Trial Outcomes & Findings for Adjuvant Melatonin for Prevention of Lung Cancer Recurrence and Mortality (NCT NCT00668707)

Last Updated: 2021-08-03

Results Overview

Disease-Free survival (DFS) at 2 years post-surgery. DFS is measured by the number of participants in both arms who have experienced a recurrence OR mortality at 2 years.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

709 participants

Primary outcome timeframe

2 years

Results posted on

2021-08-03

Participant Flow

Participant milestones

Participant milestones
Measure	Treatment To receive 20 mg of melatonin nightly for 1 year melatonin: 20 mg ingested nightly	Placebo To receive matched supplement to the experimental arm in same schedule placebo: similar to experimental in all ways except for lack of active ingredient
Overall Study STARTED	356	353
Overall Study COMPLETED	157	173
Overall Study NOT COMPLETED	199	180

Reasons for withdrawal

Reasons for withdrawal
Measure	Treatment To receive 20 mg of melatonin nightly for 1 year melatonin: 20 mg ingested nightly	Placebo To receive matched supplement to the experimental arm in same schedule placebo: similar to experimental in all ways except for lack of active ingredient
Overall Study Cancer Recurrence	58	58
Overall Study Withdrawal by Subject	117	100
Overall Study Lost to Follow-up	3	6
Overall Study Protocol Violation	10	12
Overall Study Death	11	4

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treatment n=356 Participants To receive 20 mg of melatonin nightly for 1 year melatonin: 20 mgs ingested nightly	Placebo n=353 Participants To receive matched supplement to the experimental arm in same schedule placebo: similar to experimental in all ways except for lack of active ingredient	Total n=709 Participants Total of all reporting groups
Age, Continuous	67.2 Years STANDARD_DEVIATION 8.5 • n=356 Participants	67.2 Years STANDARD_DEVIATION 8.6 • n=353 Participants	67.2 Years STANDARD_DEVIATION 8.5 • n=709 Participants
Sex: Female, Male Female	190 Participants n=356 Participants	208 Participants n=353 Participants	398 Participants n=709 Participants
Sex: Female, Male Male	166 Participants n=356 Participants	145 Participants n=353 Participants	311 Participants n=709 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Pre-Operative Chemotherapy or Radiation	8 Participants n=356 Participants	14 Participants n=353 Participants	22 Participants n=709 Participants
Smoking History Current Smoker	47 Participants n=356 Participants	52 Participants n=353 Participants	99 Participants n=709 Participants
Smoking History Past Smoker	279 Participants n=356 Participants	263 Participants n=353 Participants	542 Participants n=709 Participants
Smoking History Never Smoked	25 Participants n=356 Participants	31 Participants n=353 Participants	56 Participants n=709 Participants
Smoking History Unknown	5 Participants n=356 Participants	7 Participants n=353 Participants	12 Participants n=709 Participants
Histological Subtype Squamous Cell	93 Participants n=356 Participants	72 Participants n=353 Participants	165 Participants n=709 Participants
Histological Subtype Adenocarcinoma	229 Participants n=356 Participants	239 Participants n=353 Participants	468 Participants n=709 Participants
Histological Subtype Large Cell	7 Participants n=356 Participants	15 Participants n=353 Participants	22 Participants n=709 Participants
Histological Subtype Bronchoalveolar	10 Participants n=356 Participants	8 Participants n=353 Participants	18 Participants n=709 Participants
Histological Subtype Undifferentiated	2 Participants n=356 Participants	3 Participants n=353 Participants	5 Participants n=709 Participants
Histological Subtype Other	14 Participants n=356 Participants	14 Participants n=353 Participants	28 Participants n=709 Participants
Histological Subtype Non-Surgical	1 Participants n=356 Participants	2 Participants n=353 Participants	3 Participants n=709 Participants
Incision Type Minimally Invasive Surgery (MIS)	213 Participants n=356 Participants	212 Participants n=353 Participants	425 Participants n=709 Participants
Incision Type MIS Converted to Open	27 Participants n=356 Participants	19 Participants n=353 Participants	46 Participants n=709 Participants
Incision Type Open	114 Participants n=356 Participants	122 Participants n=353 Participants	236 Participants n=709 Participants
Incision Type Non-Surgical	1 Participants n=356 Participants	2 Participants n=353 Participants	3 Participants n=709 Participants
Surgery Type Pneumonectomy	16 Participants n=356 Participants	21 Participants n=353 Participants	37 Participants n=709 Participants
Surgery Type Lobectomy	290 Participants n=356 Participants	284 Participants n=353 Participants	574 Participants n=709 Participants
Surgery Type Segmentectomy	18 Participants n=356 Participants	16 Participants n=353 Participants	34 Participants n=709 Participants
Surgery Type Wedge Resection	31 Participants n=356 Participants	29 Participants n=353 Participants	60 Participants n=709 Participants
Surgery Type No Operation	1 Participants n=356 Participants	3 Participants n=353 Participants	4 Participants n=709 Participants
Pathological Cancer Stage Stage I	245 Participants n=356 Participants	217 Participants n=353 Participants	462 Participants n=709 Participants
Pathological Cancer Stage Stage II	75 Participants n=356 Participants	92 Participants n=353 Participants	167 Participants n=709 Participants
Pathological Cancer Stage Stage III	32 Participants n=356 Participants	38 Participants n=353 Participants	70 Participants n=709 Participants
Pathological Cancer Stage Stage IV	2 Participants n=356 Participants	3 Participants n=353 Participants	5 Participants n=709 Participants
Pathological Cancer Stage Non-Surgical	1 Participants n=356 Participants	2 Participants n=353 Participants	3 Participants n=709 Participants

PRIMARY outcome

Timeframe: 2 years

Population: Intention to treat - all participants analyzed.

Disease-Free survival (DFS) at 2 years post-surgery. DFS is measured by the number of participants in both arms who have experienced a recurrence OR mortality at 2 years.

Outcome measures

Outcome measures
Measure	Melatonin n=356 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=353 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Lung Cancer Recurrence or Mortality - 2 Years	80 Participants	85 Participants

SECONDARY outcome

Timeframe: 2 years

Population: Intention to Treat

Participant-reported quality of life using the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 (EORTC QLQ C-30) and Lung Cancer 13 (EORTC QLQ LC13) questionnaires. Scores represent a value from 0-100. Symptom and LC13 scale: 0 represents best health, 100 worst health. Global and functional scales: 100 represents best health, 0 represents worst health. Full scoring algorithms available here: https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf

Outcome measures

Outcome measures
Measure	Melatonin n=356 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=353 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Quality of Life Symptom Scale (Baseline)	21.4 Score on a scale of 0-100 Interval 19.1 to 23.7	20.3 Score on a scale of 0-100 Interval 18.0 to 22.6
Quality of Life Symptom Scale (1Y)	18.2 Score on a scale of 0-100 Interval 15.7 to 20.7	17.0 Score on a scale of 0-100 Interval 14.3 to 19.5
Quality of Life Symptom Scale (2Y)	17.3 Score on a scale of 0-100 Interval 14.6 to 20.0	15.8 Score on a scale of 0-100 Interval 13.2 to 18.5
Quality of Life Functional Scale (Baseline)	75.8 Score on a scale of 0-100 Interval 73.2 to 78.5	75.5 Score on a scale of 0-100 Interval 72.9 to 78.2
Quality of Life Functional Scale (1Y)	79.9 Score on a scale of 0-100 Interval 77.0 to 82.8	81.1 Score on a scale of 0-100 Interval 78.2 to 84.1
Quality of Life Functional Scale (2Y)	80.2 Score on a scale of 0-100 Interval 77.0 to 83.3	80.5 Score on a scale of 0-100 Interval 77.4 to 83.7
Quality of Life Global Scale (Baseline)	64.5 Score on a scale of 0-100 Interval 61.3 to 67.8	62.7 Score on a scale of 0-100 Interval 59.5 to 66.0
Quality of Life Global Scale (1Y)	69.6 Score on a scale of 0-100 Interval 65.9 to 73.3	71.6 Score on a scale of 0-100 Interval 67.9 to 75.3
Quality of Life Global Scale (2Y)	70.7 Score on a scale of 0-100 Interval 66.7 to 74.7	72.7 Score on a scale of 0-100 Interval 68.8 to 76.7
Quality of Life LC13 Scale (Baseline)	17.4 Score on a scale of 0-100 Interval 15.3 to 19.4	19.0 Score on a scale of 0-100 Interval 17.0 to 21.0
Quality of Life LC13 Scale (1Y)	17.8 Score on a scale of 0-100 Interval 15.5 to 20.0	18.1 Score on a scale of 0-100 Interval 15.9 to 20.4
Quality of Life LC13 Scale (2Y)	17.1 Score on a scale of 0-100 Interval 14.7 to 19.5	17.5 Score on a scale of 0-100 Interval 15.2 to 19.9

SECONDARY outcome

Timeframe: 2 years

Population: Intention to Treat

Measured using the Multidimensional Fatigue Inventory 20 (MFI-20) questionnaire. Scores are on a scale of 0-100, where 100 is the best health and 0 is the worst health.

Outcome measures

Outcome measures
Measure	Melatonin n=356 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=353 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Fatigue Baseline	59.8 Score on a scale of 0-100 Interval 56.3 to 62.9	57.0 Score on a scale of 0-100 Interval 53.8 to 60.1
Fatigue 1Y	61.4 Score on a scale of 0-100 Interval 57.9 to 64.9	62.4 Score on a scale of 0-100 Interval 58.9 to 65.9
Fatigue 2Y	62.7 Score on a scale of 0-100 Interval 59.0 to 66.5	63.1 Score on a scale of 0-100 Interval 59.4 to 66.8

SECONDARY outcome

Timeframe: 2 years

Population: Intention to Treat

Measured using the Medical Outcomes Study (MOS) Sleep Survey. Scales used were Sleep Adequacy and Sleep problems Index II. Scores are on a scale of 0-100. Sleep Adequacy: 100 represents best health; 0 represents worst health. Problems index: 0 represents best health; 100 represents worst health.

Outcome measures

Outcome measures
Measure	Melatonin n=356 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=353 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Sleep Sleep Adequacy (Baseline)	56.7 Score on a scale of 0-100 Interval 52.5 to 61.0	53.8 Score on a scale of 0-100 Interval 49.5 to 58.0
Sleep Sleep Adequacy (1Y)	60.9 Score on a scale of 0-100 Interval 56.1 to 65.7	61.5 Score on a scale of 0-100 Interval 56.7 to 66.3
Sleep Sleep Adequacy (2Y)	59.4 Score on a scale of 0-100 Interval 54.2 to 64.5	60.5 Score on a scale of 0-100 Interval 55.4 to 65.5
Sleep Sleep Problems Index II (baseline)	32.7 Score on a scale of 0-100 Interval 29.9 to 35.6	33.6 Score on a scale of 0-100 Interval 30.8 to 36.4
Sleep Sleep Problems Index II (1Y)	28.0 Score on a scale of 0-100 Interval 24.9 to 31.2	27.7 Score on a scale of 0-100 Interval 24.5 to 30.8
Sleep Sleep Problems Index II (2Y)	27.5 Score on a scale of 0-100 Interval 24.2 to 30.8	26.9 Score on a scale of 0-100 Interval 23.6 to 30.2

SECONDARY outcome

Timeframe: 3 months

Population: Only those recruited from the Ottawa Hospital were included in this analysis.

Calculated using the Brief Pain Inventory. Each scale ranges from 0-10, where 0 is no pain and 10 is the worst possible pain.

Outcome measures

Outcome measures
Measure	Melatonin n=156 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=157 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Pain Levels Baseline	2.4 Score on a scale of 0-10 Standard Deviation 2.4	2.3 Score on a scale of 0-10 Standard Deviation 2.2
Pain Levels 3 months	2.3 Score on a scale of 0-10 Standard Deviation 2.1	2.4 Score on a scale of 0-10 Standard Deviation 2.2

SECONDARY outcome

Timeframe: 2 years

Population: Only participants recruited from The Ottawa Hospital were included in the analysis.

Measured using the Beck Anxiety Inventory. Scored range from 0-63, where 0 is no anxiety and 63 is the worst possible anxiety.

Outcome measures

Outcome measures
Measure	Melatonin n=156 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=157 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Anxiety Baseline	8.2 Score on a scale of 0-63 Standard Deviation 8.5	8.3 Score on a scale of 0-63 Standard Deviation 8.4
Anxiety 2Y	6.2 Score on a scale of 0-63 Standard Deviation 6.9	6.4 Score on a scale of 0-63 Standard Deviation 7.6

SECONDARY outcome

Timeframe: 2 years

Population: Only participants recruited from The Ottawa Hospital were included in the analysis.

Measured using the Beck Depression Inventory II. Scores range from 0-63, where 0 is no depression and 63 is the worst possible depression.

Outcome measures

Outcome measures
Measure	Melatonin n=156 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=157 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Depression Baseline	8.1 Score on a scale of 0-63 Standard Deviation 7.2	8.6 Score on a scale of 0-63 Standard Deviation 8.5
Depression 2Y	6.6 Score on a scale of 0-63 Standard Deviation 5.9	7.7 Score on a scale of 0-63 Standard Deviation 8.0

SECONDARY outcome

Timeframe: 2 years

Population: Only those who received adjuvant chemotherapy were included in this analysis.

Number of participants who experienced an adverse event related to their adjuvant chemotherapy

Outcome measures

Outcome measures
Measure	Melatonin n=66 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=68 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Adverse Events (Chemotherapy)	44 Participants	48 Participants

SECONDARY outcome

Timeframe: up to 5 years

Population: Intention to treat - all participants analyzed.

Measured as disease-free survival (DFS) at 5 years. DFS was measured by the incidence of a recurrence OR mortality up to 5 years post-surgery.

Outcome measures

Outcome measures
Measure	Melatonin n=356 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=353 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Lung Cancer Recurrence or Mortality - 5 Years All participants	133 Participants	130 Participants
Lung Cancer Recurrence or Mortality - 5 Years Early Stage Cancer	109 Participants	99 Participants
Lung Cancer Recurrence or Mortality - 5 Years Late Stage Cancer	23 Participants	31 Participants

SECONDARY outcome

Timeframe: 6 months

Population: Participants who qualified for the sub-study only.

NK cell cytotoxicity changes from baseline to 6 months

Outcome measures

Outcome measures
Measure	Melatonin n=35 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=37 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Blood Tests to Examine the Effects of Melatonin on the Immune System (Raw Values) Cytotoxicity (baseline)	49.8 Percent killing of K62 cells Standard Error 3.6	42.7 Percent killing of K62 cells Standard Error 3.3
Blood Tests to Examine the Effects of Melatonin on the Immune System (Raw Values) Cytotoxicity (6 months)	49.2 Percent killing of K62 cells Standard Error 3.0	46.4 Percent killing of K62 cells Standard Error 3.8

SECONDARY outcome

Timeframe: 2 years

Population: Only those who received adjuvant radiation were included in this analysis.

Number of participants who experienced an adverse event related to their adjuvant radiation therapy

Outcome measures

Outcome measures
Measure	Melatonin n=22 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=21 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Adverse Events (Radiation)	8 Participants	5 Participants

SECONDARY outcome

Timeframe: 6 months

Population: Only those who were enrolled in the sub study and qualified for analysis were included.

Differences in NK cell cytotoxicity between both arms

Outcome measures

Outcome measures
Measure	Melatonin n=35 Participants To receive 20 mg of melatonin nightly for 1 year following surgery.	Placebo n=37 Participants To receive 20 mg placebo nightly for 1 year following surgery placebo: similar to experimental in all ways except for lack of active ingredient
Blood Tests to Examine the Effects of Melatonin on the Immune System (Comparison Between Groups)	1.1 Ratio of percent cytotoxicity Interval 0.97 to 1.23	1.16 Ratio of percent cytotoxicity Interval 0.96 to 1.37

Adverse Events

Melatonin

Serious events: 84 serious events

Other events: 184 other events

Deaths: 95 deaths

Placebo

Serious events: 89 serious events

Other events: 166 other events

Deaths: 91 deaths

Serious adverse events

Other adverse events

Additional Information

Mark Legacy, Clinical Trial Coordinator

The Centre for Health Innovation

Phone: 613-792-1222

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Melatonin n=356 participants at risk To receive 20 mg of melatonin nightly for 1 year post-surgery	Placebo n=353 participants at risk To receive 20 mg placebo nightly for 1 year post-surgery placebo: similar to experimental in all ways except for lack of active ingredient
Injury, poisoning and procedural complications Osteophyte fracture	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Hypercalcemia	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Neutropenia	0.84% 3/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.57% 2/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Angina	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Aortic Valve Replacement	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Apical thrombosis	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Atrial Fibrillation	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Myocardial infarction	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders NSTEMI	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.57% 2/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Pericardial Effusion	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders STEMI	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Eye disorders Left para-opthalmic aneurysm	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Eye disorders Retinal Tear	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Gastrointestinal disorders Adbominal Abcess	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Gastrointestinal disorders Cholecystitis	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Gastrointestinal disorders Diarrhea	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Gastrointestinal disorders Gall bladder removal	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Gastrointestinal disorders Lower GI Bleeding	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Gastrointestinal disorders Pancreatitis	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Gastrointestinal disorders Perforated Bowel	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Gastrointestinal disorders SBO	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Gastrointestinal disorders Upper GI bleeding	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
General disorders Dehydration	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
General disorders Fatigue	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Infections and infestations Chest Infection	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Infections and infestations Fever	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Infections and infestations Sepsis	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Back pain	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Back sprain	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Broken elbow	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Discitis	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Hip replacement surgery	0.56% 2/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Left above-knee amputation	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Left total knee arthroplasty	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Patella and fibular fracture	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Shoulder Replacement Surgery	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Toe Amputation	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Injury, poisoning and procedural complications Weakness	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder Cancer Recurrence	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Other adverse events
Measure	Melatonin n=356 participants at risk To receive 20 mg of melatonin nightly for 1 year post-surgery	Placebo n=353 participants at risk To receive 20 mg placebo nightly for 1 year post-surgery placebo: similar to experimental in all ways except for lack of active ingredient
Nervous system disorders Syncope	1.1% 4/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Nervous system disorders Vertigo	0.84% 3/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.57% 2/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Nervous system disorders Vivid Dreams	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.85% 3/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Psychiatric disorders Anorexia	0.84% 3/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	2.0% 7/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Psychiatric disorders Anxiety	0.56% 2/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.57% 2/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Psychiatric disorders Depression	1.1% 4/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	1.4% 5/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Psychiatric disorders Hallucinations	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Psychiatric disorders Insomnia	11.0% 39/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	10.2% 36/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Renal and urinary disorders Anal fissures	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Renal and urinary disorders burning sensation when urinating	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Renal and urinary disorders Difficulty Urinating	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Anemia	0.56% 2/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.85% 3/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Blood/bone marrow - Other (myelotoxicity)	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Elevated ALT	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders ELevated AST	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Elevated creatinine levels	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Elevated TNI	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Hyperglycemia	0.56% 2/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Hypokalemia	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	1.1% 4/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Leukopenia	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Neutropenia	3.4% 12/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	2.0% 7/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Blood and lymphatic system disorders Thrombic event	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Angina	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.57% 2/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Atrial Arrhythmia	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.57% 2/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Atrial fibrillation	1.1% 4/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Cardiac - Intra-Op Bleeding	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Cardiac Embolism	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Coronary Artery Calcification	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Heart Palpitations	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Hypertension	0.56% 2/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Hypotension	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.57% 2/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Syncope	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Tachycardia	1.4% 5/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Cardiac disorders Thoracic Aortic Calcification	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Ear and labyrinth disorders Hearing loss	0.84% 3/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Ear and labyrinth disorders Hot swollen ears	0.00% 0/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Ear and labyrinth disorders ruptured eardrum	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Ear and labyrinth disorders Tinnitus	1.1% 4/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	2.0% 7/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Endocrine disorders Hyperthyroidism	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.00% 0/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Eye disorders Blurred Vision	0.28% 1/356 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.	0.28% 1/353 • 2 Years An adverse event is any untoward medical occurrence in a patient administered a medicinal product which does not necessarily have to have a causal relationship with this treatment. A serious adverse event is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or results in prolonging of existing hospitalization, results in a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.