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Efficacy and Safety Study of Darolutamide (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer (ARAMIS)

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ClinicalTrials.gov Identifier: NCT02200614
Recruitment Status : Completed
First Posted : July 25, 2014
Results First Posted : October 29, 2019
Last Update Posted : June 28, 2022
Sponsor:
Collaborator:
Orion Corporation, Orion Pharma
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Prostate Cancer Non-Metastatic
Castration-Resistant
Interventions Drug: Darolutamide (Nubeqa, BAY1841788)
Drug: Placebo
Enrollment 1509
Recruitment Details Study was conducted at multiple centers in 36 countries between 12 September 2014 (first participant first visit) and 14 June 2021 (last participant last visit).
Pre-assignment Details From 2696 participants who signed informed consent, 1187 participants were discontinued from screening. A total of 1509 participants were randomly assigned to either darolutamide arm or placebo arm. The study was unblinded on 30 OCT 2018 and participants in the placebo arm could cross over to open-label darolutamide treatment.
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]). Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Period Title: Double Blind Treatment
Started [1] 955 554
Completed [2] 591 170
Not Completed 364 384
Reason Not Completed
Adverse Event             86             48
Confirmed metastasis             120             140
Judgment of the investigator             59             99
Metastasis by local reading             1             3
Other reason             6             2
Personal reason             77             85
Protocol deviation             14             7
Not treated             1             0
[1]
Randomized
[2]
Ongoing with treatment
Period Title: Open Label
Started 591 [1] 170 [1]
Completed [2] 295 114
Not Completed 296 56
Reason Not Completed
Adverse Event             41             11
Confirmed metastasis             1             0
Judgment of the investigator             29             2
Metastasis by local reading             138             27
Other reason             22             4
Personal reason             60             8
Protocol deviation             3             2
Missing             2             2
[1]
Not all participants from treatment period entered follow-up
[2]
Moving to roll-over study
Arm/Group Title Darolutamide (BAY1841788) Placebo Total
Hide Arm/Group Description Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]). Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]). Total of all reporting groups
Overall Number of Baseline Participants 955 554 1509
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 955 participants 554 participants 1509 participants
73.9  (7.8) 73.2  (8.2) 73.6  (8.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 955 participants 554 participants 1509 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
955
 100.0%
554
 100.0%
1509
 100.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 955 participants 554 participants 1509 participants
Asia
122
  12.8%
71
  12.8%
193
  12.8%
Black or African American
28
   2.9%
24
   4.3%
52
   3.4%
White
760
  79.6%
434
  78.3%
1194
  79.1%
Missing
36
   3.8%
19
   3.4%
55
   3.6%
Other
9
   0.9%
6
   1.1%
15
   1.0%
1.Primary Outcome
Title Metastasis-Free Survival
Hide Description Metastasis-Free Survival (MFS) is defined as the time from randomisation to evidence of metastasis or death from any cause, whichever occurs first (cut-off date 15 Nov 2019)
Time Frame From randomization to the time approximately 385 MFS events were observed (approximately 48 months)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description:
Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]).
Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Overall Number of Participants Analyzed 955 554
Median (95% Confidence Interval)
Unit of Measure: months
40.37 [1] 
(34.33 to NA)
18.43
(15.51 to 22.34)
[1]
NA = value cannot be estimated due to censored data, insufficient number of participants with events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Darolutamide (BAY1841788), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.000001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.413
Confidence Interval (2-Sided) 95%
0.341 to 0.500
Estimation Comments Hazard ratio and 95% Confidence Interval (CI) was based on Cox Regression Model, stratified by Prostate-specific antigen doubling time (PSADT) (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (No, Yes).
2.Secondary Outcome
Title Overall Survival - Primary Analysis
Hide Description Overall Survival (OS) was defined as the time from randomization to death due to any cause.
Time Frame From randomization of the first subject to the time approximatively 140 death events were observed (approximately 48 months)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description:
Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]).
Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Overall Number of Participants Analyzed 955 554
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(44.45 to NA)
NA [1] 
(NA to NA)
[1]
NA = value cannot be estimated due to censored data, insufficient number of participants with events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Darolutamide (BAY1841788), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.045210
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.706
Confidence Interval (2-Sided) 95%
0.501 to 0.994
Estimation Comments The hazard ratio and its 95% CI were based on Cox Regression Model, stratified by Prostate-specific antigen doubling time (PSADT) (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (No, Yes).
3.Secondary Outcome
Title Time to Pain Progression - Primary Analysis
Hide Description Time to pain progression (PP) is defined as time from randomization to pain progression, where progression is defined as an increase of 2 or more points from baseline in question 3 of the Brief Pain Inventory-Short Form questionnaire (BPI-SF) related to the worst pain in the last 24 hours taken as a 7-day average for post-baseline scores, or initiation of short or long-acting opioids for pain, whichever comes first. Initiation or change in the use of other non-opioid analgesics is not used in the analysis of pain progression.
Time Frame From randomization until last study treatment (assessed every 4 months) (approximately 48 months)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description:
Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]).
Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Overall Number of Participants Analyzed 955 554
Median (95% Confidence Interval)
Unit of Measure: months
40.31
(33.21 to 41.20)
25.36
(19.09 to 29.63)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Darolutamide (BAY1841788), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.000008
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.647
Confidence Interval (2-Sided) 95%
0.533 to 0.785
Estimation Comments The hazard ratio and its 95% CI were based on Cox Regression Model, stratified by Prostate-specific antigen doubling time (PSADT) (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (No, Yes).
4.Secondary Outcome
Title Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Primary Analysis
Hide Description The time to cytotoxic chemotherapy was defined as the time from randomization to the start of the first cytotoxic chemotherapy cycle.
Time Frame From randomization until last study treatment (assessed every 4 months) (approximately 48 months)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description:
Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]).
Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Overall Number of Participants Analyzed 955 554
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
38.21
(35.55 to 41.89)
[1]
NA = value cannot be estimated due to censored data, insufficient number of participants with events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Darolutamide (BAY1841788), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.000001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.433
Confidence Interval (2-Sided) 95%
0.314 to 0.595
Estimation Comments The hazard ratio and its 95% CI were based on Cox Regression Model, stratified by Prostate-specific antigen doubling time (PSADT) (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (No, Yes).
5.Secondary Outcome
Title Time to First Symptomatic Skeletal Event (SSE) - Primary Analysis
Hide Description The time to the first SSE was defined as the time from randomization to the occurrence of the first SSE.
Time Frame From randomization until last study treatment (assessed every 4 months) (approximately 48 months)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description:
Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]).
Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Overall Number of Participants Analyzed 955 554
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA = value cannot be estimated due to censored data, insufficient number of participants with events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Darolutamide (BAY1841788), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.011262
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.428
Confidence Interval (2-Sided) 95%
0.218 to 0.842
Estimation Comments The hazard ratio and its 95% CI were based on Cox Regression Model, stratified by Prostate-specific antigen doubling time (PSADT) (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (No, Yes).
6.Secondary Outcome
Title Overall Survival - Final Analysis
Hide Description Overall Survival (OS) was defined as the time from randomization to death due to any cause. The final analysis was done at the time of the data cut-off (15 NOV 2019).
Time Frame From randomization of the first subject to the time approximatively 254 death events were observed (approximately 56 months)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description:
Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]).
Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Overall Number of Participants Analyzed 955 554
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(56.14 to NA)
NA [1] 
(46.91 to NA)
[1]
NA = value cannot be estimated due to censored data, insufficient number of participants with events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Darolutamide (BAY1841788), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003048
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.685
Confidence Interval (2-Sided) 95%
0.533 to 0.881
Estimation Comments The hazard ratio and its 95% CI were based on Cox Regression Model, stratified by Prostate-specific antigen doubling time (PSADT) (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (No, Yes).
7.Secondary Outcome
Title Time to Pain Progression - Final Analysis
Hide Description For time to pain progression, the analysis performed using the primary completion cut-off data (03 SEP 2018) was considered final and no new analysis was performed for time to pain progression.
Time Frame From randomization until last study treatment (assessed every 4 months) (approximately 48 months)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description:
Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]).
Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Overall Number of Participants Analyzed 955 554
Median (95% Confidence Interval)
Unit of Measure: months
40.31
(33.21 to 41.20)
25.36
(19.09 to 29.63)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Darolutamide (BAY1841788), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.000008
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.647
Confidence Interval (2-Sided) 95%
0.533 to 0.785
Estimation Comments The hazard ratio and its 95% CI were based on Cox Regression Model, stratified by Prostate-specific antigen doubling time (PSADT) (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (No, Yes).
8.Secondary Outcome
Title Time to Initiation of First Cytotoxic Chemotherapy for Prostate Cancer - Final Analysis
Hide Description The time to cytotoxic chemotherapy was defined as the time from randomization to the start of the first cytotoxic chemotherapy cycle. The final analysis was done at the time of the data cut-off (15 NOV 2019).
Time Frame From randomization until initiation of first cytotoxic chemotherapy treatment (approximately 59 months)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description:
Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]).
Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Overall Number of Participants Analyzed 955 554
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA = value cannot be estimated due to censored data, insufficient number of participants with events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Darolutamide (BAY1841788), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.000044
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.579
Confidence Interval (2-Sided) 95%
0.444 to 0.755
Estimation Comments The hazard ratio and its 95% CI were based on Cox Regression Model, stratified by Prostate-specific antigen doubling time (PSADT) (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (No, Yes).
9.Secondary Outcome
Title Time to First Symptomatic Skeletal Event (SSE) - Final Analysis
Hide Description The time to the first SSE was defined as the time from randomization to the occurrence of the first SSE. The final analysis was done at the time of the data cut-off (15 NOV 2019).
Time Frame From randomization until occurrence of first SSE event (approximately 59 months)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Darolutamide (BAY1841788) Placebo
Hide Arm/Group Description:
Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]).
Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
Overall Number of Participants Analyzed 955 554
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA = value cannot be estimated due to censored data, insufficient number of participants with events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Darolutamide (BAY1841788), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005294
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.484
Confidence Interval (2-Sided) 95%
0.287 to 0.815
Estimation Comments The hazard ratio and its 95% CI were based on Cox Regression Model, stratified by Prostate-specific antigen doubling time (PSADT) (≤ 6 months vs. > 6 months) and use of osteoclast-targeted therapy (No, Yes).
Time Frame From start of study drug administration until 30 days after last treatment (last cut-off date 14 JUN 2021)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Darolutamide (DB) Darolutamide (DB+OL) Placebo (DB) Placebo+Darolutamide (CO)
Hide Arm/Group Description Participants received Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg (double blind [DB]). Participants received Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. Participants in the darolutamide treatment arm were ongoing with open-label darolutamide treatment (darolutamide double-blind [DB] + open-label [OL]). Participants received matching placebo 2 tablets twice daily with food (double blind [DB]). Participants received matching placebo 2 tablets twice daily with food. Participants from the placebo arm crossed over to receive open-label darolutamide treatment (placebo-darolutamide cross-over [CO]).
All-Cause Mortality
Darolutamide (DB) Darolutamide (DB+OL) Placebo (DB) Placebo+Darolutamide (CO)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   155/954 (16.25%)      224/954 (23.48%)      137/554 (24.73%)      16/170 (9.41%)    
Hide Serious Adverse Events
Darolutamide (DB) Darolutamide (DB+OL) Placebo (DB) Placebo+Darolutamide (CO)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   251/954 (26.31%)      367/954 (38.47%)      121/554 (21.84%)      43/170 (25.29%)    
Blood and lymphatic system disorders         
Anaemia * 1  3/954 (0.31%)  4 8/954 (0.84%)  9 0/554 (0.00%)  0 1/170 (0.59%)  1
Febrile neutropenia * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Leukopenia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Lymphopenia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Neutropenia * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 1/554 (0.18%)  1 0/170 (0.00%)  0
Autoimmune haemolytic anaemia * 1  1/954 (0.10%)  1 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Immune thrombocytopenia * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Cardiac disorders         
Acute myocardial infarction * 1  5/954 (0.52%)  5 6/954 (0.63%)  6 0/554 (0.00%)  0 0/170 (0.00%)  0
Angina pectoris * 1  4/954 (0.42%)  5 4/954 (0.42%)  5 2/554 (0.36%)  2 1/170 (0.59%)  1
Angina unstable * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Aortic valve stenosis * 1  2/954 (0.21%)  2 3/954 (0.31%)  3 1/554 (0.18%)  1 0/170 (0.00%)  0
Arrhythmia * 1  2/954 (0.21%)  2 3/954 (0.31%)  3 0/554 (0.00%)  0 1/170 (0.59%)  1
Arteriosclerosis coronary artery * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Atrial fibrillation * 1  8/954 (0.84%)  11 9/954 (0.94%)  12 3/554 (0.54%)  3 3/170 (1.76%)  3
Atrial flutter * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Atrioventricular block * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Atrioventricular block complete * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Atrioventricular block second degree * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Bradycardia * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 1/554 (0.18%)  1 0/170 (0.00%)  0
Cardiac arrest * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 3/554 (0.54%)  3 0/170 (0.00%)  0
Cardiac failure * 1  8/954 (0.84%)  9 12/954 (1.26%)  14 4/554 (0.72%)  5 2/170 (1.18%)  2
Cardiac failure acute * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Cardiac failure congestive * 1  1/954 (0.10%)  1 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Conduction disorder * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Coronary artery disease * 1  2/954 (0.21%)  3 4/954 (0.42%)  5 1/554 (0.18%)  1 0/170 (0.00%)  0
Coronary artery occlusion * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Coronary artery stenosis * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Hypertensive heart disease * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Myocardial infarction * 1  4/954 (0.42%)  4 11/954 (1.15%)  12 2/554 (0.36%)  3 2/170 (1.18%)  2
Myocardial ischaemia * 1  2/954 (0.21%)  2 3/954 (0.31%)  4 1/554 (0.18%)  1 0/170 (0.00%)  0
Palpitations * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Sinus bradycardia * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Tachycardia * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Acute coronary syndrome * 1  0/954 (0.00%)  0 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Cardiac disorder * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Aortic valve disease * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Cardiovascular insufficiency * 1  1/954 (0.10%)  2 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Sinus node dysfunction * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Congenital, familial and genetic disorders         
Pyloric stenosis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Ear and labyrinth disorders         
Vertigo * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Vertigo positional * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Eye disorders         
Cataract * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Glaucoma * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Retinal detachment * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Retinal vascular disorder * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Visual impairment * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Macular hole * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Gastrointestinal disorders         
Abdominal mass * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Abdominal pain * 1  2/954 (0.21%)  2 3/954 (0.31%)  3 1/554 (0.18%)  1 0/170 (0.00%)  0
Abdominal pain lower * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Abdominal pain upper * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Constipation * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Diarrhoea * 1  2/954 (0.21%)  3 3/954 (0.31%)  5 0/554 (0.00%)  0 0/170 (0.00%)  0
Enterocolitis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Gastric haemorrhage * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Gastritis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Gastrointestinal disorder * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Gastrointestinal haemorrhage * 1  1/954 (0.10%)  1 3/954 (0.31%)  4 1/554 (0.18%)  1 0/170 (0.00%)  0
Gastrointestinal necrosis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Gastrointestinal pain * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Haemorrhoids * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Hiatus hernia * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Ileus * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Incarcerated inguinal hernia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Inguinal hernia * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 1/170 (0.59%)  1
Intestinal infarction * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Intestinal ischaemia * 1  0/954 (0.00%)  0 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Intestinal obstruction * 1  4/954 (0.42%)  4 4/954 (0.42%)  4 0/554 (0.00%)  0 0/170 (0.00%)  0
Melaena * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Pancreatic cyst * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Pancreatitis acute * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Plicated tongue * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Proctitis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Rectal haemorrhage * 1  3/954 (0.31%)  3 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Rectal stenosis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Small intestinal obstruction * 1  1/954 (0.10%)  1 3/954 (0.31%)  6 2/554 (0.36%)  3 0/170 (0.00%)  0
Small intestinal perforation * 1  1/954 (0.10%)  2 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Umbilical hernia * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Upper gastrointestinal haemorrhage * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Pneumoperitoneum * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Anal haemorrhage * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  3 0/170 (0.00%)  0
Subileus * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Lower gastrointestinal haemorrhage * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Large intestine polyp * 1  3/954 (0.31%)  3 3/954 (0.31%)  3 1/554 (0.18%)  1 0/170 (0.00%)  0
Large intestinal obstruction * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Enterovesical fistula * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Bowel movement irregularity * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Hiatus hernia, obstructive * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Obstructive pancreatitis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
General disorders         
Asthenia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Chest pain * 1  3/954 (0.31%)  3 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Death * 1  4/954 (0.42%)  4 6/954 (0.63%)  6 1/554 (0.18%)  1 0/170 (0.00%)  0
Gait disturbance * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Pyrexia * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Sudden death * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Sudden cardiac death * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
General physical health deterioration * 1  5/954 (0.52%)  7 7/954 (0.73%)  11 0/554 (0.00%)  0 0/170 (0.00%)  0
Hepatobiliary disorders         
Cholangitis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Cholangitis acute * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Cholecystitis acute * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 1/554 (0.18%)  1 1/170 (0.59%)  1
Cholecystitis chronic * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Cholelithiasis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Cholestasis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Hepatic function abnormal * 1  1/954 (0.10%)  2 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Liver disorder * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Bile duct stenosis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Biliary obstruction * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Immune system disorders         
Hypersensitivity * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Infections and infestations         
Appendicitis * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 1/554 (0.18%)  1 0/170 (0.00%)  0
Bronchitis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Cellulitis * 1  0/954 (0.00%)  0 2/954 (0.21%)  2 1/554 (0.18%)  1 1/170 (0.59%)  1
Cellulitis gangrenous * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  2 0/170 (0.00%)  0
Dengue fever * 1  0/954 (0.00%)  0 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Diverticulitis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Endocarditis * 1  1/954 (0.10%)  2 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Erysipelas * 1  2/954 (0.21%)  2 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Gastroenteritis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 2/554 (0.36%)  2 0/170 (0.00%)  0
Hepatitis C * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Herpes zoster * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Infectious mononucleosis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Influenza * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 1/554 (0.18%)  1 0/170 (0.00%)  0
Meningitis bacterial * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Osteomyelitis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Perinephric abscess * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Pneumonia * 1  15/954 (1.57%)  18 20/954 (2.10%)  24 6/554 (1.08%)  6 1/170 (0.59%)  2
Pneumonia pneumococcal * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Pneumonia staphylococcal * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Pulmonary tuberculosis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Pyelonephritis * 1  3/954 (0.31%)  3 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Pyelonephritis acute * 1  2/954 (0.21%)  3 3/954 (0.31%)  4 1/554 (0.18%)  1 0/170 (0.00%)  0
Sepsis * 1  1/954 (0.10%)  1 3/954 (0.31%)  3 0/554 (0.00%)  0 1/170 (0.59%)  1
Septic shock * 1  1/954 (0.10%)  2 2/954 (0.21%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Sialoadenitis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Tick-borne viral encephalitis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Upper respiratory tract infection * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Urinary tract infection * 1  7/954 (0.73%)  7 12/954 (1.26%)  13 0/554 (0.00%)  0 1/170 (0.59%)  1
Vestibular neuronitis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Wound infection * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 1/170 (0.59%)  1
Urosepsis * 1  2/954 (0.21%)  3 4/954 (0.42%)  10 0/554 (0.00%)  0 1/170 (0.59%)  1
Acute endocarditis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Urinary tract infection bacterial * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Infective exacerbation of chronic obstructive airways disease * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Abdominal sepsis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  2
Wound abscess * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Klebsiella bacteraemia * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Intervertebral discitis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Abdominal abscess * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Bacterial infection * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Arthritis infective * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Respiratory syncytial virus infection * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Severe acute respiratory syndrome * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Respiratory tract infection * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Cholecystitis infective * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Device related infection * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Medical device site infection * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Varicella zoster virus infection * 1  1/954 (0.10%)  2 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Medical device site joint infection * 1  1/954 (0.10%)  2 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
COVID-19 * 1  0/954 (0.00%)  0 4/954 (0.42%)  7 0/554 (0.00%)  0 1/170 (0.59%)  1
Diverticulitis intestinal perforated * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
COVID-19 pneumonia * 1  0/954 (0.00%)  0 4/954 (0.42%)  5 0/554 (0.00%)  0 0/170 (0.00%)  0
Suspected COVID-19 * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Injury, poisoning and procedural complications         
Alcohol poisoning * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Ankle fracture * 1  1/954 (0.10%)  1 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Bite * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Facial bones fracture * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Fall * 1  3/954 (0.31%)  3 4/954 (0.42%)  4 1/554 (0.18%)  1 0/170 (0.00%)  0
Femoral neck fracture * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Femur fracture * 1  2/954 (0.21%)  2 4/954 (0.42%)  4 1/554 (0.18%)  1 0/170 (0.00%)  0
Fibula fracture * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Foot fracture * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Fracture * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Hand fracture * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Head injury * 1  0/954 (0.00%)  0 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Hip fracture * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Humerus fracture * 1  0/954 (0.00%)  0 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Incisional hernia * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Ligament sprain * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Multiple injuries * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Patella fracture * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Radiation proctitis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Radius fracture * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Rib fracture * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Road traffic accident * 1  2/954 (0.21%)  3 4/954 (0.42%)  5 1/554 (0.18%)  1 0/170 (0.00%)  0
Subdural haematoma * 1  1/954 (0.10%)  1 4/954 (0.42%)  4 1/554 (0.18%)  1 0/170 (0.00%)  0
Tibia fracture * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Ulna fracture * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Wrist fracture * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Stenosis of vesicourethral anastomosis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Contusion * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Thermal burn * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Postoperative ileus * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Vascular procedure complication * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Heart injury * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Skull fracture * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Vascular graft complication * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Flatback syndrome * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Craniocerebral injury * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Incarcerated parastomal hernia * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Investigations         
Alanine aminotransferase increased * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Aspartate aminotransferase increased * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Biopsy prostate * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Blood creatinine increased * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Body temperature increased * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Prostatic specific antigen increased * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Transaminases increased * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Urine output decreased * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Angiocardiogram * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 2/554 (0.36%)  2 0/170 (0.00%)  0
Metabolism and nutrition disorders         
Cachexia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Dehydration * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Diabetes mellitus * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Hyperglycaemia * 1  3/954 (0.31%)  4 3/954 (0.31%)  4 1/554 (0.18%)  1 0/170 (0.00%)  0
Hyperkalaemia * 1  1/954 (0.10%)  2 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Hypoglycaemia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Decreased appetite * 1  4/954 (0.42%)  4 4/954 (0.42%)  4 0/554 (0.00%)  0 0/170 (0.00%)  0
Musculoskeletal and connective tissue disorders         
Arthralgia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Back pain * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Flank pain * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Kyphosis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Muscular weakness * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Osteoarthritis * 1  3/954 (0.31%)  3 4/954 (0.42%)  4 1/554 (0.18%)  1 0/170 (0.00%)  0
Pain in extremity * 1  0/954 (0.00%)  0 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Rheumatoid arthritis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Rotator cuff syndrome * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Spinal osteoarthritis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Intervertebral disc protrusion * 1  0/954 (0.00%)  0 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Spinal pain * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Rapidly progressive osteoarthritis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Spinal stenosis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Acute leukaemia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Basal cell carcinoma * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Benign hepatic neoplasm * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Bladder cancer * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Bladder neoplasm * 1  3/954 (0.31%)  4 4/954 (0.42%)  5 0/554 (0.00%)  0 1/170 (0.59%)  1
Bladder transitional cell carcinoma * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  3
Carcinoid tumour * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Choroid melanoma * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Colon cancer * 1  3/954 (0.31%)  4 3/954 (0.31%)  4 0/554 (0.00%)  0 0/170 (0.00%)  0
Diffuse large B-cell lymphoma * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Gastric cancer * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 2/554 (0.36%)  2 0/170 (0.00%)  0
Laryngeal cancer * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Lipoma * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Lung adenocarcinoma * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Lymphoma * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Malignant melanoma in situ * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Meningioma * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Mesothelioma * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Metastases to spine * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Myelodysplastic syndrome * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Neoplasm malignant * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Pancreatic carcinoma * 1  3/954 (0.31%)  3 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Pituitary tumour * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Rectal adenocarcinoma * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Rectal cancer * 1  2/954 (0.21%)  3 2/954 (0.21%)  3 1/554 (0.18%)  1 0/170 (0.00%)  0
Renal cancer * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Squamous cell carcinoma * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Thymoma * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Transitional cell carcinoma * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Tumour pain * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Gastrointestinal stromal tumour * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Colorectal adenocarcinoma * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Adenocarcinoma pancreas * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Neuroendocrine carcinoma * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  2
Lung neoplasm malignant * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 1/554 (0.18%)  1 0/170 (0.00%)  0
Prostate cancer * 1  0/954 (0.00%)  0 3/954 (0.31%)  3 1/554 (0.18%)  1 1/170 (0.59%)  1
Brain neoplasm * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Colon neoplasm * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Salivary gland neoplasm * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Lung neoplasm * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Rectal neoplasm * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Hepatocellular carcinoma * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Neuroendocrine tumour of the lung * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Nervous system disorders         
Autonomic nervous system imbalance * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Bulbar palsy * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Carotid artery stenosis * 1  2/954 (0.21%)  2 2/954 (0.21%)  3 0/554 (0.00%)  0 1/170 (0.59%)  1
Cerebral infarction * 1  2/954 (0.21%)  2 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Cerebral ischaemia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 1/554 (0.18%)  2 0/170 (0.00%)  0
Cerebrovascular accident * 1  2/954 (0.21%)  2 6/954 (0.63%)  6 3/554 (0.54%)  3 1/170 (0.59%)  1
Dizziness * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Haemorrhage intracranial * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  2 0/170 (0.00%)  0
Haemorrhagic stroke * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Myelopathy * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Normal pressure hydrocephalus * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Presyncope * 1  1/954 (0.10%)  2 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Seizure * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Subarachnoid haemorrhage * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Syncope * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 2/554 (0.36%)  2 0/170 (0.00%)  0
Transient ischaemic attack * 1  1/954 (0.10%)  1 4/954 (0.42%)  4 1/554 (0.18%)  2 0/170 (0.00%)  0
Brain oedema * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Perineurial cyst * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
IIIrd nerve disorder * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Cognitive disorder * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Ischaemic stroke * 1  5/954 (0.52%)  6 5/954 (0.52%)  6 2/554 (0.36%)  2 1/170 (0.59%)  1
Partial seizures * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Parkinson's disease * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Vertebrobasilar stroke * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Product Issues         
Device dislocation * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 1/554 (0.18%)  2 0/170 (0.00%)  0
Device occlusion * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Psychiatric disorders         
Delirium * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Depression * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Major depression * 1  1/954 (0.10%)  2 1/954 (0.10%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Renal and urinary disorders         
Azotaemia * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Calculus bladder * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Calculus urinary * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 1/170 (0.59%)  1
Dysuria * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 3/554 (0.54%)  3 0/170 (0.00%)  0
Haematuria * 1  11/954 (1.15%)  13 25/954 (2.62%)  29 7/554 (1.26%)  7 0/170 (0.00%)  0
Hydronephrosis * 1  3/954 (0.31%)  3 8/954 (0.84%)  10 4/554 (0.72%)  4 2/170 (1.18%)  3
Nephritis * 1  0/954 (0.00%)  0 2/954 (0.21%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Nephrolithiasis * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Oliguria * 1  1/954 (0.10%)  2 1/954 (0.10%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Pollakiuria * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Renal colic * 1  2/954 (0.21%)  2 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Renal failure * 1  1/954 (0.10%)  1 4/954 (0.42%)  4 4/554 (0.72%)  4 0/170 (0.00%)  0
Ureteric obstruction * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 0/554 (0.00%)  0 1/170 (0.59%)  1
Ureteric stenosis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Urinary retention * 1  16/954 (1.68%)  17 33/954 (3.46%)  37 20/554 (3.61%)  20 6/170 (3.53%)  6
Urinary tract disorder * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Urine flow decreased * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Urinary tract obstruction * 1  7/954 (0.73%)  9 11/954 (1.15%)  13 3/554 (0.54%)  3 1/170 (0.59%)  1
Renal impairment * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 1/170 (0.59%)  1
Chronic kidney disease * 1  0/954 (0.00%)  0 2/954 (0.21%)  2 2/554 (0.36%)  2 1/170 (0.59%)  1
Urethral stenosis * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Acute kidney injury * 1  4/954 (0.42%)  4 7/954 (0.73%)  7 3/554 (0.54%)  3 1/170 (0.59%)  1
Lower urinary tract symptoms * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Bladder outlet obstruction * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Ureterolithiasis * 1  2/954 (0.21%)  2 3/954 (0.31%)  3 1/554 (0.18%)  1 0/170 (0.00%)  0
Reproductive system and breast disorders         
Benign prostatic hyperplasia * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Prostatic obstruction * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Prostate induration * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Perineal pain * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Acute respiratory failure * 1  2/954 (0.21%)  3 2/954 (0.21%)  3 3/554 (0.54%)  5 0/170 (0.00%)  0
Chronic obstructive pulmonary disease * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 3/554 (0.54%)  5 0/170 (0.00%)  0
Cough * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Dyspnoea * 1  4/954 (0.42%)  5 5/954 (0.52%)  6 2/554 (0.36%)  2 0/170 (0.00%)  0
Epistaxis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Haemoptysis * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Pleural effusion * 1  3/954 (0.31%)  3 3/954 (0.31%)  3 1/554 (0.18%)  1 0/170 (0.00%)  0
Pneumonia aspiration * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 1/170 (0.59%)  1
Pulmonary artery thrombosis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Pulmonary embolism * 1  5/954 (0.52%)  5 7/954 (0.73%)  7 1/554 (0.18%)  1 1/170 (0.59%)  1
Pulmonary thrombosis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Respiratory distress * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Respiratory failure * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 1/554 (0.18%)  1 0/170 (0.00%)  0
Pulmonary mass * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Skin and subcutaneous tissue disorders         
Dermatitis allergic * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Skin mass * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Surgical and medical procedures         
Angioplasty * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Bladder catheterisation * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Hip arthroplasty * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Inguinal hernia repair * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Orchidectomy * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Transurethral prostatectomy * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 1/554 (0.18%)  1 0/170 (0.00%)  0
Nephrostomy * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Coronary angioplasty * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Artificial urinary sphincter implant * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Radiotherapy to brain * 1  0/954 (0.00%)  0 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Prostatectomy * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Pulmonary resection * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Vascular disorders         
Aortic aneurysm * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Aortic dissection * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Aortic stenosis * 1  3/954 (0.31%)  3 3/954 (0.31%)  3 0/554 (0.00%)  0 0/170 (0.00%)  0
Aortic thrombosis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Arteriosclerosis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Circulatory collapse * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Hypertension * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Hypotension * 1  2/954 (0.21%)  2 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Lymphoedema * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Orthostatic hypotension * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Peripheral ischaemia * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Thrombosis * 1  1/954 (0.10%)  1 2/954 (0.21%)  2 0/554 (0.00%)  0 0/170 (0.00%)  0
Venous thrombosis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Subclavian vein thrombosis * 1  0/954 (0.00%)  0 0/954 (0.00%)  0 1/554 (0.18%)  1 0/170 (0.00%)  0
Deep vein thrombosis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Iliac artery stenosis * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Embolism * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
Peripheral arterial occlusive disease * 1  1/954 (0.10%)  1 1/954 (0.10%)  1 0/554 (0.00%)  0 0/170 (0.00%)  0
1
Term from vocabulary, MedDRA (24.0)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Darolutamide (DB) Darolutamide (DB+OL) Placebo (DB) Placebo+Darolutamide (CO)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   673/954 (70.55%)      742/954 (77.78%)      354/554 (63.90%)      110/170 (64.71%)    
Blood and lymphatic system disorders         
Anaemia * 1  60/954 (6.29%)  76 93/954 (9.75%)  136 28/554 (5.05%)  33 7/170 (4.12%)  7
Neutropenia * 1  13/954 (1.36%)  17 21/954 (2.20%)  27 4/554 (0.72%)  4 2/170 (1.18%)  2
Cardiac disorders         
Atrial fibrillation * 1  19/954 (1.99%)  20 26/954 (2.73%)  30 6/554 (1.08%)  8 3/170 (1.76%)  4
Eye disorders         
Cataract * 1  11/954 (1.15%)  11 15/954 (1.57%)  16 5/554 (0.90%)  6 4/170 (2.35%)  4
Gastrointestinal disorders         
Abdominal pain * 1  25/954 (2.62%)  27 35/954 (3.67%)  39 12/554 (2.17%)  14 2/170 (1.18%)  2
Abdominal pain upper * 1  14/954 (1.47%)  16 16/954 (1.68%)  19 14/554 (2.53%)  15 3/170 (1.76%)  3
Constipation * 1  65/954 (6.81%)  70 84/954 (8.81%)  94 36/554 (6.50%)  41 8/170 (4.71%)  11
Diarrhoea * 1  69/954 (7.23%)  87 87/954 (9.12%)  114 33/554 (5.96%)  37 15/170 (8.82%)  16
Nausea * 1  53/954 (5.56%)  59 60/954 (6.29%)  76 32/554 (5.78%)  37 6/170 (3.53%)  6
Vomiting * 1  17/954 (1.78%)  19 21/954 (2.20%)  24 10/554 (1.81%)  12 3/170 (1.76%)  3
General disorders         
Asthenia * 1  37/954 (3.88%)  42 43/954 (4.51%)  53 20/554 (3.61%)  23 7/170 (4.12%)  8
Fatigue * 1  126/954 (13.21%)  164 142/954 (14.88%)  198 47/554 (8.48%)  60 9/170 (5.29%)  9
Oedema peripheral * 1  43/954 (4.51%)  49 57/954 (5.97%)  67 17/554 (3.07%)  19 4/170 (2.35%)  4
Pyrexia * 1  18/954 (1.89%)  25 21/954 (2.20%)  28 5/554 (0.90%)  7 5/170 (2.94%)  9
Infections and infestations         
Bronchitis * 1  13/954 (1.36%)  17 23/954 (2.41%)  30 9/554 (1.62%)  10 3/170 (1.76%)  3
Influenza * 1  28/954 (2.94%)  33 36/954 (3.77%)  42 8/554 (1.44%)  8 2/170 (1.18%)  2
Nasopharyngitis * 1  39/954 (4.09%)  50 56/954 (5.87%)  78 23/554 (4.15%)  27 8/170 (4.71%)  11
Pneumonia * 1  10/954 (1.05%)  11 22/954 (2.31%)  24 5/554 (0.90%)  5 3/170 (1.76%)  3
Upper respiratory tract infection * 1  26/954 (2.73%)  29 34/954 (3.56%)  40 10/554 (1.81%)  13 3/170 (1.76%)  7
Urinary tract infection * 1  44/954 (4.61%)  59 73/954 (7.65%)  130 31/554 (5.60%)  37 12/170 (7.06%)  12
COVID-19 * 1  0/954 (0.00%)  0 6/954 (0.63%)  6 0/554 (0.00%)  0 4/170 (2.35%)  4
Injury, poisoning and procedural complications         
Fall * 1  41/954 (4.30%)  44 62/954 (6.50%)  69 23/554 (4.15%)  27 7/170 (4.12%)  8
Rib fracture * 1  16/954 (1.68%)  17 28/954 (2.94%)  30 8/554 (1.44%)  10 6/170 (3.53%)  6
Contusion * 1  12/954 (1.26%)  17 21/954 (2.20%)  26 2/554 (0.36%)  2 2/170 (1.18%)  2
Investigations         
Alanine aminotransferase increased * 1  6/954 (0.63%)  8 13/954 (1.36%)  16 1/554 (0.18%)  1 6/170 (3.53%)  9
Aspartate aminotransferase increased * 1  12/954 (1.26%)  16 23/954 (2.41%)  29 1/554 (0.18%)  1 6/170 (3.53%)  10
Blood creatinine increased * 1  23/954 (2.41%)  32 37/954 (3.88%)  51 14/554 (2.53%)  19 3/170 (1.76%)  3
Weight decreased * 1  40/954 (4.19%)  42 65/954 (6.81%)  72 14/554 (2.53%)  17 8/170 (4.71%)  8
Weight increased * 1  14/954 (1.47%)  15 25/954 (2.62%)  27 7/554 (1.26%)  8 3/170 (1.76%)  3
Metabolism and nutrition disorders         
Hyperkalaemia * 1  16/954 (1.68%)  24 22/954 (2.31%)  32 9/554 (1.62%)  10 0/170 (0.00%)  0
Hypokalaemia * 1  10/954 (1.05%)  10 12/954 (1.26%)  13 2/554 (0.36%)  2 4/170 (2.35%)  4
Decreased appetite * 1  30/954 (3.14%)  34 40/954 (4.19%)  49 16/554 (2.89%)  18 1/170 (0.59%)  1
Musculoskeletal and connective tissue disorders         
Arthralgia * 1  106/954 (11.11%)  146 135/954 (14.15%)  190 58/554 (10.47%)  69 17/170 (10.00%)  19
Back pain * 1  92/954 (9.64%)  104 118/954 (12.37%)  142 52/554 (9.39%)  59 9/170 (5.29%)  9
Muscle spasms * 1  19/954 (1.99%)  20 20/954 (2.10%)  21 4/554 (0.72%)  4 0/170 (0.00%)  0
Myalgia * 1  18/954 (1.89%)  21 24/954 (2.52%)  28 7/554 (1.26%)  8 2/170 (1.18%)  3
Osteoarthritis * 1  16/954 (1.68%)  20 26/954 (2.73%)  33 3/554 (0.54%)  3 3/170 (1.76%)  3
Pain in extremity * 1  60/954 (6.29%)  79 71/954 (7.44%)  105 19/554 (3.43%)  25 5/170 (2.94%)  6
Nervous system disorders         
Dizziness * 1  39/954 (4.09%)  47 48/954 (5.03%)  64 14/554 (2.53%)  17 2/170 (1.18%)  2
Headache * 1  41/954 (4.30%)  59 53/954 (5.56%)  75 14/554 (2.53%)  15 4/170 (2.35%)  7
Psychiatric disorders         
Depression * 1  20/954 (2.10%)  20 25/954 (2.62%)  27 9/554 (1.62%)  10 2/170 (1.18%)  2
Insomnia * 1  26/954 (2.73%)  28 35/954 (3.67%)  38 11/554 (1.99%)  11 8/170 (4.71%)  8
Renal and urinary disorders         
Dysuria * 1  24/954 (2.52%)  27 32/954 (3.35%)  37 27/554 (4.87%)  30 5/170 (2.94%)  5
Haematuria * 1  37/954 (3.88%)  48 66/954 (6.92%)  96 27/554 (4.87%)  39 12/170 (7.06%)  13
Nephrolithiasis * 1  14/954 (1.47%)  17 21/954 (2.20%)  25 4/554 (0.72%)  4 3/170 (1.76%)  3
Nocturia * 1  17/954 (1.78%)  17 23/954 (2.41%)  24 10/554 (1.81%)  10 2/170 (1.18%)  2
Pollakiuria * 1  41/954 (4.30%)  46 51/954 (5.35%)  63 18/554 (3.25%)  20 4/170 (2.35%)  4
Urinary incontinence * 1  15/954 (1.57%)  15 24/954 (2.52%)  25 14/554 (2.53%)  14 3/170 (1.76%)  3
Urinary retention * 1  25/954 (2.62%)  27 39/954 (4.09%)  47 24/554 (4.33%)  29 1/170 (0.59%)  1
Reproductive system and breast disorders         
Gynaecomastia * 1  21/954 (2.20%)  21 30/954 (3.14%)  30 6/554 (1.08%)  6 1/170 (0.59%)  1
Pelvic pain * 1  13/954 (1.36%)  15 16/954 (1.68%)  19 12/554 (2.17%)  13 1/170 (0.59%)  1
Respiratory, thoracic and mediastinal disorders         
Cough * 1  29/954 (3.04%)  34 33/954 (3.46%)  38 11/554 (1.99%)  11 6/170 (3.53%)  6
Dyspnoea * 1  26/954 (2.73%)  28 32/954 (3.35%)  34 16/554 (2.89%)  22 2/170 (1.18%)  3
Skin and subcutaneous tissue disorders         
Pruritus * 1  17/954 (1.78%)  20 22/954 (2.31%)  25 12/554 (2.17%)  14 2/170 (1.18%)  4
Rash * 1  17/954 (1.78%)  17 24/954 (2.52%)  27 4/554 (0.72%)  4 2/170 (1.18%)  2
Vascular disorders         
Hypertension * 1  66/954 (6.92%)  86 87/954 (9.12%)  117 31/554 (5.60%)  39 6/170 (3.53%)  7
Hot flush * 1  54/954 (5.66%)  58 67/954 (7.02%)  73 25/554 (4.51%)  25 3/170 (1.76%)  3
1
Term from vocabulary, MedDRA (24.0)
*
Indicates events were collected by non-systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
 
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Therapeutic Area Head
Organization: Bayer
Phone: 1-888-8422937
EMail: clinical-trials-contact@bayer.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02200614    
Other Study ID Numbers: 17712
2013-003820-36 ( EudraCT Number )
First Submitted: July 22, 2014
First Posted: July 25, 2014
Results First Submitted: August 30, 2019
Results First Posted: October 29, 2019
Last Update Posted: June 28, 2022