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Clinical Trial Results:
Evaluation of Insuman Implantable 400 IU/ml in Patients with Type 1 Diabetes Treated with the Medtronic MiniMed Implantable Pump System Using Insuplant 400 IU/mL

Summary
EudraCT number	2010-021373-37
Trial protocol	FR NL SE BE
Global end of trial date	01 Feb 2018

Results information
Results version number	v1(current)
This version publication date	14 Feb 2019
First version publication date	14 Feb 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

HUBIN_L_05335

ISRCTN number

US NCT number

NCT01194882

WHO universal trial number (UTN)

U1111-1116-7658

Other trial identifiers

STUDY NAME: HUBIN

Sponsor organisation name

Sanofi aventis recherche & développement

Sponsor organisation address

1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

21 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Feb 2018

Was the trial ended prematurely?

Main objective of the trial

To compare Insuman Implantable 400 International Units (IU)/ml versus Insuplant 400 IU/ml with respect to the pump refill accuracy during a 4 refill cycle period (comparative phase = 160±20 days); To assess efficacy measured by haemoglobin glycosylated (HBA1c) change in Insuman Implantable 400 IU/ml group versus Insuplant 400 IU/ml group after a 4 refill cycle period (comparative phase = 160±20 days).

Protection of trial subjects

Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Nov 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 75

Country: Number of subjects enrolled

Sweden: 29

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

France: 365

Worldwide total number of subjects

472

EEA total number of subjects

472

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

403

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 17 sites in 4 countries between 16 November 2010 and 01 February 2018. A total of 472 subjects were included in study which consisted of 3 phases: comparative phase, non-comparative phase and treatment phase with Insuman Implantable.

Screening details

Of 472 subjects, 169 subjects were randomized in 1:1 ratio (Insuman Implantable : Insuplant) in comparative phase & 307 were included in non-comparative and treatment phase with Insuman Implantable. i.e. out of the included subjects, two-third subjects participated in two phases and one-third participated only in the Insuman non-comparative phase.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

All Subjects

Arm description

Subjects earlier treated with Insuplant 400 International Units Per Millilitre (IU/mL) were included in the study and received Insuman Implantable 400 IU/mL or Insuplant IU/mL for 4 refill cycles in comparative phase and Insuplant 400 IU/mL for 4 refill cycles as per standard care in non-comparative phase. Comparative phase was followed by a treatment phase with only Insuman Implantable 400 IU/mL until its availability on the market. Each pump refill cycle was 40±5 days.

Arm type

Experimental

Investigational medicinal product name

Insuman Implantable

Investigational medicinal product code

Other name

Human insulin (rapid acting)

Pharmaceutical forms

Solution for infusion

Routes of administration

Intraperitoneal use

Dosage and administration details

The glucose targets and insulin dose were established by the Investigator on a subject basis and as per American Diabetes Association guidelines. Treatments was administered by Continuous IntraPeritoneal Insulin Infusion (CIPII) through an implantable pump system.

Investigational medicinal product name

Insuplant

Investigational medicinal product code

Other name

Human insulin semi synthetic porcine derived

Pharmaceutical forms

Solution for infusion

Routes of administration

Intraperitoneal use

Dosage and administration details

Number of subjects in period 1	All Subjects
Started	472
Completed	356
Not completed	116
Other than specified above	26
Consent withdrawn by subject	18
Adverse Event	65
Lost to follow-up	1
Lack of efficacy	6

Baseline characteristics

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Reporting group title

All Subjects

Reporting group description

Reporting group values	All Subjects	Total
Number of subjects	472	472
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	50.18 ( 12.82 )	-
Gender categorical
Units: Subjects
Female	298	298
Male	174	174
Baseline HbA1c
Data for baseline HbA1c is reported for 365 subjects.
Units: Percentage of HbA1c
arithmetic mean (standard deviation)	7.96 ( 1.28 )	-
Actual Baseline Insulin Dose
Data for actual baseline insulin dose is reported for 223 subjects.
Units: IU/day
arithmetic mean (standard deviation)	49.90 ( 25.96 )	-

End points

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Reporting group title

All Subjects

Reporting group description

Subject analysis set title

Insuman (Comparative Phase)

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received Insuman Implantable 400 IU/mL for 4 refill cycles i.e. 6 Months by continuous intraperitoneal insulin infusion through an implantable pump system.

Subject analysis set title

Insuplant (Comparative Phase)

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received Insuplant 400 IU/mL for 4 refill cycles i.e. 6 Months by continuous intraperitoneal insulin infusion through an implantable pump system.

Subject analysis set title

Insuplant Phase

Subject analysis set type

Per protocol

Subject analysis set description

Subjects (who were not included in comparative phase) received Insuplant 400 IU/mL for 4 refill cycles as per standard care by continuous intraperitoneal insulin infusion through an implantable pump system.

Subject analysis set title

Insuman Phase

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received Insuman 400 IU/mL for 4 refill cycles as per standard care by continuous intraperitoneal insulin infusion through an implantable pump system and avoided pump ex-plantation.

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Modified Intent to Treat (mITT) Population

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End point title

Percentage Refill Accuracy After 4 Refill Cycles: Modified Intent to Treat (mITT) Population

End point description

Refill accuracy was calculated as a percentage difference between the theoretical refill volume calculated by the personal pump communicator (PPC) using programmed values and the actual refill volume used by weight measurement after 4 refill cycles. Analysis was performed on mITT population for refill accuracy. mITT population included subjects who had given their informed consent, for whom there was confirmation of successful allocation of a randomization number through the study treatment allocation system, and who received at least one administration of the study drug and had an evaluation for each primary outcome. Subjects who had no available or no valid post-baseline refill value were excluded from the mITT population for refill accuracy.

End point type

Primary

End point timeframe

From baseline up to refill cycle 4 (i.e. Month 6)

End point values	Insuman (Comparative Phase)	Insuplant (Comparative Phase)
Number of subjects analysed	66	64
Units: percentage accuracy
arithmetic mean (standard deviation)	0.06 ( 8.00 )	2.82 ( 5.91 )

Comparative Phase: Insuman vs Insuplant

Statistical analysis description

Analysis was performed using Analysis of variance (ANOVA) method.

Comparison groups

Insuman (Comparative Phase) v Insuplant (Comparative Phase)

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

= 0.0273

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

-2.76

Confidence interval

level

95%

sides

2-sided

lower limit

-5.21

upper limit

-0.31

Variability estimate

Standard error of the mean

Dispersion value

1.24

Notes
[1] - Non-inferiority of Insuman Implantable over Insuplant was demonstrated if upper limit of 2-sided 95% confidence interval (CI) of the intergroup difference was <5%.

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Per Protocol (PP) Population

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End point title

Percentage Refill Accuracy After 4 Refill Cycles: Per Protocol (PP) Population

End point description

Refill accuracy was calculated as a percentage difference between the theoretical refill volume calculated by the PPC using programmed values and the actual refill volume used by weight measurement after 4 refill cycles. Analysis was performed on PP population for refill accuracy. PP population was a subset of mITT population without major protocol violations for each primary parameter.

End point type

Primary

End point timeframe

From baseline up to refill cycle 4 (i.e. Month 6)

End point values	Insuman (Comparative Phase)	Insuplant (Comparative Phase)
Number of subjects analysed	62	56
Units: percentage accuracy
arithmetic mean (standard deviation)	-0.08 ( 8.14 )	3.07 ( 6.17 )

Comparative Phase: Insuman vs Insuplant

Statistical analysis description

Analysis was performed using ANOVA method.

Comparison groups

Insuman (Comparative Phase) v Insuplant (Comparative Phase)

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

P-value

= 0.0205

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

-3.15

Confidence interval

level

95%

sides

2-sided

lower limit

-5.81

upper limit

-0.5

Variability estimate

Standard error of the mean

Dispersion value

1.34

Notes
[2] - Non-inferiority of Insuman Implantable over Insuplant was demonstrated if upper limit of 2-sided 95% confidence interval (CI) of the intergroup difference was <5%.

Primary: Change From Baseline in HbA1c to Month 6: mITT Population

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End point title

Change From Baseline in HbA1c to Month 6: mITT Population

End point description

Change in HbA1c was calculated by subtracting baseline value from Month 6 value. Analysis was performed on mITT population for HbA1c.

End point type

Primary

End point timeframe

Baseline, Month 6

End point values	Insuman (Comparative Phase)	Insuplant (Comparative Phase)
Number of subjects analysed	84	84
Units: percentage of HbA1c
arithmetic mean (standard deviation)	-0.27 ( 0.70 )	-0.20 ( 0.79 )

Comparative Phase: Insuman vs Insuplant

Statistical analysis description

Analysis was performed using ANOVA method.

Comparison groups

Insuplant (Comparative Phase) v Insuman (Comparative Phase)

Number of subjects included in analysis

168

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

= 0.543

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

0.16

Variability estimate

Standard error of the mean

Dispersion value

0.12

Notes
[3] - Non-inferiority of Insuman Implantable over Insuplant was demonstrated if upper limit of 2-sided 95% CI of the inter group difference was 0.4%.

Primary: Change From Baseline in HbA1c to Month 6: PP Population

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End point title

Change From Baseline in HbA1c to Month 6: PP Population

End point description

Change in HbA1c was calculated by subtracting baseline value from Month 6 value. Analysis was performed on PP population for HbA1c.

End point type

Primary

End point timeframe

Baseline, Month 6

End point values	Insuman (Comparative Phase)	Insuplant (Comparative Phase)
Number of subjects analysed	75	69
Units: percentage of HbA1c
arithmetic mean (standard deviation)	-0.25 ( 0.67 )	-0.12 ( 0.74 )

Comparative Phase: Insuman vs Insuplant

Statistical analysis description

Analysis was performed using ANOVA method.

Comparison groups

Insuman (Comparative Phase) v Insuplant (Comparative Phase)

Number of subjects included in analysis

144

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

P-value

= 0.2808

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.12

Notes
[4] - Non-inferiority of Insuman Implantable over Insuplant was demonstrated if upper limit of 2-sided 95% CI of the inter group difference was 0.4%.

Secondary: Actual Daily Insulin Dose at Month 6: mITT Population

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End point title

Actual Daily Insulin Dose at Month 6: mITT Population

End point description

Actual daily insulin doses were calculated at each refill from actual amount used after conversion in International Units (IU), and reported to the time between the refill and the previous refill in days. Analysis was performed on mITT population for HbA1c. Here "number analyzed" signifies number of subjects with available data for this end point.

End point type

Secondary

End point timeframe

Month 6

End point values	Insuman (Comparative Phase)	Insuplant (Comparative Phase)
Number of subjects analysed	61	61
Units: IU/day
arithmetic mean (standard deviation)	56.72 ( 23.16 )	54.30 ( 22.86 )

No statistical analyses for this end point

Secondary: Actual Daily Insulin Dose at Month 6: PP Population

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End point title

Actual Daily Insulin Dose at Month 6: PP Population

End point description

Actual daily insulin doses were calculated at each refill from actual amount used after conversion in IU, and reported to the time between the refill and the previous refill in days. Analysis was performed on PP population for HbA1c. Here "number analyzed" signifies number of subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Month 6

End point values	Insuman (Comparative Phase)	Insuplant (Comparative Phase)
Number of subjects analysed	57	53
Units: IU/day
arithmetic mean (standard deviation)	56.24 ( 21.57 )	55.80 ( 23.68 )

No statistical analyses for this end point

Secondary: Number of Subjects With At Least One Severe Hypoglycemic Events

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End point title

Number of Subjects With At Least One Severe Hypoglycemic Events

End point description

Severe hypoglycemia was an event in which the subject required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Diurnal (day-time) hypoglycaemia occurring during the waking period and nocturnal hypoglycaemia, which occurred while the subject was asleep, after bedtime and before getting up in the morning. Analysis was performed on safety population composed of all randomized subjects exposed to the study drug, i.e. who received at least one administration of the study drug.

End point type

Secondary

End point timeframe

From Baseline up to Month 6

End point values	Insuman (Comparative Phase)	Insuplant (Comparative Phase)
Number of subjects analysed	84	84
Units: subjects
number (not applicable)
At least one severe hypoglycaemia	12	11
At least one nocturnal severe hypoglycaemia	1	3
At least one diurnal severe hypoglycaemia	10	8

No statistical analyses for this end point

Secondary: Number of Subjects With At Least One Hyperglycemia With Ketonemia

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End point title

Number of Subjects With At Least One Hyperglycemia With Ketonemia

End point description

Hyperglycaemia is defined as blood glucose value above 300 mg/dL (16.7 mmol/L) with no apparent medical, dietary or insulin dosage reason. Subjects with at least one hyperglycaemia with ketonemia and ketonemia > 0.5 mmol/l were reported. Analysis was performed on safety population.

End point type

Secondary

End point timeframe

From Baseline up to Month 6

End point values	Insuman (Comparative Phase)	Insuplant (Comparative Phase)
Number of subjects analysed	84	84
Units: subjects
number (not applicable)
At least one hyperglycaemia with ketonemia	13	15
At least 1 hyperglycaemia with ketonemia>0.5mmol/l	2	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All Adverse Events (AEs) were collected from signature of informed consent form until the end of the study i.e. end of Insuman non comparative phase (maximum treatment exposure: 6.6 years) regardless of seriousness/relationship to investigational product.

Adverse event reporting additional description

Reported AEs & deaths are treatment-emergent AEs that is AEs that developed/worsened & deaths occurred during ‘on treatment period’ (time interval between first Insuman administration & 10 days after last study drug administration).Safety population. 3 subjects from comparative phase(1 from Insuman & 2 from Insuplant) were not included in analysis.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Insuman comparative phase

Reporting group description

Subjects received Insuman Implantable 400 IU/mL for 4 refill cycles i.e. 6 Months by continuous intraperitoneal insulin infusion through an implantable pump system (Medtronic Minimed implantable pump). Out of 84 subjects, 1 subject was not included in safety population.

Reporting group title

Insuplant comparative phase

Reporting group description

Subjects received Insuplant 400 IU/mL for 4 refill cycles i.e. 6 Months by continuous intraperitoneal insulin infusion through an implantable pump system (Medtronic Minimed implantable pump). Out of 84 subjects, 2 subjects were not included in safety population.

Reporting group title

Insuplant phase

Reporting group description

Subjects who were not included in comparative phase, received Insuplant 400 IU/mL for 4 refill cycles as per standard care by continuous intraperitoneal insulin infusion through an implantable pump system (Medtronic Minimed implantable pump).

Reporting group title

Insuman phase

Reporting group description

Subjects received Insuman 400 IU/mL for 4 refill cycles as per standard care by continuous intraperitoneal insulin infusion through an implantable pump system (Medtronic Minimed implantable pump) and avoided pump ex-plantation.

Serious adverse events	Insuman comparative phase	Insuplant comparative phase	Insuplant phase	Insuman phase
Total subjects affected by serious adverse events
subjects affected / exposed	64 / 83 (77.11%)	61 / 82 (74.39%)	113 / 159 (71.07%)	101 / 148 (68.24%)
number of deaths (all causes)	1	2	3	5
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder Cancer
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast Cancer
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	3 / 159 (1.89%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast Neoplasm
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hodgkin's Disease Lymphocyte Depletion Type Stage Iii
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Adenocarcinoma
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic Gastric Cancer
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Prostate Cancer
subjects affected / exposed	2 / 83 (2.41%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal Cancer
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous Cell Carcinoma
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Adventitial Cystic Disease
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arterial Disorder
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arterial Insufficiency
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arterial Occlusive Disease
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arteritis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolism Venous
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intermittent Claudication
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic Hypotension
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Arterial Occlusive Disease
subjects affected / exposed	1 / 83 (1.20%)	1 / 82 (1.22%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Artery Occlusion
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Artery Stenosis
subjects affected / exposed	2 / 83 (2.41%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Ischaemia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superior Vena Cava Stenosis
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Arterial Therapeutic Procedure
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast Prosthesis Implantation
subjects affected / exposed	1 / 83 (1.20%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Caesarean Section
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cataract Operation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystectomy
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary Angioplasty
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary Artery Bypass
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary Revascularisation
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cyst Removal
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Finger Repair Operation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric Bypass
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hospitalisation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hysterectomy
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leg Amputation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mammoplasty
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Change
subjects affected / exposed	3 / 83 (3.61%)	7 / 82 (8.54%)	11 / 159 (6.92%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	3 / 4	8 / 8	10 / 11	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Implantation
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Removal
subjects affected / exposed	1 / 83 (1.20%)	3 / 82 (3.66%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 1	3 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Cystectomy
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreas Transplant
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Percutaneous Coronary Intervention
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Nerve Operation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Revascularisation
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostatic Operation
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal Sympathetic Nerve Ablation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal Transplant
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal Operation
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rotator Cuff Repair
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus Operation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stent Placement
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical Vascular Shunt
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tendon Operation
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toe Amputation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transplant
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Delivery
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Live Birth
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pre-Eclampsia
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	5 / 148 (3.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Unintended Pregnancy
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Catheter Site Pain
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest Pain
subjects affected / exposed	1 / 83 (1.20%)	1 / 82 (1.22%)	1 / 159 (0.63%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General Physical Health Deterioration
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised Oedema
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Granuloma
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired Healing
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	2 / 83 (2.41%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Site Atrophy
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Site Erosion
subjects affected / exposed	2 / 83 (2.41%)	1 / 82 (1.22%)	1 / 159 (0.63%)	3 / 148 (2.03%)
occurrences causally related to treatment / all	2 / 2	2 / 2	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Site Erythema
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Site Haemorrhage
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	3 / 148 (2.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Site Inflammation
subjects affected / exposed	3 / 83 (3.61%)	1 / 82 (1.22%)	1 / 159 (0.63%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	3 / 3	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Site Pain
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	1 / 159 (0.63%)	11 / 148 (7.43%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	10 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema Due To Cardiac Disease
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema Peripheral
subjects affected / exposed	2 / 83 (2.41%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prolapse
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden Death
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Swelling
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Amyloidosis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic Shock
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug Hypersensitivity
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Insulin Autoimmune Syndrome
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Breast Enlargement
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Genital Prolapse
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic Ovarian Cyst
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Menometrorrhagia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Cyst
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine Polyp
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic Obstructive Pulmonary Disease
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea Exertional
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal Pain
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pulmonary Oedema
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sleep Apnoea Syndrome
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	3 / 83 (3.61%)	0 / 82 (0.00%)	2 / 159 (1.26%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Major Depression
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mania
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric Decompensation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sleep Disorder
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal Ideation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide Attempt
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood Glucose Fluctuation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood Glucose Increased
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiovascular Evaluation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Heart Rate Increased
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laparoscopy
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Observation
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Weight Increased
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Abdominal Wall Wound
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Accidental Exposure To Product
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Accidental Overdose
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acetabulum Fracture
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Animal Bite
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ankle Fracture
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle Fracture
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Complications Of Transplanted Pancreas
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electric Shock
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	3 / 159 (1.89%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femoral Neck Fracture
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur Fracture
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	3 / 159 (1.89%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot Fracture
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus Fracture
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint Dislocation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament Sprain
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Limb Injury
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	3 / 148 (2.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Lower Limb Fracture
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural Nausea
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pubis Fracture
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road Traffic Accident
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scapula Fracture
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scar
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin Injury
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid Haemorrhage
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural Haematoma
subjects affected / exposed	1 / 83 (1.20%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Thoracic Vertebral Fracture
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tibia Fracture
subjects affected / exposed	1 / 83 (1.20%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ulna Fracture
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper Limb Fracture
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vth Nerve Injury
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound Dehiscence
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wrist Fracture
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute Coronary Syndrome
subjects affected / exposed	2 / 83 (2.41%)	1 / 82 (1.22%)	2 / 159 (1.26%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina Pectoris
subjects affected / exposed	2 / 83 (2.41%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic Valve Stenosis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial Fibrillation
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cardiac Arrest
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Cardiac Disorder
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac Failure
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiovascular Disorder
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary Artery Disease
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary Artery Stenosis
subjects affected / exposed	2 / 83 (2.41%)	1 / 82 (1.22%)	3 / 159 (1.89%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic Cardiomyopathy
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial Infarction
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Myocardial Ischaemia
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Balance Disorder
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carotid Artery Stenosis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carpal Tunnel Syndrome
subjects affected / exposed	1 / 83 (1.20%)	1 / 82 (1.22%)	3 / 159 (1.89%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular Accident
subjects affected / exposed	1 / 83 (1.20%)	2 / 82 (2.44%)	3 / 159 (1.89%)	5 / 148 (3.38%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Extrapyramidal Disorder
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemic Coma
subjects affected / exposed	8 / 83 (9.64%)	5 / 82 (6.10%)	8 / 159 (5.03%)	6 / 148 (4.05%)
occurrences causally related to treatment / all	6 / 26	1 / 6	4 / 13	3 / 13
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Hypoglycaemic Seizure
subjects affected / exposed	3 / 83 (3.61%)	2 / 82 (2.44%)	2 / 159 (1.26%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	1 / 5	2 / 2	1 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemic Unconsciousness
subjects affected / exposed	6 / 83 (7.23%)	2 / 82 (2.44%)	13 / 159 (8.18%)	6 / 148 (4.05%)
occurrences causally related to treatment / all	1 / 17	1 / 2	5 / 19	3 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lacunar Stroke
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Loss Of Consciousness
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nerve Compression
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	1 / 159 (0.63%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient Ischaemic Attack
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Microcytic Anaemia
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pernicious Anaemia
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Meniere's Disease
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otosclerosis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 83 (0.00%)	3 / 82 (3.66%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	3 / 83 (3.61%)	3 / 82 (3.66%)	2 / 159 (1.26%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic Retinopathy
subjects affected / exposed	1 / 83 (1.20%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal Aneurysm
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal Detachment
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal Haemorrhage
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal Vein Occlusion
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vitreous Haemorrhage
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Discomfort
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Hernia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain
subjects affected / exposed	1 / 83 (1.20%)	1 / 82 (1.22%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 1	2 / 2	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain Upper
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal Haemorrhage
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired Gastric Emptying
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal Hernia
subjects affected / exposed	2 / 83 (2.41%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Obstruction
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Prolapse
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intra-Abdominal Haematoma
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mesenteric Artery Thrombosis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	3 / 148 (2.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 14
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic Cyst
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal Prolapse
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical Hernia
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	4 / 159 (2.52%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	9 / 148 (6.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis Acute
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug-Induced Liver Injury
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Mass
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Decubitus Ulcer
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic Foot
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eczema
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hidradenitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin Erosion
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin Lesion
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin Ulcer
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder Irritation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic Nephropathy
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
End Stage Renal Disease
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incontinence
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal Colic
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal Failure
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	3 / 159 (1.89%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Renal Impairment
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Bladder Polyp
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Incontinence
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Thyroid Mass
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthropathy
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back Pain
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diastasis Recti Abdominis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot Deformity
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral Disc Disorder
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral Disc Protrusion
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar Spinal Stenosis
subjects affected / exposed	0 / 83 (0.00%)	2 / 82 (2.44%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal Pain
subjects affected / exposed	1 / 83 (1.20%)	2 / 82 (2.44%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis Of Jaw
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain In Extremity
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periarthritis
subjects affected / exposed	2 / 83 (2.41%)	1 / 82 (1.22%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid Arthritis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Osteoarthritis
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Synovial Cyst
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tendon Disorder
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tenosynovitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	2 / 159 (1.26%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Trigger Finger
subjects affected / exposed	3 / 83 (3.61%)	2 / 82 (2.44%)	5 / 159 (3.14%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal Wall Abscess
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal Abscess
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 83 (2.41%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Catheter Site Infection
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device Related Infection
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic Foot Infection
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis Staphylococcal
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	5 / 148 (3.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis Norovirus
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis Viral
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes Zoster
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infected Skin Ulcer
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Localised Infection
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung Abscess
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Site Infection
subjects affected / exposed	12 / 83 (14.46%)	5 / 82 (6.10%)	5 / 159 (3.14%)	11 / 148 (7.43%)
occurrences causally related to treatment / all	8 / 12	2 / 5	3 / 5	9 / 13
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post Procedural Infection
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelitis
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 83 (0.00%)	2 / 82 (2.44%)	2 / 159 (1.26%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Tract Infection
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	3 / 159 (1.89%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	2 / 148 (1.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral Infection
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Acetonaemia
subjects affected / exposed	6 / 83 (7.23%)	9 / 82 (10.98%)	9 / 159 (5.66%)	5 / 148 (3.38%)
occurrences causally related to treatment / all	5 / 8	8 / 10	9 / 11	3 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes Mellitus Inadequate Control
subjects affected / exposed	5 / 83 (6.02%)	7 / 82 (8.54%)	10 / 159 (6.29%)	18 / 148 (12.16%)
occurrences causally related to treatment / all	4 / 7	4 / 7	3 / 13	18 / 25
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic Ketoacidosis
subjects affected / exposed	1 / 83 (1.20%)	1 / 82 (1.22%)	6 / 159 (3.77%)	5 / 148 (3.38%)
occurrences causally related to treatment / all	0 / 1	1 / 2	6 / 7	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic Ketosis
subjects affected / exposed	0 / 83 (0.00%)	1 / 82 (1.22%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	9 / 83 (10.84%)	11 / 82 (13.41%)	19 / 159 (11.95%)	20 / 148 (13.51%)
occurrences causally related to treatment / all	6 / 10	10 / 11	19 / 26	24 / 30
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	13 / 83 (15.66%)	3 / 82 (3.66%)	9 / 159 (5.66%)	18 / 148 (12.16%)
occurrences causally related to treatment / all	3 / 13	1 / 3	7 / 16	6 / 26
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ketosis
subjects affected / exposed	1 / 83 (1.20%)	3 / 82 (3.66%)	4 / 159 (2.52%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 1	2 / 5	3 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	1 / 159 (0.63%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Overweight
subjects affected / exposed	1 / 83 (1.20%)	0 / 82 (0.00%)	0 / 159 (0.00%)	0 / 148 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Weight Fluctuation
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	0 / 159 (0.00%)	1 / 148 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Insuman comparative phase	Insuplant comparative phase	Insuplant phase	Insuman phase
Total subjects affected by non serious adverse events
subjects affected / exposed	74 / 83 (89.16%)	66 / 82 (80.49%)	130 / 159 (81.76%)	101 / 148 (68.24%)
Vascular disorders
Hypertension
subjects affected / exposed	4 / 83 (4.82%)	5 / 82 (6.10%)	4 / 159 (2.52%)	9 / 148 (6.08%)
occurrences all number	4	5	4	9
Lymphocele
subjects affected / exposed	0 / 83 (0.00%)	3 / 82 (3.66%)	8 / 159 (5.03%)	6 / 148 (4.05%)
occurrences all number	0	3	8	7
Surgical and medical procedures
Cataract Operation
subjects affected / exposed	2 / 83 (2.41%)	7 / 82 (8.54%)	1 / 159 (0.63%)	1 / 148 (0.68%)
occurrences all number	3	7	1	1
Nervous system disorders
Headache
subjects affected / exposed	6 / 83 (7.23%)	8 / 82 (9.76%)	10 / 159 (6.29%)	9 / 148 (6.08%)
occurrences all number	7	11	15	11
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 83 (0.00%)	0 / 82 (0.00%)	4 / 159 (2.52%)	8 / 148 (5.41%)
occurrences all number	0	0	4	8
Influenza Like Illness
subjects affected / exposed	4 / 83 (4.82%)	1 / 82 (1.22%)	5 / 159 (3.14%)	11 / 148 (7.43%)
occurrences all number	4	1	5	14
Medical Device Site Pain
subjects affected / exposed	1 / 83 (1.20%)	2 / 82 (2.44%)	7 / 159 (4.40%)	14 / 148 (9.46%)
occurrences all number	1	2	7	14
Oedema Peripheral
subjects affected / exposed	0 / 83 (0.00%)	5 / 82 (6.10%)	3 / 159 (1.89%)	5 / 148 (3.38%)
occurrences all number	0	7	4	5
Pyrexia
subjects affected / exposed	3 / 83 (3.61%)	0 / 82 (0.00%)	3 / 159 (1.89%)	8 / 148 (5.41%)
occurrences all number	3	0	3	9
Eye disorders
Macular Oedema
subjects affected / exposed	5 / 83 (6.02%)	3 / 82 (3.66%)	3 / 159 (1.89%)	1 / 148 (0.68%)
occurrences all number	5	5	3	1
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	5 / 83 (6.02%)	3 / 82 (3.66%)	14 / 159 (8.81%)	16 / 148 (10.81%)
occurrences all number	6	3	17	18
Diarrhoea
subjects affected / exposed	3 / 83 (3.61%)	3 / 82 (3.66%)	8 / 159 (5.03%)	12 / 148 (8.11%)
occurrences all number	4	4	8	12
Gastrointestinal Disorder
subjects affected / exposed	4 / 83 (4.82%)	1 / 82 (1.22%)	8 / 159 (5.03%)	0 / 148 (0.00%)
occurrences all number	5	1	8	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 83 (1.20%)	4 / 82 (4.88%)	11 / 159 (6.92%)	7 / 148 (4.73%)
occurrences all number	1	4	12	10
Oropharyngeal Pain
subjects affected / exposed	4 / 83 (4.82%)	1 / 82 (1.22%)	8 / 159 (5.03%)	2 / 148 (1.35%)
occurrences all number	4	1	16	2
Psychiatric disorders
Depression
subjects affected / exposed	10 / 83 (12.05%)	2 / 82 (2.44%)	7 / 159 (4.40%)	2 / 148 (1.35%)
occurrences all number	10	2	7	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 83 (13.25%)	4 / 82 (4.88%)	8 / 159 (5.03%)	5 / 148 (3.38%)
occurrences all number	11	4	10	5
Back Pain
subjects affected / exposed	12 / 83 (14.46%)	7 / 82 (8.54%)	8 / 159 (5.03%)	9 / 148 (6.08%)
occurrences all number	19	8	11	9
Musculoskeletal Pain
subjects affected / exposed	5 / 83 (6.02%)	3 / 82 (3.66%)	8 / 159 (5.03%)	4 / 148 (2.70%)
occurrences all number	5	3	9	5
Pain In Extremity
subjects affected / exposed	6 / 83 (7.23%)	3 / 82 (3.66%)	11 / 159 (6.92%)	7 / 148 (4.73%)
occurrences all number	6	3	12	8
Tendonitis
subjects affected / exposed	8 / 83 (9.64%)	6 / 82 (7.32%)	9 / 159 (5.66%)	5 / 148 (3.38%)
occurrences all number	8	6	10	5
Infections and infestations
Bronchitis
subjects affected / exposed	24 / 83 (28.92%)	20 / 82 (24.39%)	27 / 159 (16.98%)	13 / 148 (8.78%)
occurrences all number	36	35	38	15
Cystitis
subjects affected / exposed	4 / 83 (4.82%)	2 / 82 (2.44%)	14 / 159 (8.81%)	9 / 148 (6.08%)
occurrences all number	5	5	15	13
Ear Infection
subjects affected / exposed	5 / 83 (6.02%)	3 / 82 (3.66%)	7 / 159 (4.40%)	3 / 148 (2.03%)
occurrences all number	5	3	9	3
Gastroenteritis
subjects affected / exposed	10 / 83 (12.05%)	9 / 82 (10.98%)	15 / 159 (9.43%)	10 / 148 (6.76%)
occurrences all number	11	9	20	12
Influenza
subjects affected / exposed	10 / 83 (12.05%)	9 / 82 (10.98%)	25 / 159 (15.72%)	20 / 148 (13.51%)
occurrences all number	10	11	32	28
Nasopharyngitis
subjects affected / exposed	12 / 83 (14.46%)	9 / 82 (10.98%)	16 / 159 (10.06%)	19 / 148 (12.84%)
occurrences all number	16	9	17	26
Pharyngitis
subjects affected / exposed	5 / 83 (6.02%)	3 / 82 (3.66%)	2 / 159 (1.26%)	2 / 148 (1.35%)
occurrences all number	6	3	3	2
Pneumonia
subjects affected / exposed	2 / 83 (2.41%)	1 / 82 (1.22%)	2 / 159 (1.26%)	8 / 148 (5.41%)
occurrences all number	2	1	2	9
Rhinitis
subjects affected / exposed	6 / 83 (7.23%)	3 / 82 (3.66%)	10 / 159 (6.29%)	1 / 148 (0.68%)
occurrences all number	7	4	14	1
Sinusitis
subjects affected / exposed	8 / 83 (9.64%)	7 / 82 (8.54%)	7 / 159 (4.40%)	6 / 148 (4.05%)
occurrences all number	10	7	7	6
Tonsillitis
subjects affected / exposed	6 / 83 (7.23%)	5 / 82 (6.10%)	5 / 159 (3.14%)	0 / 148 (0.00%)
occurrences all number	8	5	5	0
Tooth Abscess
subjects affected / exposed	6 / 83 (7.23%)	2 / 82 (2.44%)	6 / 159 (3.77%)	3 / 148 (2.03%)
occurrences all number	6	3	7	5
Tooth Infection
subjects affected / exposed	4 / 83 (4.82%)	3 / 82 (3.66%)	10 / 159 (6.29%)	5 / 148 (3.38%)
occurrences all number	5	4	12	6
Tracheitis
subjects affected / exposed	7 / 83 (8.43%)	0 / 82 (0.00%)	5 / 159 (3.14%)	1 / 148 (0.68%)
occurrences all number	9	0	6	1
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 83 (0.00%)	3 / 82 (3.66%)	8 / 159 (5.03%)	1 / 148 (0.68%)
occurrences all number	0	3	8	1
Urinary Tract Infection
subjects affected / exposed	14 / 83 (16.87%)	8 / 82 (9.76%)	18 / 159 (11.32%)	15 / 148 (10.14%)
occurrences all number	25	16	29	21
Metabolism and nutrition disorders
Acetonaemia
subjects affected / exposed	7 / 83 (8.43%)	10 / 82 (12.20%)	8 / 159 (5.03%)	4 / 148 (2.70%)
occurrences all number	9	14	9	4
Diabetes Mellitus Inadequate Control
subjects affected / exposed	12 / 83 (14.46%)	13 / 82 (15.85%)	24 / 159 (15.09%)	15 / 148 (10.14%)
occurrences all number	12	18	28	15
Hyperglycaemia
subjects affected / exposed	18 / 83 (21.69%)	8 / 82 (9.76%)	30 / 159 (18.87%)	15 / 148 (10.14%)
occurrences all number	21	10	34	15
Ketosis
subjects affected / exposed	6 / 83 (7.23%)	0 / 82 (0.00%)	6 / 159 (3.77%)	2 / 148 (1.35%)
occurrences all number	8	0	7	2
Vitamin D Deficiency
subjects affected / exposed	2 / 83 (2.41%)	7 / 82 (8.54%)	5 / 159 (3.14%)	4 / 148 (2.70%)
occurrences all number	2	7	5	4

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Were there any global substantial amendments to the protocol? Yes

18 Mar 2011

Following amendments were made: - To comply with the standard practice in the real life for the Insuplant non comparative phase: time to refill and blood withdrawal for HbA1c and anti-insulin antibodies were scheduled according to the site usual care. - Inclusion criteria for Insuman non comparative phase were added. Subjets who didn’t participate to the comparative phase nor to the Insuplant non-comparative phase were allowed to participate directly to the Insuman non-comparative phase. - Correction of a mistake in the initial version of the protocol: no blood sample was collected for fasting plasma glucose, lipid profile (total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides) and chemistry (aspartate transferase, alanine transaminase, serum creatinine).

06 Jun 2011

- To allow the inclusion, in the Insuman non-comparative phase, of subjects not previously treated with Minimed implantable pump, but requiring CIPII therapy. - To allow subjects being pregnant during Insuman non-comparative phase to continue their treatment with Insuman Implantable 400 IU/mL as the duration of this phase was planned to end only when the product was marketed and as the safety profile of insulin is well established in pregnancy.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
Evaluation of Insuman Implantable 400 IU/ml in Patients with Type 1 Diabetes Treated with the Medtronic MiniMed Implantable Pump System Using Insuplant 400 IU/mL

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Modified Intent to Treat (mITT) Population

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Modified Intent to Treat (mITT) Population

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Per Protocol (PP) Population

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Per Protocol (PP) Population

Primary: Change From Baseline in HbA1c to Month 6: mITT Population

Primary: Change From Baseline in HbA1c to Month 6: mITT Population

Primary: Change From Baseline in HbA1c to Month 6: PP Population

Primary: Change From Baseline in HbA1c to Month 6: PP Population

Secondary: Actual Daily Insulin Dose at Month 6: mITT Population

Secondary: Actual Daily Insulin Dose at Month 6: mITT Population

Secondary: Actual Daily Insulin Dose at Month 6: PP Population

Secondary: Actual Daily Insulin Dose at Month 6: PP Population

Secondary: Number of Subjects With At Least One Severe Hypoglycemic Events

Secondary: Number of Subjects With At Least One Severe Hypoglycemic Events

Secondary: Number of Subjects With At Least One Hyperglycemia With Ketonemia

Secondary: Number of Subjects With At Least One Hyperglycemia With Ketonemia

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Italy
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Malta
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Outside EU/EEA

Clinical trials

Clinical Trial Results: Evaluation of Insuman Implantable 400 IU/ml in Patients with Type 1 Diabetes Treated with the Medtronic MiniMed Implantable Pump System Using Insuplant 400 IU/mL

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Modified Intent to Treat (mITT) Population

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Modified Intent to Treat (mITT) Population

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Per Protocol (PP) Population

Primary: Percentage Refill Accuracy After 4 Refill Cycles: Per Protocol (PP) Population

Primary: Change From Baseline in HbA1c to Month 6: mITT Population

Primary: Change From Baseline in HbA1c to Month 6: mITT Population

Primary: Change From Baseline in HbA1c to Month 6: PP Population

Primary: Change From Baseline in HbA1c to Month 6: PP Population

Secondary: Actual Daily Insulin Dose at Month 6: mITT Population

Secondary: Actual Daily Insulin Dose at Month 6: mITT Population

Secondary: Actual Daily Insulin Dose at Month 6: PP Population

Secondary: Actual Daily Insulin Dose at Month 6: PP Population

Secondary: Number of Subjects With At Least One Severe Hypoglycemic Events

Secondary: Number of Subjects With At Least One Severe Hypoglycemic Events

Secondary: Number of Subjects With At Least One Hyperglycemia With Ketonemia

Secondary: Number of Subjects With At Least One Hyperglycemia With Ketonemia

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Evaluation of Insuman Implantable 400 IU/ml in Patients with Type 1 Diabetes Treated with the Medtronic MiniMed Implantable Pump System Using Insuplant 400 IU/mL