012 | |
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| 166 | Research Site | Budapest | Hungary | 1036 | |
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| 172 | Research Site | Kiskunhalas | Hungary | 6400 | |
| 173 | Research Site | Kistarcsa | Hungary | 2143 | |
| 174 | Research Site | Veszprem | Hungary | 8200 | |
| 175 | Research Site | Zalaegerszeg | Hungary | 8900 | |
| 176 | Research Site | Cork | Ireland | ||
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| 189 | Research Site | Pisa | Italy | 56124 | |
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| 194 | Research Site | Verona | Italy | 37126 | |
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| 196 | Research Site | Daegu | Korea, Republic of | 700-712 | |
| 197 | Research Site | Guri-si | Korea, Republic of | 471-701 | |
| 198 | Research Site | Gwangju | Korea, Republic of | 501-757 | |
| 199 | Research Site | Incheon | Korea, Republic of | 405-760 | |
| 200 | Research Site | Seoul | Korea, Republic of | 110-744 | |
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| 202 | Research Site | Seoul | Korea, Republic of | 136-705 | |
| 203 | Research Site | Suwon-si, Gyeonggi-do | Korea, Republic of | 443-380 | |
| 204 | Research Site | Liepaja | Latvia | 3401 | |
| 205 | Research Site | Riga | Latvia | 1011 | |
| 206 | Research Site | Riga | Latvia | 1012 | |
| 207 | Research Site | Vilnius | Lithuania | 09310 | |
| 208 | Research Site | Vilnius | Lithuania | 10323 | |
| 209 | Research Site | Mexicali | Baja California Norte | Mexico | 21100 |
| 210 | Research Site | Mexicalli | Baja California Norte | Mexico | 21200 |
| 211 | Research Site | Mexico | Distrito Federal | Mexico | 06100 |
| 212 | Research Site | Mexico | Distrito Federal | Mexico | 06700 |
| 213 | Research Site | Leon | Guanajuato | Mexico | 37000 |
| 214 | Research Site | Leon | Guanajuato | Mexico | 37520 |
| 215 | Research Site | Monterrey | Nuevo León | Mexico | 64460 |
| 216 | Research Site | Queretaro | Querétaro | Mexico | 76000 |
| 217 | Research Site | Ciudad Obregon | Sonora | Mexico | 85000 |
| 218 | Research Site | Leiden | Netherlands | 2333 ZA | |
| 219 | Research Site | Rotterdam | Netherlands | 3015 CE | |
| 220 | Research Site | Venlo | Netherlands | 5912 BL | |
| 221 | Research Site | Christchurch | New Zealand | 8022 | |
| 222 | Research Site | Grafton, Auckland | New Zealand | 1023 | |
| 223 | Research Site | Elverum | Norway | 2408 | |
| 224 | Research Site | Hamar | Norway | 2317 | |
| 225 | Research Site | Oslo | Norway | 0050 | |
| 226 | Research Site | Stavanger | Norway | 4005 | |
| 227 | Research Site | Lima | Peru | Lima 27 | |
| 228 | Research Site | Lima | Peru | Lima 33 | |
| 229 | Research Site | Lima | Peru | Lima11 | |
| 230 | Research Site | Bialystok | Poland | 15-351 | |
| 231 | Research Site | Bialystok | Poland | 15-879 | |
| 232 | Research Site | Dabrowka Dopiewo | Poland | 62-069 | |
| 233 | Research Site | Elblag | Poland | 82-300 | |
| 234 | Research Site | Gdynia | Poland | 81-384 | |
| 235 | Research Site | Gliwice | Poland | 44-100 | |
| 236 | Research Site | Katowice | Poland | 40-040 | |
| 237 | Research Site | Kielce | Poland | 25-317 | |
| 238 | Research Site | Krakow | Poland | 30-510 | |
| 239 | Research Site | Kraków | Poland | 31-501 | |
| 240 | Research Site | Lodz | Poland | 09-245 | |
| 241 | Research Site | Lodz | Poland | 90-558 | |
| 242 | Research Site | Poznan | Poland | 60-356 | |
| 243 | Research Site | Poznan | Poland | 60-702 | |
| 244 | Research Site | Swidnik | Poland | 21-040 | |
| 245 | Research Site | Torun | Poland | 87-100 | |
| 246 | Research Site | Warszawa | Poland | 01-192 | |
| 247 | Research Site | Warszawa | Poland | 02-507 | |
| 248 | Research Site | Warszawa | Poland | 04-730 | |
| 249 | Research Site | Wroclaw | Poland | 50-088 | |
| 250 | Research Site | Wroclaw | Poland | 51-124 | |
| 251 | Research Site | Wroclaw | Poland | 53-224 | |
| 252 | Research Site | Bucharest | Romania | 011172 | |
| 253 | Research Site | Bucharest | Romania | 011863 | |
| 254 | Research Site | Bucharest | Romania | 030463 | |
| 255 | Research Site | Bucuresti | Romania | 011863 | |
| 256 | Research Site | Bucuresti | Romania | 020125 | |
| 257 | Research Site | Oradea | Romania | 410028 | |
| 258 | Research Site | Targu Mures | Romania | 540142 | |
| 259 | Research Site | Arkhangelsk | Russian Federation | 163001 | |
| 260 | Research Site | Ekaterinburg | Russian Federation | 620102 | |
| 261 | Research Site | Ivanovo | Russian Federation | 153025 | |
| 262 | Research Site | Moscow | Russian Federation | 101990 | |
| 263 | Research Site | Moscow | Russian Federation | 115522 | |
| 264 | Research Site | Moscow | Russian Federation | 117036 | |
| 265 | Research Site | Moscow | Russian Federation | 127299 | |
| 266 | Research Site | Nizhniy Novgorod | Russian Federation | 603155 | |
| 267 | Research Site | Petrozavodsk | Russian Federation | 185019 | |
| 268 | Research Site | Saint Petersburg | Russian Federation | 190103 | |
| 269 | Research Site | Saint Petersburg | Russian Federation | 194291 | |
| 270 | Research Site | Saint-Petersburg | Russian Federation | 199034 | |
| 271 | Research Site | Yaroslavl | Russian Federation | 150003 | |
| 272 | Research Site | Banska Bystrica | Slovakia | 974 01 | |
| 273 | Research Site | Bratislava | Slovakia | 813 69 | |
| 274 | Research Site | Bratislava | Slovakia | 826 06 | |
| 275 | Research Site | Kosice-Saca | Slovakia | 040 15 | |
| 276 | Research Site | Lucenec | Slovakia | 984 01 | |
| 277 | Research Site | Piestany | Slovakia | 921 12 | |
| 278 | Research Site | Trencin | Slovakia | 911 01 | |
| 279 | Research Site | Johannesburg | Gauteng | South Africa | 2196 |
| 280 | Research Site | Pretoria | Gauteng | South Africa | 0181 |
| 281 | Research Site | Pretoria | Gauteng | South Africa | 0184 |
| 282 | Research Site | Parow | Western Cape | South Africa | 7500 |
| 283 | Research Site | Somerset West | Western Cape | South Africa | 7130 |
| 284 | Research Site | Tygerberg | South Africa | 7505 | |
| 285 | Research Site | Granada | Andalucía | Spain | 18012 |
| 286 | Research Site | Sevilla | Andalucía | Spain | 41009 |
| 287 | Research Site | Santander | Cantabria | Spain | 39008 |
| 288 | Research Site | Barcelona | Cataluña | Spain | 08003 |
| 289 | Research Site | Sant Joan Despi | Cataluña | Spain | 08970 |
| 290 | Research Site | A Coruña | Galicia | Spain | 15006 |
| 291 | Research Site | Madrid | Spain | 28006 | |
| 292 | Research Site | Madrid | Spain | 28046 | |
| 293 | Research Site | Linköping | Sweden | 581 85 | |
| 294 | Research Site | Mölndal | Sweden | 431 80 | |
| 295 | Research Site | Stockholm | Sweden | 141 86 | |
| 296 | Research Site | Umeå | Sweden | 907 36 | |
| 297 | Research Site | Tainan | Taiwan | 70403 | |
| 298 | Research Site | Taipei | Taiwan | 10002 | |
| 299 | Research Site | Adana | Turkey | 01330 | |
| 300 | Research Site | Istanbul | Turkey | 34093 | |
| 301 | Research Site | Istanbul | Turkey | 34890 | |
| 302 | Research Site | Izmir | Turkey | 35100 | |
| 303 | Research Site | Birmingham | United Kingdom | B15 2SQ | |
| 304 | Research Site | Cambridge | United Kingdom | CB2 0QQ | |
| 305 | Research Site | Cardiff | United Kingdom | CF14 5GJ | |
| 306 | Research Site | Chorley | United Kingdom | PR7 7NA | |
| 307 | Research Site | Edinburgh | United Kingdom | EH4 2XU | |
| 308 | Research Site | Glasgow | United Kingdom | G20 0SP | |
| 309 | Research Site | Liverpool | United Kingdom | L22 0LG | |
| 310 | Research Site | Manchester | United Kingdom | M15 6SX | |
| 311 | Research Site | Northwood | United Kingdom | HA6 2RN | |
| 312 | Research Site | Norwich | United Kingdom | NR4 7TJ | |
| 313 | Research Site | Reading | United Kingdom | RG2 0FT | |
| 314 | Research Site | Sheffield | United Kingdom | S5 7AU | |
| 315 | Research Site | Sidcup | United Kingdom | DA14 6LT | |
| 316 | Research Site | Staffordshire | United Kingdom | WS11 5XY | |
| 317 | Research Site | Warwick | United Kingdom | CV34 5BW |
Sponsors and Collaborators
- Amgen
Investigators
- Study Director: MD, Amgen
Study Documents (Full-Text)
More Information
Additional Information:
Publications
Responsible Party:
Amgen
ClinicalTrials.gov Identifier:
NCT01631214
Other Study ID Numbers:
- 20110142
- 2011-003142-41
First Posted:
Jun 29, 2012
Last Update Posted:
Dec 17, 2018
Last Verified:
Nov 1, 2018
Keywords provided by Amgen
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The study was conducted at 270 centers in 41 countries globally from 04 May 2012 to 29 June 2017. |
|---|---|
| Pre-assignment Detail | Participants were randomized in a 1:1 ratio to receive romosozumab or alendronate for 12 months. Randomization was stratified by age (< 75 vs. ≥ 75 years). After completion of the double-blind trial period, all participants received open-label alendronate until the end of the trial, with blinding to the initial treatment assignment maintained. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Period Title: Overall Study | ||
| STARTED | 2047 | 2046 |
| Received Double-blind Treatment | 2040 | 2038 |
| Completed Double-blind Period | 1823 | 1831 |
| Completed Primary Analysis Period | 1576 | 1574 |
| COMPLETED | 1503 | 1523 |
| NOT COMPLETED | 544 | 523 |
Baseline Characteristics
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate | Total |
|---|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. | Total of all reporting groups |
| Overall Participants | 2047 | 2046 | 4093 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
74.2
(7.5)
|
74.4
(7.5)
|
74.3
(7.5)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
2047
100%
|
2046
100%
|
4093
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
662
32.3%
|
631
30.8%
|
1293
31.6%
|
| Not Hispanic or Latino |
1385
67.7%
|
1415
69.2%
|
2800
68.4%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| American Indian or Alaska Native |
7
0.3%
|
5
0.2%
|
12
0.3%
|
| Asian |
149
7.3%
|
137
6.7%
|
286
7%
|
| Black or African American |
23
1.1%
|
19
0.9%
|
42
1%
|
| Native Hawaiian or Other Pacific Islander |
2
0.1%
|
0
0%
|
2
0%
|
| White |
1415
69.1%
|
1447
70.7%
|
2862
69.9%
|
| Multiple |
4
0.2%
|
2
0.1%
|
6
0.1%
|
| Other |
446
21.8%
|
436
21.3%
|
882
21.5%
|
| Missing |
1
0%
|
0
0%
|
1
0%
|
| Age Strata per Randomization (Count of Participants) | |||
| < 75 years |
976
47.7%
|
973
47.6%
|
1949
47.6%
|
| ≥ 75 years |
1071
52.3%
|
1073
52.4%
|
2144
52.4%
|
| Severe Vertebral Fracture (Count of Participants) | |||
| Presence |
1321
64.5%
|
1369
66.9%
|
2690
65.7%
|
| Absence |
726
35.5%
|
677
33.1%
|
1403
34.3%
|
| Total Hip Bone Mineral Density (BMD) T-score (Count of Participants) | |||
| ≤ -2.5 |
1384
67.6%
|
1356
66.3%
|
2740
66.9%
|
| > -2.5 |
662
32.3%
|
690
33.7%
|
1352
33%
|
| Missing |
1
0%
|
0
0%
|
1
0%
|
Outcome Measures
| Title | Percentage of Participants With New Vertebral Fractures Through Month 24 |
|---|---|
| Description | All fracture assessments were performed by blinded central imaging readers. New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader using the Semiquantitative method. |
| Time Frame | 24 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Randomized participants with a baseline and ≥ 1 postbaseline evaluation of vertebral fracture, including participants who had vertebrae with missing Genant semiquantitative scores at baseline whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1834 | 1825 |
| Number [percentage of participants] |
8.0
0.4%
|
4.1
0.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | The primary endpoints were tested at the 5% level (2-sided), accounting for multiplicity using the Hochberg procedure. If the larger of the 2 p-values was significant at the 0.05 level (2-sided), the statistical testing continued to the secondary endpoint in the testing sequence. | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on a logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.48 | |
| Confidence Interval |
(2-Sided) 95% 0.36 to 0.64 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.15 |
|
| Estimation Comments | Values < 1 for odds ratio favor romosozumab. The standard error (SE) represents the standard error of log(odds ratio). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | The risk ratio (ratio of percentages, Romosozumab:Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T-score at the total hip (≤ -2.5, > -2.5). Values < 1 for risk ratio favor romosozumab. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.50 | |
| Confidence Interval |
(2-Sided) 95% 0.38 to 0.66 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.14 |
|
| Estimation Comments | SE represents the standard error of log (risk ratio). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | The absolute risk reduction (difference in percentages, Alendronate - Romosozumab) was based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline. Positive values for absolute risk reduction favor romosozumab. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Absolute risk reduction |
| Estimated Value | 4.03 | |
| Confidence Interval |
(2-Sided) 95% 2.50 to 5.57 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.78 |
|
| Estimation Comments | ||
| Title | Percentage of Participants With a Clinical Fracture at the Primary Analysis |
|---|---|
| Description | All fracture assessments were performed by blinded central imaging readers. Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded. |
| Time Frame | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants. Missing values for clinical fractures were imputed using last observation carried forward. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
13.0
0.6%
|
9.7
0.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | The primary endpoints were tested at the 5% level (2-sided), accounting for multiplicity using the Hochberg procedure. If the larger of the 2 p-values was significant at the 0.05 level (2-sided), the statistical testing continued to the secondary endpoint in the testing sequence. | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.73 | |
| Confidence Interval |
(2-Sided) 95% 0.61 to 0.88 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.09 |
|
| Estimation Comments | Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio) | |
| Title | Percentage of Participants With a Nonvertebral Fracture at the Primary Analysis |
|---|---|
| Description | A nonvertebral fracture was defined as a documented fracture excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. |
| Time Frame | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
10.6
0.5%
|
8.7
0.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | If the 2 primary endpoints and the specified BMD secondary endpoints were all significant, the nonvertebral fracture at the primary analysis was evaluated based on a 1-sided test (overall α=0.025) determined by the Lan-DeMets alpha spending function that approximates a Pocock boundary, 0.0233 (1-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.040 |
| Comments | The adjusted 2-sided p-value is reported. | |
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.81 | |
| Confidence Interval |
(2-Sided) 95% 0.66 to 0.99 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.10 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With Any Fracture at the Primary Analysis |
|---|---|
| Description | All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures. |
| Time Frame | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
19.1
0.9%
|
13.0
0.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.65 | |
| Confidence Interval |
(2-Sided) 95% 0.56 to 0.76 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.08 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 24 |
|---|---|
| Description | A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4 according to the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader using the Semiquantitative method. |
| Time Frame | 24 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Randomized participants with a baseline and ≥ 1 postbaseline evaluation of vertebral fracture, including participants who had vertebrae with missing Genant semiquantitative scores at baseline whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1834 | 1825 |
| Number [percentage of participants] |
9.2
0.4%
|
4.8
0.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.49 | |
| Confidence Interval |
(2-Sided) 95% 0.37 to 0.64 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.14 |
|
| Estimation Comments | Values < 1 for odds ratio favor romosozumab. The standard error (SE) represents the standard error of log(odds ratio). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | The risk ratio (ratio of percentages, Romosozumab:Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T-score at the total hip (≤ -2.5, > -2.5). Values < 1 for risk ratio favor romosozumab. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.52 | |
| Confidence Interval |
(2-Sided) 95% 0.40 to 0.66 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.13 |
|
| Estimation Comments | SE represents the standard error of log (risk ratio). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | The absolute risk reduction (difference in percentages, Alendronate - Romosozumab) was based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline. Positive values for absolute risk reduction favor romosozumab. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Absolute risk reduction |
| Estimated Value | 4.44 | |
| Confidence Interval |
(2-Sided) 95% 2.80 to 6.08 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.84 |
|
| Estimation Comments | ||
| Title | Percentage of Participants With a Major Nonvertebral Fracture at the Primary Analysis |
|---|---|
| Description | Major nonvertebral fractures included a subset of nonvertebral fractures including pelvis, distal femur (ie, femur excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus (ie, humerus excluding elbow), forearm, and hip. |
| Time Frame | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
9.6
0.5%
|
7.1
0.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.004 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.73 | |
| Confidence Interval |
(2-Sided) 95% 0.59 to 0.90 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.11 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a Hip Fracture at the Primary Analysis |
|---|---|
| Description | Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter. |
| Time Frame | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
3.2
0.2%
|
2.0
0.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.015 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.62 | |
| Confidence Interval |
(2-Sided) 95% 0.42 to 0.92 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.20 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 24 |
|---|---|
| Description | A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4 according to the Genant Semiquantitative Scoring method. A participant had multiple new or worsening vertebral fractures when there were ≥ 2 vertebrae from T4 to L4 with ≥ 1 grade increase from the previous grade. The multiple new or worsening vertebral fractures need not have occurred at the same visit. Incident vertebral fractures were confirmed by a second independent reader. |
| Time Frame | 24 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Randomized participants with a baseline and ≥ 1 postbaseline evaluation of vertebral fracture, including participants who had vertebrae with missing Genant semiquantitative scores at baseline whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1834 | 1825 |
| Number [percentage of participants] |
2.5
0.1%
|
1.3
0.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.008 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.51 | |
| Confidence Interval |
(2-Sided) 95% 0.31 to 0.85 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.25 |
|
| Estimation Comments | Values < 1 for odds ratio favor romosozumab. The standard error (SE) represents the standard error of log(odds ratio). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | The risk ratio (ratio of percentages, Romosozumab:Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T-score at the total hip (≤ -2.5, > -2.5). Values < 1 for risk ratio favor romosozumab. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.52 | |
| Confidence Interval |
(2-Sided) 95% 0.32 to 0.85 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.25 |
|
| Estimation Comments | SE represents the standard error of log (risk ratio). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | The absolute risk reduction (difference in percentages, Alendronate - Romosozumab) was based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline. Positive values for absolute risk reduction favor romosozumab. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Absolute risk reduction |
| Estimated Value | 1.21 | |
| Confidence Interval |
(2-Sided) 95% 0.33 to 2.10 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.45 |
|
| Estimation Comments | ||
| Title | Percentage of Participants With a Clinical Fracture Through Month 24 |
|---|---|
| Description | Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded. |
| Time Frame | 24 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants; Missing values for clinical fractures were imputed using last observation carried forward. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
9.6
0.5%
|
7.1
0.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.005 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.74 | |
| Confidence Interval |
(2-Sided) 95% 0.59 to 0.91 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.11 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a Nonvertebral Fracture Through Month 24 |
|---|---|
| Description | A nonvertebral fracture was defined as a documented fracture excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. |
| Time Frame | 24 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
7.8
0.4%
|
6.3
0.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.074 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.81 | |
| Confidence Interval |
(2-Sided) 95% 0.64 to 1.02 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.12 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a Hip Fracture Through Month 24 |
|---|---|
| Description | Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter. |
| Time Frame | 24 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
2.1
0.1%
|
1.5
0.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.17 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% 0.46 to 1.15 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.24 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a Clinical Vertebral Fracture Through Month 24 |
|---|---|
| Description | A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic. |
| Time Frame | 24 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants; Last observation carried forward imputation was used. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
2.1
0.1%
|
0.9
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.41 | |
| Confidence Interval |
(2-Sided) 95% 0.24 to 0.71 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.28 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a Clinical Fracture Through Month 12 |
|---|---|
| Description | Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded. |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants; Missing values for clinical fractures were imputed using last observation carried forward. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
5.4
0.3%
|
3.9
0.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.027 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% 0.54 to 0.96 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.15 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With New Vertebral Fractures Through Month 12 |
|---|---|
| Description | New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader. |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Randomized participants with a baseline and ≥ 1 postbaseline evaluation of vertebral fracture, including participants who had vertebrae with missing Genant semiquantitative scores at baseline whose first postbaseline spinal radiograph showed no fracture on the same vertebrae. Last observation carried forward imputation was used. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1703 | 1696 |
| Number [percentage of participants] |
5.0
0.2%
|
3.2
0.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.008 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Based on a logistic regression model adjusted for age strata, baseline total hip BMD T-score and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.63 | |
| Confidence Interval |
(2-Sided) 95% 0.44 to 0.89 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.18 |
|
| Estimation Comments | Values < 1 for odds ratio favor romosozumab. The standard error (SE) represents the standard error of log(odds ratio). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | The risk ratio (ratio of percentages, Romosozumab:Alendronate) was based on the Mantel Haenszel method, adjusted for age strata (<75 vs. ≥75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T-score at the total hip (≤ -2.5, > -2.5). Values < 1 for risk ratio favor romosozumab. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.64 | |
| Confidence Interval |
(2-Sided) 95% 0.46 to 0.89 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.17 |
|
| Estimation Comments | SE represents the standard error of log (risk ratio). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | The absolute risk reduction (difference in percentages, Alendronate - Romosozumab) was based on the Mantel-Haenszel method adjusted for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline. Positive values for absolute risk reduction favor romosozumab. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Absolute risk reduction |
| Estimated Value | 1.84 | |
| Confidence Interval |
(2-Sided) 95% 0.51 to 3.17 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.68 |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Any Fracture Through Month 12 |
|---|---|
| Description | All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures. |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
9.2
0.4%
|
6.5
0.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.002 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.71 | |
| Confidence Interval |
(2-Sided) 95% 0.57 to 0.88 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.11 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a Nonvertebral Fracture Through Month 12 |
|---|---|
| Description | A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
4.6
0.2%
|
3.4
0.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.057 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.74 | |
| Confidence Interval |
(2-Sided) 95% 0.54 to 1.01 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.16 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a Hip Fracture Through Month 12 |
|---|---|
| Description | Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter. |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
1.1
0.1%
|
0.7
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.19 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.64 | |
| Confidence Interval |
(2-Sided) 95% 0.33 to 1.26 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.34 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a Major Osteoporotic Fracture Through Month 12 |
|---|---|
| Description | Major osteoporotic fractures included clinical vertebral fractures and fractures of the hip, forearm and humerus. Fractures associated with high trauma severity or pathologic fractures were excluded. |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
4.2
0.2%
|
3.0
0.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.053 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% 0.52 to 1.01 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.17 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percentage of Participants With a Clinical Vertebral Fracture Through Month 12 |
|---|---|
| Description | A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic. |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants; Last observation carried forward imputation was used. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 2047 | 2046 |
| Number [percentage of participants] |
0.9
0%
|
0.5
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | 0.14 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | Model adjusted for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.56 | |
| Confidence Interval |
(2-Sided) 95% 0.26 to 1.22 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.39 |
|
| Estimation Comments | Based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. Hazard ratio < 1 favors romosozumab; SE represents the standard error of log (hazard ratio). | |
| Title | Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 24 |
|---|---|
| Description | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Time Frame | Baseline and month 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 24; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1577 | 1571 |
| Least Squares Mean (Standard Error) [percent change] |
7.2
(0.2)
|
15.3
(0.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an analysis of covariance (ANCOVA) model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction. | |
| Type of Statistical Test | Superiority | |
| Comments | If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05. | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 8.1 | |
| Confidence Interval |
(2-Sided) 95% 7.58 to 8.57 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.3 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 24 |
|---|---|
| Description | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Time Frame | Baseline and month 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 24; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1627 | 1622 |
| Least Squares Mean (Standard Error) [percent change] |
3.5
(0.1)
|
7.2
(0.1)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction. | |
| Type of Statistical Test | Superiority | |
| Comments | If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05. | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 3.8 | |
| Confidence Interval |
(2-Sided) 95% 3.42 to 4.10 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.2 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at at Month 24 |
|---|---|
| Description | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Time Frame | Baseline and month 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 24; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1627 | 1622 |
| Least Squares Mean (Standard Error) [percent change] |
2.3
(0.2)
|
6.0
(0.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction. | |
| Type of Statistical Test | Superiority | |
| Comments | If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05. | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 3.8 | |
| Confidence Interval |
(2-Sided) 95% 3.40 to 4.14 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.2 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 12 |
|---|---|
| Description | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Time Frame | Baseline and month 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants with a baseline and ≥ 1 post-baseline evaluation at or before month 12; Last observation carried forward imputation was used. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1718 | 1722 |
| Least Squares Mean (Standard Error) [percent change] |
5.0
(0.1)
|
13.7
(0.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction. | |
| Type of Statistical Test | Superiority | |
| Comments | If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05. | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 8.7 | |
| Confidence Interval |
(2-Sided) 95% 8.31 to 9.09 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.2 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Bone Mineral Density at the Total Hip at Month 12 |
|---|---|
| Description | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Time Frame | Baseline and month 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants with a baseline and ≥ 1 post-baseline evaluation at or before month 12; Last observation carried forward imputation was used. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1781 | 1781 |
| Least Squares Mean (Standard Error) [percent change] |
2.8
(0.1)
|
6.2
(0.1)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction. | |
| Type of Statistical Test | Superiority | |
| Comments | If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05. | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 3.3 | |
| Confidence Interval |
(2-Sided) 95% 3.03 to 3.60 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.1 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Bone Mineral Density at the Femoral Neck at Month 12 |
|---|---|
| Description | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Time Frame | Baseline and month 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants with a baseline and ≥ 1 post-baseline evaluation at or before month 12; Last observation carried forward imputation was used. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1781 | 1781 |
| Least Squares Mean (Standard Error) [percent change] |
1.7
(0.1)
|
4.9
(0.1)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction. | |
| Type of Statistical Test | Superiority | |
| Comments | If the differences in both primary end points were significant with the use of the Hochberg procedure, a fixed-sequence testing procedure was used for bone mineral density and the key secondary end point of nonvertebral fracture to adjust for multiple comparisons and to maintain an overall significance level of 0.05. | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 3.2 | |
| Confidence Interval |
(2-Sided) 95% 2.90 to 3.54 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.2 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Bone Mineral Density of the Lumbar Spine at Month 36 |
|---|---|
| Description | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Time Frame | Baseline and month 36 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 36; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1597 | 1593 |
| Least Squares Mean (Standard Error) [percent change] |
7.8
(0.2)
|
15.2
(0.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction. | |
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 7.4 | |
| Confidence Interval |
(2-Sided) 95% 6.84 to 7.89 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.3 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 36 |
|---|---|
| Description | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Time Frame | Baseline and month 36 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 36; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1653 | 1653 |
| Least Squares Mean (Standard Error) [percent change] |
3.5
(0.1)
|
7.2
(0.1)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction. | |
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 3.7 | |
| Confidence Interval |
(2-Sided) 95% 3.29 to 4.02 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.2 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 36 |
|---|---|
| Description | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. |
| Time Frame | Baseline and month 36 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants with a baseline and ≥ 1 post-baseline evaluation during the open-label period at or before month 36; Missing values were imputed by carrying forward the last non-missing post-baseline value in the open-label treatment period prior to the missing value. |
| Arm/Group Title | Alendronate/Alendronate | Romosozumab/Alendronate |
|---|---|---|
| Arm/Group Description | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. |
| Measure Participants | 1653 | 1653 |
| Least Squares Mean (Standard Error) [percent change] |
2.4
(0.2)
|
6.0
(0.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Alendronate/Alendronate, Romosozumab/Alendronate |
|---|---|---|
| Comments | Between-group comparisons of the percent change from baseline in bone mineral density were analyzed using an ANCOVA model adjusted for treatment, age strata, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction. | |
| Type of Statistical Test | Superiority | |
| Comments | This endpoint was not included in the sequential testing procedure and was analyzed without multiplicity adjustment at a significance level of 0.05 (two-sided). | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 3.6 | |
| Confidence Interval |
(2-Sided) 95% 3.18 to 3.97 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.2 |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | Double-blind treatment phase: 12 months. Overall study period: From first dose of study drug up to the end of study for participants who received at any open-label dose and up to the end of the double-blind period for participants who did not. The median duration of follow-up time was 36 months. | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | The safety analysis set included all randomized subjects who received ≥ 1 active dose of investigational product in the 12-month double-blind alendronate-controlled study period. Two participants randomized to alendronate received romosozumab in error and are counted in the romosozumab group for safety. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. | |||||||
| Arm/Group Title | Double-blind Period: Alendronate 70 mg QW | Double-blind Period: Romosozumab 210 mg QM | Overall Study: Alendronate / Alendronate | Overall Study: Romosozumab / Alendronate | ||||
| Arm/Group Description | Participants received 70 mg alendronate once a week (QW) and placebo to romosozumab subcutaneously once a month for 12 months during the double-blind treatment period. | Participants received 210 mg romosozumab subcutaneously once a month (QM) and placebo to alendronate orally once a week for the first 12 months during the double-blind treatment period. | Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Participants received 210 romosozumab mg subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. | ||||
All Cause Mortality |
||||||||
| Double-blind Period: Alendronate 70 mg QW | Double-blind Period: Romosozumab 210 mg QM | Overall Study: Alendronate / Alendronate | Overall Study: Romosozumab / Alendronate | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 22/2014 (1.1%) | 30/2040 (1.5%) | 103/2014 (5.1%) | 101/2040 (5%) | ||||
Serious Adverse Events |
||||||||
| Double-blind Period: Alendronate 70 mg QW | Double-blind Period: Romosozumab 210 mg QM | Overall Study: Alendronate / Alendronate | Overall Study: Romosozumab / Alendronate | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 278/2014 (13.8%) | 262/2040 (12.8%) | 638/2014 (31.7%) | 611/2040 (30%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 3/2014 (0.1%) | 1/2040 (0%) | 9/2014 (0.4%) | 7/2040 (0.3%) | ||||
| Anaemia of chronic disease | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Anaemia vitamin B12 deficiency | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Haemorrhagic anaemia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Hypochromic anaemia | 1/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 0/2040 (0%) | ||||
| Iron deficiency anaemia | 2/2014 (0.1%) | 1/2040 (0%) | 4/2014 (0.2%) | 2/2040 (0.1%) | ||||
| Leukopenia | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Microcytic anaemia | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Neutropenia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Normochromic normocytic anaemia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Splenomegaly | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Thrombocytopenia | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Cardiac disorders | ||||||||
| Acute coronary syndrome | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Acute left ventricular failure | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Acute myocardial infarction | 2/2014 (0.1%) | 8/2040 (0.4%) | 15/2014 (0.7%) | 16/2040 (0.8%) | ||||
| Angina pectoris | 3/2014 (0.1%) | 2/2040 (0.1%) | 6/2014 (0.3%) | 7/2040 (0.3%) | ||||
| Angina unstable | 2/2014 (0.1%) | 2/2040 (0.1%) | 7/2014 (0.3%) | 5/2040 (0.2%) | ||||
| Aortic valve stenosis | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Arrhythmia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Arrhythmia supraventricular | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Arteriospasm coronary | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Atrial fibrillation | 4/2014 (0.2%) | 3/2040 (0.1%) | 17/2014 (0.8%) | 12/2040 (0.6%) | ||||
| Atrial flutter | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Atrioventricular block complete | 3/2014 (0.1%) | 0/2040 (0%) | 4/2014 (0.2%) | 1/2040 (0%) | ||||
| Bradyarrhythmia | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Bradycardia | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Cardiac arrest | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Cardiac disorder | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Cardiac failure | 5/2014 (0.2%) | 5/2040 (0.2%) | 25/2014 (1.2%) | 18/2040 (0.9%) | ||||
| Cardiac failure acute | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Cardiac failure chronic | 1/2014 (0%) | 0/2040 (0%) | 5/2014 (0.2%) | 1/2040 (0%) | ||||
| Cardiac failure congestive | 5/2014 (0.2%) | 2/2040 (0.1%) | 12/2014 (0.6%) | 9/2040 (0.4%) | ||||
| Cardiac tamponade | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Cardiac valve disease | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Cardio-respiratory arrest | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Cardiogenic shock | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 3/2040 (0.1%) | ||||
| Cardiomyopathy | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Cardiopulmonary failure | 1/2014 (0%) | 1/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Coronary artery disease | 0/2014 (0%) | 1/2040 (0%) | 5/2014 (0.2%) | 3/2040 (0.1%) | ||||
| Coronary artery occlusion | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Ischaemic cardiomyopathy | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Left ventricular failure | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Mitral valve incompetence | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Myocardial fibrosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Myocardial infarction | 3/2014 (0.1%) | 5/2040 (0.2%) | 8/2014 (0.4%) | 8/2040 (0.4%) | ||||
| Myocardial ischaemia | 1/2014 (0%) | 3/2040 (0.1%) | 4/2014 (0.2%) | 6/2040 (0.3%) | ||||
| Palpitations | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Pericardial effusion | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Sinus bradycardia | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Sinus node dysfunction | 1/2014 (0%) | 0/2040 (0%) | 5/2014 (0.2%) | 1/2040 (0%) | ||||
| Stress cardiomyopathy | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Supraventricular extrasystoles | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Supraventricular tachycardia | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Tachycardia | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Tricuspid valve incompetence | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Ventricular extrasystoles | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Ventricular tachycardia | 0/2014 (0%) | 2/2040 (0.1%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Ear and labyrinth disorders | ||||||||
| Vertigo | 1/2014 (0%) | 2/2040 (0.1%) | 2/2014 (0.1%) | 5/2040 (0.2%) | ||||
| Vertigo positional | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Vestibular ataxia | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Endocrine disorders | ||||||||
| Basedow's disease | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Goitre | 2/2014 (0.1%) | 0/2040 (0%) | 4/2014 (0.2%) | 1/2040 (0%) | ||||
| Hypercorticoidism | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Hyperparathyroidism | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Hyperthyroidism | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Toxic goitre | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Eye disorders | ||||||||
| Amaurosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Cataract | 4/2014 (0.2%) | 3/2040 (0.1%) | 9/2014 (0.4%) | 11/2040 (0.5%) | ||||
| Diplopia | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Endocrine ophthalmopathy | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Entropion | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Glaucoma | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Macular fibrosis | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Neovascular age-related macular degeneration | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Retinal artery thrombosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Retinal detachment | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Retinal haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Strabismus | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Visual impairment | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Vitreous prolapse | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Abdominal adhesions | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Abdominal hernia | 2/2014 (0.1%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Abdominal pain | 1/2014 (0%) | 1/2040 (0%) | 3/2014 (0.1%) | 5/2040 (0.2%) | ||||
| Abdominal pain upper | 1/2014 (0%) | 2/2040 (0.1%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Anal incontinence | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Chronic gastritis | 1/2014 (0%) | 2/2040 (0.1%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Colitis ulcerative | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Constipation | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 3/2040 (0.1%) | ||||
| Crohn's disease | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Diarrhoea | 0/2014 (0%) | 4/2040 (0.2%) | 3/2014 (0.1%) | 6/2040 (0.3%) | ||||
| Diverticulum | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Diverticulum intestinal | 2/2014 (0.1%) | 1/2040 (0%) | 3/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Diverticulum intestinal haemorrhagic | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Duodenal polyp | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Duodenal ulcer | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Duodenal ulcer perforation | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Dyspepsia | 0/2014 (0%) | 2/2040 (0.1%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Dysphagia | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Enteritis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Enterocolitis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Erosive oesophagitis | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Femoral hernia | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Femoral hernia incarcerated | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Food poisoning | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Gastric ulcer | 1/2014 (0%) | 1/2040 (0%) | 3/2014 (0.1%) | 4/2040 (0.2%) | ||||
| Gastric ulcer haemorrhage | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Gastritis | 1/2014 (0%) | 1/2040 (0%) | 6/2014 (0.3%) | 4/2040 (0.2%) | ||||
| Gastrointestinal haemorrhage | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 6/2040 (0.3%) | ||||
| Gastrointestinal inflammation | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Gastrooesophageal reflux disease | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 4/2040 (0.2%) | ||||
| Haemorrhoidal haemorrhage | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Hiatus hernia | 0/2014 (0%) | 2/2040 (0.1%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Ileus | 1/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 0/2040 (0%) | ||||
| Inguinal hernia | 1/2014 (0%) | 1/2040 (0%) | 4/2014 (0.2%) | 2/2040 (0.1%) | ||||
| Inguinal hernia strangulated | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Intestinal haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Intestinal obstruction | 0/2014 (0%) | 2/2040 (0.1%) | 2/2014 (0.1%) | 4/2040 (0.2%) | ||||
| Intestinal ulcer | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Intra-abdominal haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Intussusception | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Irritable bowel syndrome | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Large intestinal stenosis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Large intestinal ulcer | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Large intestine polyp | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Lower gastrointestinal haemorrhage | 0/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Mechanical ileus | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Melaena | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Mesenteric arterial occlusion | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Nausea | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Obstruction gastric | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Oesophageal ulcer | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Pancreatitis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Pancreatitis acute | 1/2014 (0%) | 2/2040 (0.1%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Peptic ulcer | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Peptic ulcer perforation | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Peritoneal adhesions | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Peritoneal haemorrhage | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Rectal haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Rectal prolapse | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Salivary gland calculus | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Upper gastrointestinal haemorrhage | 0/2014 (0%) | 3/2040 (0.1%) | 0/2014 (0%) | 5/2040 (0.2%) | ||||
| Volvulus | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Vomiting | 1/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 3/2040 (0.1%) | ||||
| General disorders | ||||||||
| Adverse event | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Asthenia | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 3/2040 (0.1%) | ||||
| Chest pain | 0/2014 (0%) | 2/2040 (0.1%) | 2/2014 (0.1%) | 3/2040 (0.1%) | ||||
| Death | 2/2014 (0.1%) | 1/2040 (0%) | 21/2014 (1%) | 14/2040 (0.7%) | ||||
| Feeling abnormal | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| General physical health deterioration | 0/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Hypothermia | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Impaired healing | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Malaise | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Multiple organ dysfunction syndrome | 0/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 3/2040 (0.1%) | ||||
| Non-cardiac chest pain | 2/2014 (0.1%) | 1/2040 (0%) | 4/2014 (0.2%) | 1/2040 (0%) | ||||
| Oedema peripheral | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Pain | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Peripheral swelling | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Pyrexia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Strangulated hernia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Sudden death | 2/2014 (0.1%) | 1/2040 (0%) | 4/2014 (0.2%) | 6/2040 (0.3%) | ||||
| Ulcer haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Vessel puncture site haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Hepatobiliary disorders | ||||||||
| Ampulla of Vater stenosis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Bile duct stenosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Bile duct stone | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Biliary cirrhosis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Biliary colic | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Biliary fibrosis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Cholangitis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Cholangitis acute | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Cholecystitis | 1/2014 (0%) | 1/2040 (0%) | 3/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Cholecystitis acute | 1/2014 (0%) | 1/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Cholecystitis chronic | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Cholelithiasis | 6/2014 (0.3%) | 5/2040 (0.2%) | 9/2014 (0.4%) | 7/2040 (0.3%) | ||||
| Hepatic cirrhosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Hyperbilirubinaemia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Jaundice cholestatic | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Liver injury | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Immune system disorders | ||||||||
| Amyloidosis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Drug hypersensitivity | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Hypersensitivity | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Infections and infestations | ||||||||
| Abdominal abscess | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Abdominal sepsis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Abdominal wall abscess | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Appendicitis | 0/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 0/2040 (0%) | ||||
| Appendicitis perforated | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Bronchitis | 3/2014 (0.1%) | 1/2040 (0%) | 8/2014 (0.4%) | 11/2040 (0.5%) | ||||
| Bronchitis bacterial | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Campylobacter gastroenteritis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Cellulitis | 3/2014 (0.1%) | 1/2040 (0%) | 6/2014 (0.3%) | 5/2040 (0.2%) | ||||
| Cholecystitis infective | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Clostridium difficile infection | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Cystitis | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Dermatitis infected | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Device related infection | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Diverticulitis | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 6/2040 (0.3%) | ||||
| Empyema | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Endocarditis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Enterocolitis bacterial | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Erysipelas | 0/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Escherichia sepsis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Gangrene | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Gastritis viral | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Gastroenteritis | 2/2014 (0.1%) | 2/2040 (0.1%) | 6/2014 (0.3%) | 5/2040 (0.2%) | ||||
| Gastroenteritis viral | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Gastrointestinal infection | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Haematoma infection | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Hepatitis C | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Herpes zoster | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Infected bite | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Infected fistula | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Infected skin ulcer | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Infection | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Infective exacerbation of chronic obstructive airways disease | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Influenza | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 3/2040 (0.1%) | ||||
| Kidney infection | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Localised infection | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Lower respiratory tract infection | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Lung infection | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Nosocomial infection | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Oesophageal candidiasis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Osteomyelitis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Otitis media chronic | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Pancreas infection | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Peritonitis | 0/2014 (0%) | 3/2040 (0.1%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Pharyngeal abscess | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Pneumonia | 17/2014 (0.8%) | 16/2040 (0.8%) | 46/2014 (2.3%) | 54/2040 (2.6%) | ||||
| Pneumonia bacterial | 3/2014 (0.1%) | 1/2040 (0%) | 6/2014 (0.3%) | 4/2040 (0.2%) | ||||
| Post procedural infection | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Post procedural sepsis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Postoperative abscess | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Postoperative wound infection | 2/2014 (0.1%) | 1/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Pseudomembranous colitis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Pseudomonal sepsis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Pulmonary sepsis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Pyelonephritis | 1/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Pyelonephritis acute | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Pyoderma | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Respiratory tract infection | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Rhinitis | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Sepsis | 0/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 3/2040 (0.1%) | ||||
| Septic shock | 0/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Sialoadenitis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Sinusitis | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Staphylococcal sepsis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Subcutaneous abscess | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Tracheobronchitis | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Upper respiratory tract infection | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 4/2040 (0.2%) | ||||
| Urinary tract infection | 8/2014 (0.4%) | 8/2040 (0.4%) | 21/2014 (1%) | 21/2040 (1%) | ||||
| Urinary tract infection bacterial | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Urosepsis | 0/2014 (0%) | 2/2040 (0.1%) | 3/2014 (0.1%) | 4/2040 (0.2%) | ||||
| Viral diarrhoea | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Viral infection | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Wound infection | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Burns third degree | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Carbon monoxide poisoning | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Clavicle fracture | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Concussion | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Contusion | 1/2014 (0%) | 1/2040 (0%) | 7/2014 (0.3%) | 2/2040 (0.1%) | ||||
| Craniocerebral injury | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Extradural haematoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Facial bones fracture | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 3/2040 (0.1%) | ||||
| Fall | 4/2014 (0.2%) | 2/2040 (0.1%) | 11/2014 (0.5%) | 13/2040 (0.6%) | ||||
| Femoral neck fracture | 12/2014 (0.6%) | 5/2040 (0.2%) | 31/2014 (1.5%) | 15/2040 (0.7%) | ||||
| Femur fracture | 12/2014 (0.6%) | 11/2040 (0.5%) | 51/2014 (2.5%) | 42/2040 (2.1%) | ||||
| Fibula fracture | 4/2014 (0.2%) | 3/2040 (0.1%) | 9/2014 (0.4%) | 5/2040 (0.2%) | ||||
| Foot fracture | 3/2014 (0.1%) | 0/2040 (0%) | 5/2014 (0.2%) | 0/2040 (0%) | ||||
| Foreign body | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Fracture | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Fractured ischium | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Fractured sacrum | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Gastrointestinal anastomotic leak | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Graft complication | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Hand fracture | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Head injury | 1/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Hip fracture | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Humerus fracture | 7/2014 (0.3%) | 3/2040 (0.1%) | 16/2014 (0.8%) | 6/2040 (0.3%) | ||||
| Ilium fracture | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Incisional hernia | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Joint injury | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Laceration | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Ligament sprain | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Limb injury | 2/2014 (0.1%) | 1/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Lip injury | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Lumbar vertebral fracture | 1/2014 (0%) | 0/2040 (0%) | 8/2014 (0.4%) | 0/2040 (0%) | ||||
| Meniscus injury | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Muscle rupture | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Overdose | 1/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Patella fracture | 0/2014 (0%) | 2/2040 (0.1%) | 5/2014 (0.2%) | 6/2040 (0.3%) | ||||
| Post laminectomy syndrome | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Post procedural bile leak | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Post procedural haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Pubis fracture | 4/2014 (0.2%) | 0/2040 (0%) | 7/2014 (0.3%) | 3/2040 (0.1%) | ||||
| Radius fracture | 12/2014 (0.6%) | 8/2040 (0.4%) | 20/2014 (1%) | 14/2040 (0.7%) | ||||
| Rib fracture | 1/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 0/2040 (0%) | ||||
| Road traffic accident | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Scapula fracture | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Skull fracture | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Soft tissue injury | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Spinal compression fracture | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Spinal fracture | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Stoma site haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Subarachnoid haematoma | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Subarachnoid haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Subdural haematoma | 0/2014 (0%) | 2/2040 (0.1%) | 0/2014 (0%) | 4/2040 (0.2%) | ||||
| Subdural haemorrhage | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Thoracic vertebral fracture | 0/2014 (0%) | 1/2040 (0%) | 5/2014 (0.2%) | 2/2040 (0.1%) | ||||
| Tibia fracture | 5/2014 (0.2%) | 3/2040 (0.1%) | 8/2014 (0.4%) | 6/2040 (0.3%) | ||||
| Toxicity to various agents | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Ulna fracture | 6/2014 (0.3%) | 3/2040 (0.1%) | 11/2014 (0.5%) | 5/2040 (0.2%) | ||||
| Wound dehiscence | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Wound evisceration | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Wrist fracture | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Investigations | ||||||||
| Alanine aminotransferase increased | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Aspartate aminotransferase increased | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Carcinoembryonic antigen increased | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Coagulation time prolonged | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Creatinine renal clearance decreased | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Heart rate decreased | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Liver function test abnormal | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Medical observation normal | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Weight decreased | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Dehydration | 1/2014 (0%) | 1/2040 (0%) | 4/2014 (0.2%) | 4/2040 (0.2%) | ||||
| Diabetes mellitus | 2/2014 (0.1%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Diabetes mellitus inadequate control | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Diabetic ketoacidosis | 2/2014 (0.1%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Diabetic metabolic decompensation | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Electrolyte imbalance | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Failure to thrive | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Fluid overload | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Hypercalcaemia | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Hyperkalaemia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Hypoglycaemia | 2/2014 (0.1%) | 0/2040 (0%) | 5/2014 (0.2%) | 2/2040 (0.1%) | ||||
| Hypokalaemia | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 4/2040 (0.2%) | ||||
| Hyponatraemia | 2/2014 (0.1%) | 3/2040 (0.1%) | 7/2014 (0.3%) | 7/2040 (0.3%) | ||||
| Hypovolaemia | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Iron deficiency | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Metabolic disorder | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Type 1 diabetes mellitus | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 1/2014 (0%) | 1/2040 (0%) | 4/2014 (0.2%) | 2/2040 (0.1%) | ||||
| Arthritis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 4/2040 (0.2%) | ||||
| Arthropathy | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Back pain | 9/2014 (0.4%) | 2/2040 (0.1%) | 17/2014 (0.8%) | 11/2040 (0.5%) | ||||
| Cervical spinal stenosis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Extraskeletal ossification | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Foot deformity | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Fracture pain | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Groin pain | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Intervertebral disc disorder | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Intervertebral disc displacement | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Intervertebral disc protrusion | 2/2014 (0.1%) | 1/2040 (0%) | 5/2014 (0.2%) | 3/2040 (0.1%) | ||||
| Lumbar spinal stenosis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Mobility decreased | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Muscular weakness | 1/2014 (0%) | 2/2040 (0.1%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Musculoskeletal pain | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Neck pain | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Osteoarthritis | 5/2014 (0.2%) | 6/2040 (0.3%) | 11/2014 (0.5%) | 19/2040 (0.9%) | ||||
| Osteochondrosis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Osteonecrosis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Osteonecrosis of jaw | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Pain in extremity | 2/2014 (0.1%) | 0/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Pain in jaw | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Rheumatoid arthritis | 2/2014 (0.1%) | 1/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Rotator cuff syndrome | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Spinal column stenosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Spinal osteoarthritis | 0/2014 (0%) | 2/2040 (0.1%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Spinal pain | 3/2014 (0.1%) | 3/2040 (0.1%) | 4/2014 (0.2%) | 3/2040 (0.1%) | ||||
| Spondylolisthesis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Tendonitis | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Acute myeloid leukaemia | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Adenocarcinoma gastric | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Adenocarcinoma of colon | 0/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Adenocarcinoma pancreas | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Anal cancer | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| B-cell lymphoma | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Basal cell carcinoma | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Benign breast neoplasm | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Benign lung neoplasm | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Benign renal neoplasm | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Bladder cancer | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Bladder squamous cell carcinoma stage unspecified | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Brain neoplasm | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Breast cancer | 0/2014 (0%) | 2/2040 (0.1%) | 4/2014 (0.2%) | 5/2040 (0.2%) | ||||
| Breast cancer female | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Breast cancer metastatic | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Bronchial carcinoma | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Central nervous system neoplasm | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Cervix carcinoma | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Cervix carcinoma stage IV | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Cholangiocarcinoma | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Choroid melanoma | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Chronic lymphocytic leukaemia | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Colon adenoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Colon cancer | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 3/2040 (0.1%) | ||||
| Colorectal adenocarcinoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Colorectal carcinoma stage 0 | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Diffuse large B-cell lymphoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Endometrial adenocarcinoma | 0/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Endometrial cancer | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Epithelioid mesothelioma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Follicular thyroid cancer | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Gastrointestinal carcinoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Gastrointestinal stromal tumour | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Gastrointestinal tract adenoma | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Hepatic cancer | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Hepatobiliary cancer | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Hodgkin's disease | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Hypopharyngeal cancer | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Intestinal adenocarcinoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Intra-abdominal haemangioma | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Intraductal papillary mucinous neoplasm | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Intraductal proliferative breast lesion | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Intraocular melanoma | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Invasive breast carcinoma | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Invasive ductal breast carcinoma | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Lipoma | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Lung adenocarcinoma | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Lung adenocarcinoma stage 0 | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Lung neoplasm | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Lung neoplasm malignant | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 3/2040 (0.1%) | ||||
| Lymphoma | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Malignant melanoma | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Malignant melanoma in situ | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Malignant neoplasm of renal pelvis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Mediastinum neoplasm | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Meningioma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Meningioma benign | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Metastases to adrenals | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Metastases to bone | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Metastases to liver | 0/2014 (0%) | 2/2040 (0.1%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Metastases to lung | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Metastases to pancreas | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Metastases to peritoneum | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Metastatic bronchial carcinoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Metastatic neoplasm | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Myelodysplastic syndrome | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Myeloproliferative neoplasm | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Neoplasm malignant | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Neuroendocrine tumour | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Non-Hodgkin's lymphoma | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Non-Hodgkin's lymphoma unspecified histology indolent stage I | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Oesophageal adenocarcinoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Ovarian adenoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Ovarian cancer metastatic | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Pancreatic carcinoma | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Pancreatic neoplasm | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Papillary cystadenoma lymphomatosum | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 3/2040 (0.1%) | ||||
| Parathyroid tumour benign | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Plasma cell myeloma | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Rectal adenocarcinoma | 0/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Rectal cancer | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Renal cancer | 1/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Renal neoplasm | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Retroperitoneal neoplasm | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Seborrhoeic keratosis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Skin cancer | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Small cell lung cancer | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Small intestine carcinoma | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Squamous cell carcinoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Squamous cell carcinoma of lung | 0/2014 (0%) | 2/2040 (0.1%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Squamous cell carcinoma of pharynx | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Squamous cell carcinoma of skin | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Squamous cell carcinoma of the cervix | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Squamous cell carcinoma of the oral cavity | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Squamous cell carcinoma of the vulva | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Ureteric cancer | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Uterine cancer | 1/2014 (0%) | 2/2040 (0.1%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Uterine leiomyoma | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Nervous system disorders | ||||||||
| Altered state of consciousness | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Amnesia | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Amyotrophic lateral sclerosis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Aphasia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Carotid aneurysm rupture | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Carotid arteriosclerosis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Carotid artery stenosis | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 4/2040 (0.2%) | ||||
| Carpal tunnel syndrome | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Cerebral arteriosclerosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Cerebral haematoma | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Cerebral haemorrhage | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Cerebral infarction | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 3/2040 (0.1%) | ||||
| Cerebral ischaemia | 1/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Cerebrovascular accident | 7/2014 (0.3%) | 6/2040 (0.3%) | 15/2014 (0.7%) | 19/2040 (0.9%) | ||||
| Cerebrovascular disorder | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Dementia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Dementia Alzheimer's type | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Dizziness | 3/2014 (0.1%) | 1/2040 (0%) | 7/2014 (0.3%) | 9/2040 (0.4%) | ||||
| Embolic stroke | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Encephalopathy | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Epilepsy | 0/2014 (0%) | 3/2040 (0.1%) | 2/2014 (0.1%) | 5/2040 (0.2%) | ||||
| Essential tremor | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Extrapyramidal disorder | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Facial paralysis | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Generalised tonic-clonic seizure | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Haemorrhage intracranial | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Haemorrhagic stroke | 0/2014 (0%) | 2/2040 (0.1%) | 0/2014 (0%) | 4/2040 (0.2%) | ||||
| Hemiparesis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Hydrocephalus | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Hypokinesia | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Hypotonia | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Intracranial aneurysm | 2/2014 (0.1%) | 0/2040 (0%) | 3/2014 (0.1%) | 0/2040 (0%) | ||||
| Ischaemic cerebral infarction | 0/2014 (0%) | 2/2040 (0.1%) | 1/2014 (0%) | 3/2040 (0.1%) | ||||
| Ischaemic neuropathy | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Ischaemic stroke | 3/2014 (0.1%) | 2/2040 (0.1%) | 10/2014 (0.5%) | 10/2040 (0.5%) | ||||
| Loss of consciousness | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Lumbar radiculopathy | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Lumbosacral radiculopathy | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Memory impairment | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Mixed dementia | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Monoparesis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Multiple sclerosis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Multiple sclerosis relapse | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Nerve root compression | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Nervous system disorder | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Neuralgia | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Optic neuritis | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Paraesthesia | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Paraparesis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Paresis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Parkinson's disease | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Post-traumatic epilepsy | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Presyncope | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Sciatica | 2/2014 (0.1%) | 0/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Seizure | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Somnolence | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Speech disorder | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Stroke in evolution | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Syncope | 4/2014 (0.2%) | 2/2040 (0.1%) | 10/2014 (0.5%) | 5/2040 (0.2%) | ||||
| Toxic encephalopathy | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Transient ischaemic attack | 2/2014 (0.1%) | 6/2040 (0.3%) | 5/2014 (0.2%) | 11/2040 (0.5%) | ||||
| Vascular encephalopathy | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Vertebrobasilar insufficiency | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Product Issues | ||||||||
| Device breakage | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Device dislocation | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Device failure | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Device malfunction | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Psychiatric disorders | ||||||||
| Adjustment disorder | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Alcohol withdrawal syndrome | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Anxiety | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Bipolar disorder | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Completed suicide | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Confusional state | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Delirium | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Depression | 1/2014 (0%) | 1/2040 (0%) | 5/2014 (0.2%) | 1/2040 (0%) | ||||
| Disorientation | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Hypomania | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Mental disorder | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Mental status changes | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Psychotic disorder | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Schizophrenia | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Renal and urinary disorders | ||||||||
| Acute kidney injury | 0/2014 (0%) | 5/2040 (0.2%) | 2/2014 (0.1%) | 9/2040 (0.4%) | ||||
| Bladder prolapse | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Calculus bladder | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Chronic kidney disease | 3/2014 (0.1%) | 0/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Haematuria | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Nephritis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Nephrolithiasis | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Renal colic | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Renal failure | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Stress urinary incontinence | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Urethral polyp | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Urinary bladder haemorrhage | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Urinary incontinence | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Urinary retention | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Reproductive system and breast disorders | ||||||||
| Breast pain | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Colpocele | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Cystocele | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Dysfunctional uterine bleeding | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Ovarian cyst | 0/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Pelvic haematoma | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Pelvic prolapse | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Postmenopausal haemorrhage | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Uterine polyp | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Uterine prolapse | 0/2014 (0%) | 2/2040 (0.1%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Uterovaginal prolapse | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Vaginal prolapse | 0/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Acute pulmonary oedema | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Acute respiratory failure | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 5/2040 (0.2%) | ||||
| Asthma | 2/2014 (0.1%) | 2/2040 (0.1%) | 6/2014 (0.3%) | 5/2040 (0.2%) | ||||
| Asthmatic crisis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Bronchitis chronic | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Chronic obstructive pulmonary disease | 10/2014 (0.5%) | 5/2040 (0.2%) | 29/2014 (1.4%) | 24/2040 (1.2%) | ||||
| Chronic respiratory failure | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Dyspnoea | 0/2014 (0%) | 0/2040 (0%) | 4/2014 (0.2%) | 1/2040 (0%) | ||||
| Emphysema | 2/2014 (0.1%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Epistaxis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Haemoptysis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Idiopathic pulmonary fibrosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Interstitial lung disease | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Lung disorder | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Obstructive airways disorder | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Paranasal cyst | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Pleural effusion | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 3/2040 (0.1%) | ||||
| Pleurisy | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Pneumonia aspiration | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Pneumothorax | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Pulmonary congestion | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Pulmonary embolism | 2/2014 (0.1%) | 0/2040 (0%) | 5/2014 (0.2%) | 1/2040 (0%) | ||||
| Pulmonary fibrosis | 2/2014 (0.1%) | 0/2040 (0%) | 3/2014 (0.1%) | 0/2040 (0%) | ||||
| Pulmonary mass | 0/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 0/2040 (0%) | ||||
| Pulmonary oedema | 2/2014 (0.1%) | 2/2040 (0.1%) | 4/2014 (0.2%) | 2/2040 (0.1%) | ||||
| Pulmonary sarcoidosis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Respiratory acidosis | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Respiratory arrest | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Respiratory distress | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Respiratory failure | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Sleep apnoea syndrome | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Vocal cord cyst | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Angioedema | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Decubitus ulcer | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 1/2040 (0%) | ||||
| Dermatitis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Dermatitis contact | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Eczema | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Skin ulcer | 1/2014 (0%) | 0/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Social circumstances | ||||||||
| Limb prosthesis user | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Loss of personal independence in daily activities | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Surgical and medical procedures | ||||||||
| Hip arthroplasty | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Hospitalisation | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Surgery | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Umbilical hernia repair | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Vascular disorders | ||||||||
| Aortic aneurysm | 1/2014 (0%) | 1/2040 (0%) | 4/2014 (0.2%) | 1/2040 (0%) | ||||
| Aortic aneurysm rupture | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Aortic arteriosclerosis | 0/2014 (0%) | 1/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Aortic dissection | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 2/2040 (0.1%) | ||||
| Aortic stenosis | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Arteriosclerosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Blood pressure inadequately controlled | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Circulatory collapse | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 3/2040 (0.1%) | ||||
| Deep vein thrombosis | 5/2014 (0.2%) | 2/2040 (0.1%) | 9/2014 (0.4%) | 4/2040 (0.2%) | ||||
| Embolism arterial | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Extremity necrosis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Hypertension | 4/2014 (0.2%) | 1/2040 (0%) | 8/2014 (0.4%) | 8/2040 (0.4%) | ||||
| Hypertensive crisis | 2/2014 (0.1%) | 0/2040 (0%) | 5/2014 (0.2%) | 1/2040 (0%) | ||||
| Hypertensive emergency | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Hypotension | 1/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 4/2040 (0.2%) | ||||
| Hypovolaemic shock | 0/2014 (0%) | 1/2040 (0%) | 1/2014 (0%) | 2/2040 (0.1%) | ||||
| Intermittent claudication | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Labile hypertension | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Orthostatic hypotension | 1/2014 (0%) | 1/2040 (0%) | 2/2014 (0.1%) | 1/2040 (0%) | ||||
| Peripheral arterial occlusive disease | 1/2014 (0%) | 2/2040 (0.1%) | 5/2014 (0.2%) | 3/2040 (0.1%) | ||||
| Peripheral artery aneurysm | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Peripheral artery occlusion | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Peripheral artery thrombosis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Peripheral embolism | 1/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Peripheral ischaemia | 1/2014 (0%) | 1/2040 (0%) | 3/2014 (0.1%) | 1/2040 (0%) | ||||
| Phlebitis | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Shock haemorrhagic | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Subclavian artery occlusion | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
| Thrombophlebitis | 1/2014 (0%) | 0/2040 (0%) | 2/2014 (0.1%) | 2/2040 (0.1%) | ||||
| Thrombosis | 0/2014 (0%) | 0/2040 (0%) | 1/2014 (0%) | 0/2040 (0%) | ||||
| Varicose vein | 0/2014 (0%) | 0/2040 (0%) | 0/2014 (0%) | 1/2040 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| Double-blind Period: Alendronate 70 mg QW | Double-blind Period: Romosozumab 210 mg QM | Overall Study: Alendronate / Alendronate | Overall Study: Romosozumab / Alendronate | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1190/2014 (59.1%) | 1112/2040 (54.5%) | 1498/2014 (74.4%) | 1424/2040 (69.8%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 49/2014 (2.4%) | 41/2040 (2%) | 113/2014 (5.6%) | 84/2040 (4.1%) | ||||
| Eye disorders | ||||||||
| Cataract | 32/2014 (1.6%) | 46/2040 (2.3%) | 97/2014 (4.8%) | 105/2040 (5.1%) | ||||
| Gastrointestinal disorders | ||||||||
| Abdominal pain upper | 63/2014 (3.1%) | 62/2040 (3%) | 109/2014 (5.4%) | 101/2040 (5%) | ||||
| Constipation | 92/2014 (4.6%) | 75/2040 (3.7%) | 133/2014 (6.6%) | 120/2040 (5.9%) | ||||
| Diarrhoea | 93/2014 (4.6%) | 99/2040 (4.9%) | 168/2014 (8.3%) | 165/2040 (8.1%) | ||||
| Gastritis | 59/2014 (2.9%) | 53/2040 (2.6%) | 101/2014 (5%) | 92/2040 (4.5%) | ||||
| Infections and infestations | ||||||||
| Bronchitis | 100/2014 (5%) | 88/2040 (4.3%) | 187/2014 (9.3%) | 176/2040 (8.6%) | ||||
| Influenza | 57/2014 (2.8%) | 49/2040 (2.4%) | 119/2014 (5.9%) | 105/2040 (5.1%) | ||||
| Upper respiratory tract infection | 132/2014 (6.6%) | 130/2040 (6.4%) | 226/2014 (11.2%) | 205/2040 (10%) | ||||
| Urinary tract infection | 128/2014 (6.4%) | 97/2040 (4.8%) | 244/2014 (12.1%) | 180/2040 (8.8%) | ||||
| Viral upper respiratory tract infection | 233/2014 (11.6%) | 217/2040 (10.6%) | 406/2014 (20.2%) | 388/2040 (19%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Contusion | 71/2014 (3.5%) | 51/2040 (2.5%) | 161/2014 (8%) | 115/2040 (5.6%) | ||||
| Fall | 151/2014 (7.5%) | 127/2040 (6.2%) | 342/2014 (17%) | 287/2040 (14.1%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 193/2014 (9.6%) | 165/2040 (8.1%) | 380/2014 (18.9%) | 343/2040 (16.8%) | ||||
| Back pain | 221/2014 (11%) | 184/2040 (9%) | 395/2014 (19.6%) | 330/2040 (16.2%) | ||||
| Muscle spasms | 81/2014 (4%) | 70/2040 (3.4%) | 128/2014 (6.4%) | 121/2040 (5.9%) | ||||
| Musculoskeletal pain | 83/2014 (4.1%) | 70/2040 (3.4%) | 155/2014 (7.7%) | 145/2040 (7.1%) | ||||
| Osteoarthritis | 111/2014 (5.5%) | 113/2040 (5.5%) | 206/2014 (10.2%) | 189/2040 (9.3%) | ||||
| Pain in extremity | 129/2014 (6.4%) | 121/2040 (5.9%) | 253/2014 (12.6%) | 230/2040 (11.3%) | ||||
| Nervous system disorders | ||||||||
| Dizziness | 80/2014 (4%) | 85/2040 (4.2%) | 152/2014 (7.5%) | 149/2040 (7.3%) | ||||
| Headache | 110/2014 (5.5%) | 106/2040 (5.2%) | 190/2014 (9.4%) | 163/2040 (8%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Cough | 55/2014 (2.7%) | 74/2040 (3.6%) | 118/2014 (5.9%) | 147/2040 (7.2%) | ||||
| Vascular disorders | ||||||||
| Hypertension | 130/2014 (6.5%) | 113/2040 (5.5%) | 232/2014 (11.5%) | 233/2040 (11.4%) | ||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Amgen Inc. |
| Phone | 866-572-6436 |
| medinfo@amgen.com |
Responsible Party:
Amgen
ClinicalTrials.gov Identifier:
NCT01631214
Other Study ID Numbers:
- 20110142
- 2011-003142-41
First Posted:
Jun 29, 2012
Last Update Posted:
Dec 17, 2018
Last Verified:
Nov 1, 2018