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Clinical Trial Results:
A Multicenter, Open-Label Extension Study to Evaluate the Long-Term Safety and Tolerability of Faricimab in Patients with Diabetic Macular Edema

Summary
EudraCT number	2020-000402-29
Trial protocol	PT CZ DE DK HU GB SK AT PL BG IT
Global end of trial date	11 Oct 2023

Results information
Results version number	v1(current)
This version publication date	23 Oct 2024
First version publication date	23 Oct 2024
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

GR41987

ISRCTN number

-

US NCT number

NCT04432831

WHO universal trial number (UTN)

-

Sponsor organisation name

F. Hoffmann-La Roche, Ltd.

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, 4058

Public contact

F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

11 Oct 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Oct 2023

Global end of trial reached?

Yes

Global end of trial date

11 Oct 2023

Was the trial ended prematurely?

No

Main objective of the trial

To evaluate the long term ocular and systemic safety and tolerability of faricimab administered intravitreally in patients with DME

Protection of trial subjects

This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or the applicable laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. An Informed Consent Form (ICF) was required to be signed and dated by the patient or the patient's legally authorized representative before his or her participation in the study.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

05 Aug 2020

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 76

Country: Number of subjects enrolled

Australia: 23

Country: Number of subjects enrolled

Austria: 8

Country: Number of subjects enrolled

Bulgaria: 18

Country: Number of subjects enrolled

Brazil: 45

Country: Number of subjects enrolled

Canada: 16

Country: Number of subjects enrolled

Czechia: 56

Country: Number of subjects enrolled

Denmark: 2

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Germany: 11

Country: Number of subjects enrolled

Hong Kong: 10

Country: Number of subjects enrolled

Hungary: 61

Country: Number of subjects enrolled

Israel: 33

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

Japan: 48

Country: Number of subjects enrolled

Korea, Republic of: 25

Country: Number of subjects enrolled

Mexico: 10

Country: Number of subjects enrolled

Peru: 12

Country: Number of subjects enrolled

Poland: 166

Country: Number of subjects enrolled

Portugal: 20

Country: Number of subjects enrolled

Russian Federation: 27

Country: Number of subjects enrolled

Singapore: 6

Country: Number of subjects enrolled

Slovakia: 26

Country: Number of subjects enrolled

Spain: 49

Country: Number of subjects enrolled

Switzerland: 1

Country: Number of subjects enrolled

Thailand: 14

Country: Number of subjects enrolled

Türkiye: 15

Country: Number of subjects enrolled

Taiwan: 16

Country: Number of subjects enrolled

United Kingdom: 43

Country: Number of subjects enrolled

United States: 606

Worldwide total number of subjects

1474

EEA total number of subjects

448

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

750

From 65 to 84 years

714

85 years and over

10

Subject disposition

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Recruitment details

-

Screening details

A total of 1479 patients were enrolled, but 5 participants in total were excluded from the analysis populations because of Good Clinical Practice (GCP) non-compliance at a single site.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Faricimab PTI (prior Faricimab Q8W)

Arm description

This analysis group includes participants who were previously randomized to Arm A (faricimab 6 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Arm type

Experimental

Investigational medicinal product name

Faricimab

Investigational medicinal product code

RO6867461

Other name

VABYSMO®

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

Participants will receive 6 mg faricimab intravitreal injections according to a personalized treatment interval (PTI) dosing regimen.

Faricimab PTI (prior Faricimab PTI)

Arm description

This analysis group includes participants who were previously randomized to Arm B (faricimab 6 mg PTI) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Arm type

Experimental

Investigational medicinal product name

Faricimab

Investigational medicinal product code

RO6867461

Other name

VABYSMO®

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

Participants will receive 6 mg faricimab intravitreal injections according to a personalized treatment interval (PTI) dosing regimen.

Faricimab PTI (prior Aflibercept Q8W)

Arm description

This analysis group includes participants who were previously randomized to Arm C (aflibercept 2 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Arm type

Experimental

Investigational medicinal product name

Faricimab

Investigational medicinal product code

RO6867461

Other name

VABYSMO®

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

Participants will receive 6 mg faricimab intravitreal injections according to a personalized treatment interval (PTI) dosing regimen.

Number of subjects in period 1	Faricimab PTI (prior Faricimab Q8W)	Faricimab PTI (prior Faricimab PTI)	Faricimab PTI (prior Aflibercept Q8W)
Started	493	506	475
Received at Least One Dose of Study Drug	491	500	473
Completed	405	407	392
Not completed	88	99	83
Adverse event, serious fatal	23	23	17
Consent withdrawn by subject	24	28	21
Physician decision	1	3	6
Adverse event, non-fatal	7	7	7
Final End of Study Visit Not Completed	10	11	7
Pregnancy	-	1	-
Lost to follow-up	15	15	12
Reason not specified	7	11	9
Protocol deviation	1	-	2
Lack of efficacy	-	-	2

Baseline characteristics

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Reporting group title

Faricimab PTI (prior Faricimab Q8W)

Reporting group description

This analysis group includes participants who were previously randomized to Arm A (faricimab 6 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Reporting group title

Faricimab PTI (prior Faricimab PTI)

Reporting group description

This analysis group includes participants who were previously randomized to Arm B (faricimab 6 mg PTI) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Reporting group title

Faricimab PTI (prior Aflibercept Q8W)

Reporting group description

This analysis group includes participants who were previously randomized to Arm C (aflibercept 2 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Reporting group values	Faricimab PTI (prior Faricimab Q8W)	Faricimab PTI (prior Faricimab PTI)	Faricimab PTI (prior Aflibercept Q8W)	Total
Number of subjects	493	506	475	1474
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	264	243	243	750
From 65-84 years	223	261	230	714
85 years and over	6	2	2	10
Age Continuous
Units: Years
arithmetic mean (standard deviation)	63.4 ( 9.9 )	64.0 ( 9.8 )	63.5 ( 9.4 )	-
Sex: Female, Male
Units: Participants
Female	191	184	205	580
Male	302	322	270	894
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	5	4	4	13
Asian	54	52	45	151
Native Hawaiian or Other Pacific Islander	1	0	1	2
Black or African American	27	32	25	84
White	392	406	389	1187
More than one race	1	0	0	1
Unknown or Not Reported	13	12	11	36
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	68	87	79	234
Not Hispanic or Latino	415	408	386	1209
Unknown or Not Reported	10	11	10	31

End points

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Reporting group title

Faricimab PTI (prior Faricimab Q8W)

Reporting group description

This analysis group includes participants who were previously randomized to Arm A (faricimab 6 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Reporting group title

Faricimab PTI (prior Faricimab PTI)

Reporting group description

This analysis group includes participants who were previously randomized to Arm B (faricimab 6 mg PTI) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Reporting group title

Faricimab PTI (prior Aflibercept Q8W)

Reporting group description

This analysis group includes participants who were previously randomized to Arm C (aflibercept 2 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Primary: Incidence and Severity of Ocular Adverse Events in the Study Eye, with Severity Determined According to Adverse Event Severity Grading Scale

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End point title

Incidence and Severity of Ocular Adverse Events in the Study Eye, with Severity Determined According to Adverse Event Severity Grading Scale ^[1]

End point description

This is an analysis of participants with at least one ocular adverse event (AE) that occurred in the study eye. Investigators sought information on AEs at each contact with the participants. All AEs were recorded and the investigator made an assessment of the seriousness, severity (e.g., mild, moderate, or severe intensity), and causality for each AE. AEs of special interest (AESI) included the following: Sight-threatening AEs that cause a drop in visual acuity (VA) score ≥30 letters lasting more than 1 hour, are associated with severe intraocular inflammation (IOI), or require surgical or medical intervention to prevent permanent loss of sight; suspected transmission of an infectious agent by the study drug; and, cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law.

End point type

Primary

End point timeframe

From the day of the first dose of faricimab until the end of the study (up to 108 weeks)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There was no formal hypothesis testing planned for this study. This safety end point was assessed through descriptive summaries of the number of adverse events.

End point values	Faricimab PTI (prior Faricimab Q8W)	Faricimab PTI (prior Faricimab PTI)	Faricimab PTI (prior Aflibercept Q8W)
Number of subjects analysed	491	500	473
Units: Participants
Any Adverse Event (AE), Any Severity	219	188	197
AE by Severity: Mild	119	109	109
AE by Severity: Moderate	74	66	74
AE by Severity: Severe	20	10	12
AE by Severity: Missing	6	3	2
Serious Adverse Event (SAE)	31	15	26
AE Leading to Withdrawal from Study Treatment	3	0	6
Treatment-related AE	10	10	11
Treatment-related SAE	0	1	1
Any AE of Special Interest (AESI)	30	14	24
AESI: Drop in Visual Acuity Score ≥30 Letters	23	10	20
AESI: Associated with Severe IOI	1	1	1
AESI: Intervention Req. to Prev. Perm. Vision Loss	6	3	3
AESI: Suspect. Transm. of Infectious Agent by Drug	0	0	0

No statistical analyses for this end point

Primary: Incidence of Ocular Adverse Events in the Fellow Eye

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End point title

Incidence of Ocular Adverse Events in the Fellow Eye ^[2]

End point description

This is an analysis of participants with at least one ocular adverse event (AE) that occurred in the fellow eye (i.e., non-study eye). Investigators sought information on AEs at each contact with the participants. All AEs were recorded and the investigator made an assessment of the seriousness, severity, and causality for each AE. AEs of special interest (AESI) included the following: Sight-threatening AEs that cause a drop in visual acuity (VA) score ≥30 letters lasting more than 1 hour, are associated with severe intraocular inflammation (IOI), or require surgical or medical intervention to prevent permanent loss of sight; suspected transmission of an infectious agent by the study drug; and, cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law.

End point type

Primary

End point timeframe

From the day of the first dose of faricimab until the end of the study (up to 108 weeks)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There was no formal hypothesis testing planned for this study. This safety end point was assessed through descriptive summaries of the number of adverse events.

End point values	Faricimab PTI (prior Faricimab Q8W)	Faricimab PTI (prior Faricimab PTI)	Faricimab PTI (prior Aflibercept Q8W)
Number of subjects analysed	491	500	473
Units: Participants
Any Adverse Event (AE)	186	185	179
Serious Adverse Event (SAE)	16	17	15
Any AE of Special Interest (AESI)	13	16	14
AESI: Drop in Visual Acuity Score ≥30 Letters	6	9	10
AESI: Associated with Severe IOI	0	1	1
AESI: Intervention Req. to Prev. Perm. Vision Loss	7	6	4
AESI: Suspect. Transm. of Infectious Agent by Drug	0	0	0

No statistical analyses for this end point

Primary: Incidence and Severity of Non-Ocular Adverse Events, with Severity Determined According to Adverse Event Severity Grading Scale

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End point title

Incidence and Severity of Non-Ocular Adverse Events, with Severity Determined According to Adverse Event Severity Grading Scale ^[3]

End point description

This is an analysis of participants with at least one non-ocular (systemic) adverse event (AE). Investigators sought information on AEs at each contact with the participants. All AEs were recorded and the investigator made an assessment of the seriousness, severity (e.g., mild, moderate, or severe intensity), and causality for each AE. AEs of special interest (AESI) included the following: Sight-threatening AEs that cause a drop in visual acuity (VA) score ≥30 letters lasting more than 1 hour, are associated with severe intraocular inflammation (IOI), or require surgical or medical intervention to prevent permanent loss of sight; suspected transmission of an infectious agent by the study drug; and, cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law.

End point type

Primary

End point timeframe

From the day of the first dose of faricimab until the end of the study (up to 108 weeks)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There was no formal hypothesis testing planned for this study. This safety end point was assessed through descriptive summaries of the number of adverse events.

End point values	Faricimab PTI (prior Faricimab Q8W)	Faricimab PTI (prior Faricimab PTI)	Faricimab PTI (prior Aflibercept Q8W)
Number of subjects analysed	491	500	473
Units: Participants
Any Adverse Event (AE), Any Severity	317	295	297
AE by Severity: Mild	91	94	97
AE by Severity: Moderate	124	124	115
AE by Severity: Severe	102	77	85
Serious Adverse Event (SAE)	122	100	112
AE Leading to Withdrawal from Study Treatment	2	7	4
Any AE of Special Interest (AESI)	0	0	1
AESI: Drop in Visual Acuity Score ≥30 Letters	0	0	1
AESI: High ALT/AST & High Bilir. or Clin. Jaundice	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the day of the first dose of faricimab until the end of the study (up to 108 weeks)

Adverse event reporting additional description

Total number of deaths and adverse events (AEs) are reported for the Safety-Evaluable Population, which included all participant who enrolled and received at least one dose of faricimab during the study. For ocular AEs, the number of participants and events reported per term are specified to have occurred in the study eye or the fellow eye.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Faricimab PTI (prior Faricimab Q8W)

Reporting group description

This analysis group includes participants who were previously randomized to Arm A (faricimab 6 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Reporting group title

Faricimab PTI (prior Faricimab PTI)

Reporting group description

This analysis group includes participants who were previously randomized to Arm B (faricimab 6 mg PTI) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Reporting group title

Faricimab PTI (prior Aflibercept Q8W)

Reporting group description

This analysis group includes participants who were previously randomized to Arm C (aflibercept 2 mg Q8W) in one of the parent studies, GR40349 (NCT03622580) and GR40398 (NCT03622593), and then enrolled in this extension study to receive faricimab 6 mg by IVT injection according to the personalized treatment interval (PTI) dosing regimen.

Serious adverse events	Faricimab PTI (prior Faricimab Q8W)	Faricimab PTI (prior Faricimab PTI)	Faricimab PTI (prior Aflibercept Q8W)
Total subjects affected by serious adverse events
subjects affected / exposed	158 / 491 (32.18%)	124 / 500 (24.80%)	134 / 473 (28.33%)
number of deaths (all causes)	22	20	17
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chronic lymphocytic leukaemia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clear cell renal cell carcinoma
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Benign anorectal neoplasm
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon cancer metastatic
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 491 (0.00%)	4 / 500 (0.80%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast neoplasm
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometrial cancer stage III
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer stage IV
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cancer
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukaemia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasm malignant
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuroendocrine carcinoma of the skin
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal cancer metastatic
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Ovarian fibroma
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 491 (0.00%)	2 / 500 (0.40%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cancer stage IV
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Spinal cord neoplasm
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Angiopathy
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hypertensive urgency
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	2 / 491 (0.41%)	1 / 500 (0.20%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery thrombosis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 491 (0.20%)	3 / 500 (0.60%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Organ failure
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Death
subjects affected / exposed	3 / 491 (0.61%)	5 / 500 (1.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 3	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 5	0 / 2
Hernia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 491 (0.00%)	2 / 500 (0.40%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Food allergy
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Contrast media allergy
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Allergy to arthropod sting
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Orchitis noninfective
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic cyst
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Chronic respiratory failure
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 491 (0.00%)	2 / 500 (0.40%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	2 / 491 (0.41%)	1 / 500 (0.20%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	2 / 491 (0.41%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Psychiatric disorders
Substance-induced psychotic disorder
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Product issues
Device leakage
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Ammonia increased
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glycosylated haemoglobin abnormal
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Heart rate increased
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SARS-CoV-2 test positive
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Precancerous cells present
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intraocular pressure increased
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Red blood cell count decreased
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Corneal abrasion
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain contusion
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract traumatic
Additional description: SAEs occurred the study eye
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Comminuted fracture
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye injury
Additional description: SAEs occurred the study eye
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 491 (0.00%)	2 / 500 (0.40%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	2 / 491 (0.41%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foreign body
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fracture displacement
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ocular procedural complication
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritoneal dialysis complication
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural constipation
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural inflammation
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Shoulder fracture
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound necrosis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular procedure complication
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute left ventricular failure
subjects affected / exposed	2 / 491 (0.41%)	2 / 500 (0.40%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 491 (0.00%)	2 / 500 (0.40%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	4 / 473 (0.85%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 491 (0.20%)	4 / 500 (0.80%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 2
Cardiac valve disease
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	7 / 491 (1.43%)	3 / 500 (0.60%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 9	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 1	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 491 (0.00%)	3 / 500 (0.60%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 4	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorder
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cardiac discomfort
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	2 / 491 (0.41%)	2 / 500 (0.40%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0
Bradycardia
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradyarrhythmia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	6 / 491 (1.22%)	5 / 500 (1.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 6	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular hypokinesia
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	9 / 491 (1.83%)	3 / 500 (0.60%)	8 / 473 (1.69%)
occurrences causally related to treatment / all	0 / 9	0 / 3	0 / 8
deaths causally related to treatment / all	0 / 3	0 / 1	0 / 3
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Amyotrophic lateral sclerosis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalomalacia
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	4 / 491 (0.81%)	3 / 500 (0.60%)	10 / 473 (2.11%)
occurrences causally related to treatment / all	0 / 4	0 / 3	1 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 3
Cerebral infarction
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lethargy
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemic unconsciousness
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Optic neuritis
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukoencephalopathy
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paraparesis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxic encephalopathy
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 491 (0.20%)	2 / 500 (0.40%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	2 / 491 (0.41%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertebral artery stenosis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vocal cord paralysis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 491 (0.41%)	2 / 500 (0.40%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Normocytic anaemia
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrogenic anaemia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Diabetic retinal oedema
Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 7[491]8, 0[500]0, 2[473]2) and the fellow eye (subjects affected [exposed] occurrences = 1[491]1, 1[500]1, 2[473]2)
subjects affected / exposed	8 / 491 (1.63%)	1 / 500 (0.20%)	4 / 473 (0.85%)
occurrences causally related to treatment / all	0 / 9	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract nuclear
Additional description: SAEs occurred in the study eye
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract cortical
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract
Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 11[491]11, 8[500]8, 15[473]15) and the fellow eye (subjects affected [exposed] occurrences = 1[491]1, 6[500]6, 0[473]0)
subjects affected / exposed	12 / 491 (2.44%)	14 / 500 (2.80%)	15 / 473 (3.17%)
occurrences causally related to treatment / all	0 / 12	0 / 14	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angle closure glaucoma
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rhegmatogenous retinal detachment
Additional description: SAEs occurred in the study eye
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal vein occlusion
Additional description: SAEs occurred in the study eye
subjects affected / exposed	2 / 491 (0.41%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal tear
Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 0[491]0, 1[500]1, 0[473]0) and the fellow eye (subjects affected [exposed] occurrences = 0[491]0, 1[500]1, 0[473]0)
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal neovascularisation
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal detachment
Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 2[491]2, 0[500]0, 0[473]0) and the fellow eye (subjects affected [exposed] occurrences = 1[491]1, 0[500]0, 1[473]1)
subjects affected / exposed	3 / 491 (0.61%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal artery occlusion
Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 0[491]0, 1[500]1, 2[473]2) and the fellow eye (subjects affected [exposed] occurrences = 1[491]1, 0[500]0, 1[473]1)
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Posterior capsule opacification
Additional description: SAEs occurred in the study eye
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neovascular age-related macular degeneration
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Iridocyclitis
Additional description: SAEs occurred in the study eye
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Iridocele
Additional description: SAEs occurred in the study eye
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glaucoma
Additional description: SAEs occurred in the study eye
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epiretinal membrane
Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 0[491]0, 0[500]0, 1[473]1) and the fellow eye (subjects affected [exposed] occurrences = 0[491]0, 0[500]0, 2[473]2)
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tractional retinal detachment
Additional description: SAEs occurred in the fellow eye
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic retinopathy
Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 0[491]0, 0[500]0, 1[473]1) and the fellow eye (subjects affected [exposed] occurrences = 2[491]2, 3[500]3, 2[473]2)
subjects affected / exposed	2 / 491 (0.41%)	3 / 500 (0.60%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uveitis
Additional description: SAEs occurred in the study eye
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vitreous haemorrhage
Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 1[491]1, 1[500]1, 2[473]2) and the fellow eye (subjects affected [exposed] occurrences = 4[491]4, 3[500]3, 6[473]6)
subjects affected / exposed	5 / 491 (1.02%)	4 / 500 (0.80%)	8 / 473 (1.69%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Faecaloma
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oral mucosal hypertrophy
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Volvulus
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Portal vein thrombosis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Biliary tract disorder
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gallbladder rupture
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Cellulite
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic foot
subjects affected / exposed	2 / 491 (0.41%)	3 / 500 (0.60%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	3 / 491 (0.61%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Diabetic nephropathy
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	2 / 491 (0.41%)	3 / 500 (0.60%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	8 / 491 (1.63%)	5 / 500 (1.00%)	5 / 473 (1.06%)
occurrences causally related to treatment / all	0 / 9	0 / 5	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
End stage renal disease
subjects affected / exposed	1 / 491 (0.20%)	2 / 500 (0.40%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subcapsular renal haematoma
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal haemorrhage
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	3 / 491 (0.61%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephropathy
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 491 (0.20%)	3 / 500 (0.60%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuropathic arthropathy
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	10 / 491 (2.04%)	9 / 500 (1.80%)	5 / 473 (1.06%)
occurrences causally related to treatment / all	0 / 10	0 / 9	0 / 5
deaths causally related to treatment / all	0 / 3	0 / 3	0 / 0
Abdominal infection
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic gangrene
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic foot infection
subjects affected / exposed	2 / 491 (0.41%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 491 (0.61%)	4 / 500 (0.80%)	6 / 473 (1.27%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	4 / 491 (0.81%)	2 / 500 (0.40%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis intestinal haemorrhagic
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endophthalmitis
Additional description: SAEs occurred in both the study eye (subjects affected [exposed] occurrences = 2[491]2, 0[500]0, 1[473]1) and the fellow eye (subjects affected [exposed] occurrences = 2[491]2, 0[500]0, 1[473]1)
subjects affected / exposed	4 / 491 (0.81%)	0 / 500 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	1 / 4	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis bacterial
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	1 / 491 (0.20%)	2 / 500 (0.40%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected dermal cyst
subjects affected / exposed	0 / 491 (0.00%)	2 / 500 (0.40%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	7 / 491 (1.43%)	0 / 500 (0.00%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Labyrinthitis
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	7 / 491 (1.43%)	4 / 500 (0.80%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis chronic
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis acute
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	5 / 491 (1.02%)	8 / 500 (1.60%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 5	0 / 9	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 491 (0.00%)	2 / 500 (0.40%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Systemic bacterial infection
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Septic endocarditis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	4 / 491 (0.81%)	2 / 500 (0.40%)	4 / 473 (0.85%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1
Staphylococcal infection
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 491 (0.41%)	0 / 500 (0.00%)	3 / 473 (0.63%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 491 (0.20%)	1 / 500 (0.20%)	2 / 473 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Hypervolaemia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 491 (0.20%)	2 / 500 (0.40%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemic hyperosmolar nonketotic syndrome
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 491 (0.00%)	0 / 500 (0.00%)	1 / 473 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 491 (0.20%)	0 / 500 (0.00%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 491 (0.00%)	1 / 500 (0.20%)	0 / 473 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	Faricimab PTI (prior Faricimab Q8W)	Faricimab PTI (prior Faricimab PTI)	Faricimab PTI (prior Aflibercept Q8W)
Total subjects affected by non serious adverse events
subjects affected / exposed	233 / 491 (47.45%)	213 / 500 (42.60%)	219 / 473 (46.30%)
Investigations
Intraocular pressure increased
Additional description: AEs occurred in the study eye
subjects affected / exposed	16 / 491 (3.26%)	12 / 500 (2.40%)	12 / 473 (2.54%)
occurrences all number	20	15	13
Vascular disorders
Hypertension
subjects affected / exposed	18 / 491 (3.67%)	20 / 500 (4.00%)	23 / 473 (4.86%)
occurrences all number	18	20	24
Eye disorders
Cataract
Additional description: AEs occurred in both the study eye (subjects affected [exposed] occurrences = 65[491]65, 60[500]60, 63[473]63) and the fellow eye (subjects affected [exposed] occurrences = 56[491]56, 41[500]41, 51[473]52)
subjects affected / exposed	90 / 491 (18.33%)	72 / 500 (14.40%)	84 / 473 (17.76%)
occurrences all number	115	91	110
Posterior capsule opacification
Additional description: AEs occurred in both the study eye (subjects affected [exposed] occurrences = 16[491]17, 17[500]17, 14[473]14) and the fellow eye (subjects affected [exposed] occurrences = 13[491]14, 20[500]20, 13[473]13)
subjects affected / exposed	19 / 491 (3.87%)	29 / 500 (5.80%)	20 / 473 (4.23%)
occurrences all number	27	34	27
Diabetic retinal oedema
Additional description: AEs occurred in the fellow eye
subjects affected / exposed	22 / 491 (4.48%)	27 / 500 (5.40%)	24 / 473 (5.07%)
occurrences all number	22	31	27
Conjunctival haemorrhage
Additional description: AEs occurred in the study eye
subjects affected / exposed	16 / 491 (3.26%)	9 / 500 (1.80%)	5 / 473 (1.06%)
occurrences all number	17	9	5
Diabetic retinopathy
Additional description: AEs occurred in the fellow eye
subjects affected / exposed	17 / 491 (3.46%)	8 / 500 (1.60%)	12 / 473 (2.54%)
occurrences all number	17	8	12
Vitreous detachment
Additional description: AEs occurred in the study eye
subjects affected / exposed	16 / 491 (3.26%)	12 / 500 (2.40%)	6 / 473 (1.27%)
occurrences all number	16	12	6
Vitreous floaters
Additional description: AEs occurred in the study eye
subjects affected / exposed	16 / 491 (3.26%)	7 / 500 (1.40%)	8 / 473 (1.69%)
occurrences all number	18	7	8
Infections and infestations
COVID-19
subjects affected / exposed	63 / 491 (12.83%)	49 / 500 (9.80%)	46 / 473 (9.73%)
occurrences all number	70	50	49
Nasopharyngitis
subjects affected / exposed	18 / 491 (3.67%)	12 / 500 (2.40%)	23 / 473 (4.86%)
occurrences all number	21	12	27
Urinary tract infection
subjects affected / exposed	16 / 491 (3.26%)	15 / 500 (3.00%)	16 / 473 (3.38%)
occurrences all number	19	17	18

More information

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Were there any global substantial amendments to the protocol? Yes

13 May 2020

Protocol Version 2: An exclusion criterion was added relating to a history of reaction or hypersensitivity to biologic agents including any component of the faricimab injection or study treatment procedures.

13 Dec 2021

Protocol Version 3: -A Final End-of-Study (FEOS) visit, to be completed 28-35 days after the last PTI dosing visit, was included for all patients. Therefore, the study was extended to a maximum of 108 weeks for patients who received their final dose of faricimab at Week 104; -The list of prohibited therapies was amended to clarify that continuous usage of topical ophthalmic corticosteroids for 100 days or more is considered prohibited therapy, and to add the use of kallidinogenase and other medications claiming to have an effect on macular pathology to the list of prohibited therapies.

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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