Trial Outcomes & Findings for Denosumab Fracture Intervention Randomized Placebo Controlled Trial in Japanese Patients With Osteoporosis (NCT NCT00680953)

NCT ID: NCT00680953

Last Updated: 2015-03-12

Results Overview

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1262 participants
• Primary outcome timeframe: Baseline to 24 months
• Results posted on: 2015-03-12

Participant Flow

Participant milestones

Measure	Denosumab Denosumab (subcutaneously - every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Placebo Placebo (subcutaneously every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Alendronate Alendronate sodium hydrate oral tablets weekly + daily calcium and vitamin D supplements for 24 months (open label reference arm).
Overall Study STARTED	500	511	251
Overall Study COMPLETED	414	416	204
Overall Study NOT COMPLETED	86	95	47

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Denosumab Fracture Intervention Randomized Placebo Controlled Trial in Japanese Patients With Osteoporosis

Baseline characteristics by cohort

Measure	Denosumab n=472 Participants Denosumab (subcutaneously - every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Placebo n=480 Participants Placebo (subcutaneously every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Alendronate n=242 Participants Alendronate sodium hydrate oral tablets weekly + daily calcium and vitamin D supplements for 24 months (open label reference arm).	Total n=1194 Participants Total of all reporting groups
Age, Continuous	69.9 years STANDARD_DEVIATION 7.36 • n=5 Participants	69.0 years STANDARD_DEVIATION 7.67 • n=7 Participants	70.2 years STANDARD_DEVIATION 7.31 • n=5 Participants	69.6 years STANDARD_DEVIATION 7.49 • n=4 Participants
Sex: Female, Male Female	449 Participants n=5 Participants	456 Participants n=7 Participants	230 Participants n=5 Participants	1135 Participants n=4 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	24 Participants n=7 Participants	12 Participants n=5 Participants	59 Participants n=4 Participants
Region of Enrollment Japan	472 participants n=5 Participants	480 participants n=7 Participants	242 participants n=5 Participants	1194 participants n=4 Participants
the number of participants with vertebral fractures	466 Participants n=5 Participants	471 Participants n=7 Participants	237 Participants n=5 Participants	1174 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline to 24 months

Outcome measures

Measure	Denosumab n=472 Participants Denosumab (subcutaneously - every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Placebo n=480 Participants Placebo (subcutaneously every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Alendronate n=242 Participants Alendronate sodium hydrate oral tablets weekly + daily calcium and vitamin D supplements for 24 months (open label reference arm).
Incidence of New or Worsening Vertebral Fractures in Osteoporotic Subjects Treated With Denosumab Compared to Placebo	3.6 Vertebral fractures Interval 2.2 to 5.8	10.3 Vertebral fractures Interval 7.8 to 13.5	7.2 Vertebral fractures Interval 4.6 to 11.4

SECONDARY outcome

Timeframe: Baseline to 24 Months

The results are expressed as percentage by Kaplan-Meier estimate the percentage of participants with non-vertebral fractures

Outcome measures

Measure	Denosumab n=472 Participants Denosumab (subcutaneously - every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Placebo n=480 Participants Placebo (subcutaneously every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Alendronate n=242 Participants Alendronate sodium hydrate oral tablets weekly + daily calcium and vitamin D supplements for 24 months (open label reference arm).
The Percentage of Non-vertebral Fractures	4.1 percentage of participants Interval 2.6 to 6.6	4.1 percentage of participants Interval 2.6 to 6.5	2.7 percentage of participants Interval 1.2 to 5.9

SECONDARY outcome

Timeframe: Baseline to 24 Months

The results are expressed as a percentage by Kaplan-Meier estimate.

Outcome measures

Measure	Denosumab n=472 Participants Denosumab (subcutaneously - every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Placebo n=480 Participants Placebo (subcutaneously every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Alendronate n=242 Participants Alendronate sodium hydrate oral tablets weekly + daily calcium and vitamin D supplements for 24 months (open label reference arm).
Percentage of Participants With Hip Fractures in Osteoporotic Participants Treated With Denosumab Compared to Treatment With Placebo.	0.0 percentage of participants Interval 0.0 to 0.0	0.5 percentage of participants Interval 0.1 to 1.9	0.0 percentage of participants Interval 0.0 to 0.0

Adverse Events

Denosumab

Serious events: 65 serious events

Other events: 475 other events

Deaths: 0 deaths

Placebo

Serious events: 68 serious events

Other events: 481 other events

Deaths: 0 deaths

Alendronate

Serious events: 30 serious events

Other events: 242 other events

Deaths: 0 deaths

Serious adverse events

Measure	Denosumab n=475 participants at risk Denosumab (subcutaneously - every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Placebo n=481 participants at risk Placebo (subcutaneously every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Alendronate n=242 participants at risk Alendronate sodium hydrate oral tablets weekly + daily calcium and vitamin D supplements for 24 months (open label reference arm).
Injury, poisoning and procedural complications Femur fracture	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Fractured ischium	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.84% 4/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.63% 3/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.62% 3/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.63% 3/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	1.2% 3/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Muscle atrophy	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Tenosynovitis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Spondylolisthesis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Head injury	0.42% 2/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Rib fracture	0.42% 2/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Ulna fracture	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Ankle fracture	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Foot fracture	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Fractured coccyx	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Heat illness	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Patella fracture	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Cerebral haemorrhage traumatic	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Fractured sacrum	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Pubis fracture	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Scapula fracture	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Tendon rupture	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Clavicle fracture	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Subarachnoid haemorrhage	0.63% 3/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Cerebral infarction	0.63% 3/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Dizziness	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Cerebellar haemorrhage	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.42% 2/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Loss of consciousness	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Cerebral haemorrhage	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.42% 2/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Altered state of consciousness	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Autonomic nervous system imbalance	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Convulsion	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Intracranial aneurysm	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Transient ischaemic attack	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Nervous system disorders Tremor	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Colonic polyp	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	1.0% 5/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Haemorrhoids	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal hernia	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Enterocolitis	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Femoral hernia, obstructive	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Gastrointestinal mucosal exfoliation	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Large intestine perforation	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Rectal prolapse	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.42% 2/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Gastric polyps	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Gastrointestinal disorder	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Pancreatitis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Proctalgia	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Inguinal hernia	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Oesophageal ulcer	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.42% 2/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.62% 3/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.42% 2/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lung	0.42% 2/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.42% 2/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bile duct cancer	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon adenoma	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lymph nodes	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.42% 2/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Large intestine carcinoma	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lymphoma	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Paget's disease of the breast	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Haemangioblastoma	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Appendicitis	0.42% 2/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Enteritis infectious	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Gastroenteritis	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Respiratory moniliasis	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Arthritis bacterial	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Diverticulitis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Herpes zoster	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Pneumonia	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.83% 2/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Pyelonephritis acute	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Sepsis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Sinusitis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Cardiac disorders Angina pectoris	0.42% 2/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Cardiac disorders Acute myocardial infarction	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Cardiac disorders Atrioventricular block complete	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Cardiac disorders Cardiac failure	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Cardiac disorders Cardiac failure acute	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Cardiac disorders Palpitations	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Cardiac disorders Mitral valve incompetence	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Hepatobiliary disorders Hepatic cyst	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Hepatobiliary disorders Cholelithiasis	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Hepatobiliary disorders Hepatic function abnormal	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Hepatobiliary disorders Cholangitis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.42% 2/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Foreign body aspiration	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Paranasal cyst	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Pleurisy	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Eye disorders Cataract	0.42% 2/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	1.5% 7/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	2.1% 5/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Eye disorders Maculopathy	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Eye disorders Macular degeneration	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Vascular disorders Aortic aneurysm	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Vascular disorders Varicose vein	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Vascular disorders Circulatory collapse	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Vascular disorders Deep vein thrombosis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Vascular disorders Hypertension	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Ear and labyrinth disorders Vertigo	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.83% 2/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Ear and labyrinth disorders Sudden hearing loss	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
General disorders Chest pain	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
General disorders Device dislocation	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
General disorders Device breakage	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Psychiatric disorders Depression	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Psychiatric disorders Dysthymic disorder	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Psychiatric disorders Neurosis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Surgical and medical procedures Cataract operation	0.42% 2/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Surgical and medical procedures Varicose vein operation	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Renal and urinary disorders Calculus urinary	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Renal and urinary disorders Mixed incontinence	0.21% 1/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Renal and urinary disorders Nephrolithiasis	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Uterine prolapse	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.42% 2/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Cystocele	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Pelvic prolapse	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Vaginal relaxation	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Metabolism and nutrition disorders Dehydration	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.42% 2/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Blood and lymphatic system disorders Iron deficiency anaemia	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Endocrine disorders Thyroid mass	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.21% 1/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Drug eruption	0.00% 0/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.00% 0/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	0.41% 1/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.

Other adverse events

Measure	Denosumab n=475 participants at risk Denosumab (subcutaneously - every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Placebo n=481 participants at risk Placebo (subcutaneously every 6 months) + daily calcium and vitamin D supplements for 24 months, followed by a 12-month period of denosumab (subcutaneously - every 6 months).	Alendronate n=242 participants at risk Alendronate sodium hydrate oral tablets weekly + daily calcium and vitamin D supplements for 24 months (open label reference arm).
Infections and infestations Nasopharyngitis	44.4% 211/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	42.2% 203/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	38.4% 93/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Infections and infestations Cystitis	5.9% 28/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	6.0% 29/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	3.7% 9/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Osteoarthritis	16.2% 77/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	8.9% 43/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	15.3% 37/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Back pain	14.5% 69/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	12.5% 60/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	11.6% 28/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Arthralgia	8.0% 38/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	6.2% 30/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	7.0% 17/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	5.7% 27/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.0% 24/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.8% 14/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Periarthritis	4.8% 23/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.4% 26/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	7.0% 17/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Pain in extremity	4.4% 21/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.2% 25/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.0% 12/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Dental caries	15.4% 73/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	13.3% 64/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	12.0% 29/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Constipation	10.3% 49/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	7.7% 37/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	8.7% 21/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Periodontitis	8.6% 41/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.6% 27/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	6.6% 16/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Stomatitis	7.4% 35/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.0% 24/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	2.9% 7/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Diarrhoea	4.8% 23/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	3.1% 15/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	6.6% 16/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Gastrointestinal disorders Gastritis	4.2% 20/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.4% 26/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.4% 13/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Contusion	16.8% 80/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	15.4% 74/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	22.3% 54/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Eczema	8.2% 39/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	8.5% 41/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	6.6% 16/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Dermatitis contact	4.4% 21/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.8% 28/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.8% 14/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Investigations Blood creatine phosphokinase increased	5.9% 28/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	4.6% 22/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	6.2% 15/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract inflammation	6.5% 31/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	7.3% 35/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	7.9% 19/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Eye disorders Cataract	5.3% 25/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.6% 27/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	5.8% 14/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Vascular disorders Hypertension	8.2% 39/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	7.5% 36/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	4.5% 11/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.
Psychiatric disorders Insomnia	5.5% 26/475 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	4.4% 21/481 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.	7.4% 18/242 • Baseline to 24 months The number of participants for which serious adverse reactions are reported are the ones included in the safety data analysis set. This data set includes all participants who received at least one dose of investigational product.

Additional Information

H. Takami

Daiichi Sankyo Co., Ltd.

Phone: +81 3 5740 3445

Email: takami.hideo.hs@daiichisankyo.co.jp

Results disclosure agreements

• Principal investigator is a sponsor employee Principal Investigator shall not publish the results of the Study at any time without the prior written approval of Sponsor.
• Publication restrictions are in place

Restriction type: OTHER