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Clinical Trial Results:
A randomised control trial of alternative treatments to Inhibit VEGf in Age-related choroidal Neovascularisation (IVAN)

Summary
EudraCT number	2007-001281-33
Trial protocol	GB
Global end of trial date	31 Dec 2013

Results information
Results version number	v1(current)
This version publication date	31 Mar 2020
First version publication date	31 Mar 2020
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

RGHT000449

ISRCTN number

ISRCTN92166560

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Belfast Health and Social Care Trust

Sponsor organisation address

Research Office, 2nd Floor King Edward Building, Royal Hospitals, Grosvenor Road, Belfast, United Kingdom, BT12 6BA

Public contact

Research Office, Belfast Health and Social Care Trust, Research.Office@belfasttrust.hscni.net

Scientific contact

Research Office, Belfast Health and Social Care Trust, Research.Office@belfasttrust.hscni.net

Sponsor organisation name

Queen's University Belfast

Sponsor organisation address

Research Governance, Ethics and Integrity, Queen’s University Belfast, 63 University Road, Belfast, United Kingdom, BT7 1NN

Public contact

Research Governance, Queen's University Belfast, researchgovernance@qub.ac.uk

Scientific contact

Research Governance, Queen's University Belfast, researchgovernance@qub.ac.uk

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

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

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

Analysis stage

Final

Date of interim/final analysis

24 Apr 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

07 Nov 2012

Global end of trial reached?

Yes

Global end of trial date

31 Dec 2013

Was the trial ended prematurely?

Main objective of the trial

To estimate the relative effectiveness of two vascular endothelial growth factor (VEGF) inhibitors, i.e. Lucentis® (ranibizumab) and Avastin® (bevacizumab), delivered into the eye by intravitreal injection on visual outcome in patients with choroidal neovascularisation (CNV) from age−related macular degeneration (AMD). To estimate the effectiveness of more frequent (continuous) versus less frequent (discontinuous) VEGF administration in improving or maintaining visual function, with stringent criteria for restarting treatment to prevent visual acuity loss in patients receiving less frequent treatment.

Protection of trial subjects

All potential participants were sent or given an invitation letter and patient information leaflet (PIL) (approved by a NHS research ethics committee) describing the study. All participants had time to read the PIL and to discuss their participation with others outside the research team (e.g. relatives or friends) if they wished. Participants had a minimum of 48 hours to decide whether they wished to take part. A member of research staff was available to answer questions that patients may have about the trial. The PIL included a phone number that patients can telephone to obtain more information. All members of the direct healthcare team are contractually bound to abide by standard NHS conditions of confidentiality. All of the clinical staff at the study sites will have attended appropriate courses on GCP and will be familiar with issues concerning informed consent. A member of research staff asked the patient whether he/she has understood the information about the trial, and whether he/she had any more questions before asking the patient if he/she was willing to take part in the trial. Written informed consent was obtained for every trial participant.

Background therapy

Wet or neovascular macular degeneration is a condition which causes severe sight loss in older people. Until recently, available treatments only slowed down the rate of sight loss with most patients becoming moderately or severely visually impaired despite optimal management. A drug known as Lucentis (Ranibizumab) was found to prevent further sight loss in over 90% of those treated. The treatment involved injection of the drug every 4 weeks into the vitreous jelly of the eye for up to two years. A very similar drug, Avastin (Bevacizumab), but which is much cheaper, also appears to have the same benefits but it had not been tested in randomised controlled trials.

Evidence for comparator

Intravitreal treatment with ranibizumab, an anti body to vascular endothelial growth factor (VEGF), was shown to be effective in neovascular age related macular degeneration compared with photodynamic therapy or no treatment. Anti-VEGF drugs were thus established as a standard of care for neovascular age-related macular degeneration. Bevacizumab, an antibody to VEGF that is licensed for treatment of bowel cancers, is the parent molecule from which ranibizumab was developed. Small non-randomised studies done while ranibizumab was awaiting marketing authorisation suggested that bevacizumab had similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. These findings were important, because every dose of ranibizumab is expensive and treatment can be needed every month for several years. There were concerns about possible side effects of both drugs, which had not been directly compared. There is also very little evidence on which to base criteria for stopping treatment and so considerable uncertainty about precisely how much treatment might cost in the longer term; this is a major concern to the NHS, not just because of the drug costs but also because of the costs involved in regular monthly treatment. The absence of robust information about the safety of bevacizumab in the treatment of neovascular age-related macular degeneration and uncertainty about treatment frequency for both bevacizumab and ranibizumab led us to undertake the Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial in the UK. The IVAN trial was designed to compare the clinical efficacy of the two drugs and to compare a reduced treatment regimen versus two years of continuous treatment.

Actual start date of recruitment

27 Mar 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Scientific research

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 610

Worldwide total number of subjects

610

EEA total number of subjects

610

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

447

85 years and over

136

Subject disposition

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Recruitment details

Between 27 March 2008 and 15 October 2010, 2, 693 patients were screened for inclusion in the trial and full informed consent was taken from 610 patients who agreed to take part in the study. All potential participants received an information leaflet.

Screening details

Of the 693 patients screened for inclusion in the trial, 28 were identified as ineligible and 37 excluded for other reasons. The remaining 628 patients were randomised into the trial. Five of these 628 participants were randomised in error and a further 13 were not treated, leaving 610 who recieved the study drugs and were included in the analyses.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Blinding implementation details

Allocations were computer generated and concealed with an internet-based system (Sealed Envelope, London, UK). Study participants and clinical assessors (nurses, optometrists, imaging technicians, and clinicians) were masked to drug allocation. Study drugs were dispensed by pharmacy staff who were unmasked, but had no other role in the study. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point both investigator and participant were unmasked.

Are arms mutually exclusive

Ranibizumab

Arm description

Intravitreal injections of ranibizumab (0.5mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

Arm type

Active comparator

Investigational medicinal product name

Lucentis

Investigational medicinal product code

Other name

Ranibizumab

Pharmaceutical forms

Injection

Routes of administration

Intravitreal use

Dosage and administration details

Administration: Intravitreal injections. Drug dose: 0·5 mg

Bevacizumab

Arm description

Intravitreal injections of bevacizumab (1.25mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

Arm type

Experimental

Investigational medicinal product name

Avastin

Investigational medicinal product code

Other name

Bevacizumab

Pharmaceutical forms

Injection

Routes of administration

Intravitreal use

Dosage and administration details

Administration: Intravitreal injections. Drug dose: 1·25 mg

Continuous

Arm description

Monthly treatment.

Arm type

Continuous treatment

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Discontinuous

Arm description

Treated if pre specified clinical and OCT criteria for active disease were met. If re-treatment was needed, a further cycle of three doses was given monthly.

Arm type

Discontinuous treatment

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Started	314	296	308	302
Completed	314	296	308	302

Baseline characteristics

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Reporting group title

Ranibizumab

Reporting group description

Intravitreal injections of ranibizumab (0.5mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

Reporting group title

Bevacizumab

Reporting group description

Intravitreal injections of bevacizumab (1.25mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

Reporting group title

Continuous

Reporting group description

Monthly treatment.

Reporting group title

Discontinuous

Reporting group description

Treated if pre specified clinical and OCT criteria for active disease were met. If re-treatment was needed, a further cycle of three doses was given monthly.

Reporting group values	Ranibizumab	Bevacizumab	Continuous	Discontinuous	Total
Number of subjects	314	296	308	302
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Age at randomisation
Units: years
arithmetic mean (standard deviation)	77.8 ± 7.6	77.7 ± 7.3	77.8 ± 8.0	77.6 ± 6.8	-
Gender categorical
Units: Subjects
Female	185	181	182	184	366
Male	129	115	126	118	244
Angina
Units: Subjects
Yes	35	51	45	41	86
No	279	245	263	261	524
Dyspnoea
Units: Subjects
Yes	57	60	57	60	117
No	256	235	249	242	491
Missing	1	1	2	0	2
Myocardial Infarction
Units: Subjects
Yes	24	22	26	20	46
No	290	274	282	282	564
Transient ischaemic attack
Units: Subjects
Yes	20	9	15	14	29
No	274	273	276	271	547
Missing	20	14	17	17	34
Stroke
Units: Subjects
Yes	7	7	4	10	14
No	307	288	304	291	595
Missing	0	1	0	1	1
DVT/PE
DVT/PE = Deep-vein thrombosis or pulmonary embolism.
Units: Subjects
Yes	16	18	16	18	34
No	297	277	292	282	574
Missing	1	1	0	2	2
Current or past smoker
Units: Subjects
Yes	200	185	194	191	385
No	109	110	111	108	219
Missing	5	1	3	3	6
Foveal centre involvement
Units: Subjects
Yes	230	223	235	218	453
No	79	66	66	79	145
Missing	5	7	7	5	12
Choroidal neovascularisation
Units: Subjects
Yes	156	162	170	148	318
No	149	125	129	145	274
Missing	9	9	9	9	18
Haemorrhage
Units: Subjects
Yes	86	88	89	85	174
No	222	204	214	212	426
Missing	6	4	5	5	10
Other foveal centre involvement
Units: Subjects
Yes	47	30	39	38	77
No	259	262	262	259	521
Missing	8	4	7	5	12
No choroidal neovascularisation or unable to grade
Units: Subjects
Yes	7	8	4	11	15
No	302	286	300	288	588
Missing	5	2	4	3	7
Geographic atrophy
Units: Subjects
Yes	25	18	24	19	43
No	284	277	280	281	561
Missing	5	1	4	2	6
Blood pressure (Systolic)
Units: mmHg
arithmetic mean (standard deviation)	141.9 ± 19.5	143.0 ± 19.5	143.2 ± 19.8	141.7 ± 19.1	-
Blood pressure (Diastolic)
Units: mmHg
arithmetic mean (standard deviation)	76.4 ± 10.2	77.1 ± 9.9	77.4 ± 10.1	76.2 ± 10.0	-
Best corrected visual acuity
Units: Letters
arithmetic mean (standard deviation)	61.8 ± 15.0	61.1 ± 15.5	60.1 ± 15.5	62.9 ± 15.0	-
Near visual acuity
Data missing for 7 patients (3 Ranibizumab, 4 Bevacizumab; 5 Continuous, 2 Discontinuous)
Units: logMAR
arithmetic mean (standard deviation)	0.66 ± 0.34	0.67 ± 0.33	0.70 ± 0.34	0.63 ± 0.32	-
Belfast reading index
Data missing for 34 patients (21 Ranibizumab, 13 Bevacizumab; 21 Continuous, 13 Discontinuous)
Units: Index
median (inter-quartile range (Q1-Q3))	36.9 (15.6 to 65.3)	35.0 (14.0 to 69.6)	33.1 (13.6 to 67.7)	40.0 (16.3 to 69.6)	-
Contrast sensitivity
Data missing for 3 patients (3 Ranibizumab, 0 Bevacizumab; 3 Continuous, 0 Discontinuous)
Units: Letters
arithmetic mean (standard deviation)	26.2 ± 6.2	26.3 ± 5.7	26.1 ± 6.0	26.4 ± 5.9	-
Total thickness at fovea
Data missing for 53 patients (24 Ranibizumab, 29 Bevacizumab; 27 Continuous, 26 Discontinuous)
Units: µm
arithmetic mean (standard deviation)	471.6 ± 192.5	465.6 ± 183.1	473.2 ± 187.9	464.1 ± 188.2	-
Retinal plus subretinal fluid thickness at fovea
Data missing for 53 patients (24 Ranibizumab, 29 Bevacizumab; 27 Continuous, 26 Discontinuous)
Units: µm
arithmetic mean (standard deviation)	271.9 ± 128.6	264.0 ± 131.6	263.9 ± 126.9	272.4 ± 133.2	-
Area of lesion, optic disc area
Data missing for 23 patients (11 Ranibizumab, 12 Bevacizumab; 10 Continuous, 13 Discontinuous)
Units: µm
median (inter-quartile range (Q1-Q3))	3.28 (1.10 to 7.76)	3.97 (1.42 to 8.24)	3.68 (1.27 to 7.81)	3.59 (1.16 to 8.42)	-
EQ-5D state score
Data missing for 2 patients (1 Ranibizumab, 1 Bevacizumab; 0 Continuous, 2 Discontinuous)
Units: Utility score
median (inter-quartile range (Q1-Q3))	0.81 (0.73 to 1.00)	0.85 (0.73 to 1.00)	0.85 (0.73 to 1.00)	0.85 (0.73 to 1.00)	-

End points

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Reporting group title

Ranibizumab

Reporting group description

Intravitreal injections of ranibizumab (0.5mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

Reporting group title

Bevacizumab

Reporting group description

Intravitreal injections of bevacizumab (1.25mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

Reporting group title

Continuous

Reporting group description

Monthly treatment.

Reporting group title

Discontinuous

Reporting group description

Treated if pre specified clinical and OCT criteria for active disease were met. If re-treatment was needed, a further cycle of three doses was given monthly.

Subject analysis set title

Ranibizumab: Baseline BCVA in fellow eye ≥75

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline BCVA in fellow eye ≥75

Subject analysis set title

Ranibizumab: Baseline BCVA in fellow eye <75

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline BCVA in fellow eye <75

Subject analysis set title

Bevacizumab: Baseline BCVA in fellow eye ≥75

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline BCVA in fellow eye ≥75

Subject analysis set title

Bevacizumab: Baseline BCVA in fellow eye <75

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline BCVA in fellow eye <75

Subject analysis set title

Continuous: Baseline BCVA in fellow eye ≥75

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline BCVA in fellow eye ≥75

Subject analysis set title

Continuous: Baseline BCVA in fellow eye <75

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline BCVA in fellow eye <75

Subject analysis set title

Discontinuous: Baseline BCVA in fellow eye ≥75

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline BCVA in fellow eye ≥75

Subject analysis set title

Discontinuous: Baseline BCVA in fellow eye <75

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline BCVA in fellow eye <75

Subject analysis set title

Ranibizumab: Baseline BCVA <55

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline BCVA in study eye <55

Subject analysis set title

Ranibizumab: Baseline BCVA ≥55

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline BCVA in study eye ≥55

Subject analysis set title

Bevacizumab: Baseline BCVA <55

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline BCVA in study eye <55

Subject analysis set title

Bevacizumab: Baseline BCVA ≥55

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline BCVA in study eye ≥55

Subject analysis set title

Continuous: Baseline BCVA <55

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline BCVA in study eye <55

Subject analysis set title

Continuous: Baseline BCVA ≥55

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline BCVA in study eye ≥55

Subject analysis set title

Disontinuous: Baseline BCVA <55

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline BCVA in study eye <55

Subject analysis set title

Disontinuous: Baseline BCVA ≥55

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline BCVA in study eye ≥55

Subject analysis set title

Ranibizumab: Baseline CNV size <6mm

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline CNV size <6mm

Subject analysis set title

Ranibizumab: Baseline CNV size ≥6mm

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline CNV size ≥6mm

Subject analysis set title

Bevacizumab: Baseline CNV size <6mm

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline CNV size <6mm

Subject analysis set title

Bevacizumab: Baseline CNV size ≥6mm

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline CNV size ≥6mm

Subject analysis set title

Continuous arm: Baseline CNV size <6mm

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline CNV size <6mm

Subject analysis set title

Continuous arm: Baseline CNV size ≥6mm

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline CNV size ≥6mm

Subject analysis set title

Discontinuous arm: Baseline CNV size <6mm

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline CNV size <6mm

Subject analysis set title

Discontinuous arm: Baseline CNV size ≥6mm

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline CNV size ≥6mm

Subject analysis set title

Ranibizumab: Baseline lesion <50% CNV

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline lesion <50% CNV

Subject analysis set title

Ranibizumab: Baseline lesion ≥50% CNV

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline lesion ≥50% CNV

Subject analysis set title

Bevacizumab: Baseline lesion <50% CNV

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline lesion <50% CNV

Subject analysis set title

Bevacizumab: Baseline lesion ≥50% CNV

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline lesion ≥50% CNV

Subject analysis set title

Continuous: Baseline lesion <50% CNV

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline lesion <50% CNV

Subject analysis set title

Continuous: Baseline lesion ≥50% CNV

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline lesion ≥50% CNV

Subject analysis set title

Discontinuous: Baseline lesion <50% CNV

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline lesion <50% CNV

Subject analysis set title

Discontinuous: Baseline lesion ≥50% CNV

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline lesion ≥50% CNV

Subject analysis set title

Ranibizumab: Baseline RAP absent

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline RAP absent

Subject analysis set title

Ranibizumab: Baseline RAP present

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Ranibizumab arm - Baseline RAP present

Subject analysis set title

Bevacizumab: Baseline RAP absent

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline RAP absent

Subject analysis set title

Bevacizumab: Baseline RAP present

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Bevacizumab arm - Baseline RAP present

Subject analysis set title

Continuous: Baseline RAP absent

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline RAP absent

Subject analysis set title

Continuous: Baseline RAP present

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Continuous arm - Baseline RAP present

Subject analysis set title

Discontinuous: Baseline RAP absent

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline RAP absent

Subject analysis set title

Discontinuous: Baseline RAP present

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subgroup: Discontinuous arm - Baseline RAP present

Subject analysis set title

Discontinuous bevacizumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Analysis group for resource use and cost effectiveness: Discontinuous bevacizumab

Subject analysis set title

Continuous bevacizumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Analysis group for resource use and cost effectiveness: Continuous bevacizumab

Subject analysis set title

Discontinuous ranibizumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Analysis group for resource use and cost effectiveness: Discontinuous ranibizumab

Subject analysis set title

Continuous ranibizumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Analysis group for resource use and cost effectiveness: Continuous ranibizumab

Primary: Best corrected visual acuity

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End point title

Best corrected visual acuity

End point description

Best corrected visual acuity (BCVA) measured as the number of letters read on a standard Early Treatment Diabetic Retinopathy Study chart.

End point type

Primary

End point timeframe

Measured at 0, 3, 6, 9, 12, 15, 18, 21 and 24 months

Ranibizumab

Bevacizumab

Continuous

Discontinuous

Ranibizumab: Baseline BCVA in fellow eye ≥75

Ranibizumab: Baseline BCVA in fellow eye <75

Bevacizumab: Baseline BCVA in fellow eye ≥75

Bevacizumab: Baseline BCVA in fellow eye <75

Continuous: Baseline BCVA in fellow eye ≥75

Continuous: Baseline BCVA in fellow eye <75

Discontinuous: Baseline BCVA in fellow eye ≥75

Discontinuous: Baseline BCVA in fellow eye <75

Ranibizumab: Baseline BCVA <55

Ranibizumab: Baseline BCVA ≥55

Bevacizumab: Baseline BCVA <55

Bevacizumab: Baseline BCVA ≥55

Continuous: Baseline BCVA <55

Continuous: Baseline BCVA ≥55

Disontinuous: Baseline BCVA <55

Disontinuous: Baseline BCVA ≥55

Ranibizumab: Baseline CNV size <6mm

Ranibizumab: Baseline CNV size ≥6mm

Bevacizumab: Baseline CNV size <6mm

Bevacizumab: Baseline CNV size ≥6mm

Continuous arm: Baseline CNV size <6mm

Continuous arm: Baseline CNV size ≥6mm

Discontinuous arm: Baseline CNV size <6mm

Discontinuous arm: Baseline CNV size ≥6mm

Ranibizumab: Baseline lesion <50% CNV

Ranibizumab: Baseline lesion ≥50% CNV

Bevacizumab: Baseline lesion <50% CNV

Bevacizumab: Baseline lesion ≥50% CNV

Continuous: Baseline lesion <50% CNV

Continuous: Baseline lesion ≥50% CNV

Discontinuous: Baseline lesion <50% CNV

Discontinuous: Baseline lesion ≥50% CNV

Ranibizumab: Baseline RAP absent

Ranibizumab: Baseline RAP present

Bevacizumab: Baseline RAP absent

Bevacizumab: Baseline RAP present

Continuous: Baseline RAP absent

Continuous: Baseline RAP present

Discontinuous: Baseline RAP absent

Discontinuous: Baseline RAP present

Number of subjects analysed

314

296

308

302

161

145

142

166

135

140

152

228

200

104

204

224

201

102

181

103

198

100

184

105

224

213

227

210

245

241

248

238

Units: Letters

arithmetic mean (standard deviation)

67.8 ± 17.0

66.1 ± 18.4

66.6 ± 17.9

67.3 ± 17.5

67.7 ± 18.1

68.1 ± 15.9

66.3 ± 17.3

66.0 ± 19.6

67.3 ± 17.6

66.2 ± 18.1

66.7 ± 17.8

67.8 ± 17.5

53.3 ± 18.0

72.3 ± 13.8

49.1 ± 18.3

73.6 ± 12.6

53.0 ± 19.0

72.8 ± 13.4

48.3 ± 16.9

73.0 ± 13.2

68.7 ± 15.9

65.6 ± 19.0

67.1 ± 17.6

64.4 ± 19.6

68.7 ± 16.0

62.4 ± 20.4

67.2 ± 17.4

67.6 ± 17.8

65.3 ± 18.5

68.0 ± 16.9

67.6 ± 17.9

65.8 ± 18.6

64.7 ± 17.7

66.7 ± 18.1

67.9 ± 18.6

67.2 ± 17.5

67.3 ± 17.2

69.7 ± 16.2

66.1 ± 18.1

70.4 ± 17.3

66.2 ± 17.8

70.3 ± 16.4

67.1 ± 17.5

69.5 ± 16.9

BCVA by drug

Statistical analysis description

Difference in BCVA at 2 years, by drug allocation. Difference is estimated using data from visits 0, 3, 6, 9, 12, 15, 18, 21 and 24, adjusted for center size. Negative values reflect a better mean VA in the ranibizumab group. Non-inferiority limit = -3.5 letters

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.26

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.37

Confidence interval

level

95%

sides

2-sided

lower limit

-3.75

upper limit

1.01

BCVA by treatment regimen

Statistical analysis description

Difference in BCVA at 2 years, by treatment regimen. Difference is estimated using data from visits 0, 3, 6, 9, 12, 15, 18, 21 and 24, adjusted for center size. Negative values reflect a better mean VA in the continuous group. Non-inferiority limit = -3.5 letters

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.18

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.63

Confidence interval

level

95%

sides

2-sided

lower limit

-4.01

upper limit

0.75

BCVA by drug: Baseline BCVA in fellow eye ≥75

Comparison groups

Ranibizumab: Baseline BCVA in fellow eye ≥75 v Bevacizumab: Baseline BCVA in fellow eye ≥75

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.3 ^[1]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.77

Confidence interval

level

95%

sides

2-sided

lower limit

-5.11

upper limit

1.57

Notes
[1] - p-value for interaction between baseline BCVA in fellow eye and drug = 0.78

BCVA by drug: Baseline BCVA in fellow eye <75

Comparison groups

Ranibizumab: Baseline BCVA in fellow eye <75 v Bevacizumab: Baseline BCVA in fellow eye <75

Number of subjects included in analysis

287

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8 ^[2]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.45

Confidence interval

level

95%

sides

2-sided

lower limit

-3.91

upper limit

3.01

Notes
[2] - p-value for interaction between baseline BCVA in fellow eye and drug = 0.78

BCVA by regimen: Baseline BCVA in fellow eye ≥75

Comparison groups

Continuous: Baseline BCVA in fellow eye ≥75 v Discontinuous: Baseline BCVA in fellow eye ≥75

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.47 ^[3]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.24

Confidence interval

level

95%

sides

2-sided

lower limit

-4.59

upper limit

2.11

Notes
[3] - p-value for interaction between baseline BCVA in fellow eye and treatment regimen = 0.93

BCVA by regimen: Baseline BCVA in fellow eye <75

Comparison groups

Continuous: Baseline BCVA in fellow eye <75 v Discontinuous: Baseline BCVA in fellow eye <75

Number of subjects included in analysis

287

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.29 ^[4]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.88

Confidence interval

level

95%

sides

2-sided

lower limit

-5.35

upper limit

1.59

Notes
[4] - p-value for interaction between baseline BCVA in fellow eye and treatment regimen = 0.93

BCVA by drug: Baseline BCVA <55

Comparison groups

Ranibizumab: Baseline BCVA <55 v Bevacizumab: Baseline BCVA <55

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.022 ^[5]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-5.2

Confidence interval

level

95%

sides

2-sided

lower limit

-9.64

upper limit

-0.75

Notes
[5] - p-value for interaction between baseline BCVA and drug = 0.47

BCVA by drug: Baseline BCVA ≥55

Comparison groups

Ranibizumab: Baseline BCVA ≥55 v Bevacizumab: Baseline BCVA ≥55

Number of subjects included in analysis

428

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.8 ^[6]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-2.44

upper limit

3.16

Notes
[6] - p-value for interaction between baseline BCVA and drug = 0.47

BCVA by regimen: Baseline BCVA <55

Comparison groups

Continuous: Baseline BCVA <55 v Disontinuous: Baseline BCVA <55

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.15 ^[7]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-3.27

Confidence interval

level

95%

sides

2-sided

lower limit

-7.74

upper limit

1.19

Notes
[7] - p-value for interaction between baseline BCVA and treatment regimen = 0.89

BCVA by regimen: Baseline BCVA ≥55

Comparison groups

Continuous: Baseline BCVA ≥55 v Disontinuous: Baseline BCVA ≥55

Number of subjects included in analysis

428

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.53 ^[8]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

1.9

Notes
[8] - p-value for interaction between baseline BCVA and treatment regimen = 0.89

BCVA by drug: Baseline CNV size <6mm

Comparison groups

Bevacizumab: Baseline CNV size <6mm v Ranibizumab: Baseline CNV size <6mm

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.13 ^[9]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.25

Confidence interval

level

95%

sides

2-sided

lower limit

-5.15

upper limit

0.66

Notes
[9] - p-value for interaction between baseline CNV size and drug = 0.33

BCVA by drug: Baseline CNV size ≥6mm

Comparison groups

Ranibizumab: Baseline CNV size ≥6mm v Bevacizumab: Baseline CNV size ≥6mm

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.69 ^[10]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

-3.18

upper limit

4.81

Notes
[10] - p-value for interaction between baseline CNV size and drug = 0.33

BCVA by regimen: Baseline CNV size <6mm

Comparison groups

Continuous arm: Baseline CNV size <6mm v Discontinuous arm: Baseline CNV size <6mm

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.02 ^[11]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-3.46

Confidence interval

level

95%

sides

2-sided

lower limit

-6.36

upper limit

-0.55

Notes
[11] - p-value for interaction between baseline CNV size and treatment regimen = 0.26

BCVA by regimen: Baseline CNV size ≥6mm

Comparison groups

Continuous arm: Baseline CNV size ≥6mm v Discontinuous arm: Baseline CNV size ≥6mm

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.4 ^[12]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.72

Confidence interval

level

95%

sides

2-sided

lower limit

-2.28

upper limit

5.72

Notes
[12] - p-value for interaction between baseline CNV size and treatment regimen = 0.26

BCVA by drug: Baseline lesion <50% CNV

Comparison groups

Ranibizumab: Baseline lesion <50% CNV v Bevacizumab: Baseline lesion <50% CNV

Number of subjects included in analysis

116

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.68 ^[13]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

-4.26

upper limit

6.56

Notes
[13] - p-value for interaction between baseline lesion CNV proportion and drug = 0.36

BCVA by drug: Baseline lesion ≥50% CNV

Comparison groups

Bevacizumab: Baseline lesion ≥50% CNV v Ranibizumab: Baseline lesion ≥50% CNV

Number of subjects included in analysis

437

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.18 ^[14]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.89

Confidence interval

level

95%

sides

2-sided

lower limit

-4.67

upper limit

0.89

Notes
[14] - p-value for interaction between baseline lesion CNV proportion and drug = 0.36

BCVA by regimen: Baseline lesion <50% CNV

Comparison groups

Continuous: Baseline lesion <50% CNV v Discontinuous: Baseline lesion <50% CNV

Number of subjects included in analysis

116

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.13 ^[15]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-4.18

Confidence interval

level

95%

sides

2-sided

lower limit

-9.58

upper limit

1.21

Notes
[15] - p-value for interaction between baseline lesion CNV proportion and treatment regimen = 0.63

BCVA by regimen: Baseline lesion ≥50% CNV

Comparison groups

Continuous: Baseline lesion ≥50% CNV v Discontinuous: Baseline lesion ≥50% CNV

Number of subjects included in analysis

437

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.49 ^[16]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.98

Confidence interval

level

95%

sides

2-sided

lower limit

-3.76

upper limit

1.81

Notes
[16] - p-value for interaction between baseline lesion CNV proportion and treatment regimen = 0.63

BCVA by drug: Baseline RAP absent

Comparison groups

Ranibizumab: Baseline RAP absent v Bevacizumab: Baseline RAP absent

Number of subjects included in analysis

486

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.16 ^[17]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.91

Confidence interval

level

95%

sides

2-sided

lower limit

-4.55

upper limit

0.73

Notes
[17] - p-value for interaction between baseline RAP present/absent and drug = 0.71

BCVA by drug: Baseline RAP present

Comparison groups

Ranibizumab: Baseline RAP present v Bevacizumab: Baseline RAP present

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.3 ^[18]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

3.61

Confidence interval

level

95%

sides

2-sided

lower limit

-3.27

upper limit

10.48

Notes
[18] - p-value for interaction between baseline RAP present/absent and drug = 0.71

BCVA by regimen: Baseline RAP absent

Comparison groups

Continuous: Baseline RAP absent v Discontinuous: Baseline RAP absent

Number of subjects included in analysis

486

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.2 ^[19]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.74

Confidence interval

level

95%

sides

2-sided

lower limit

-4.38

upper limit

0.9

Notes
[19] - p-value for interaction between baseline RAP present/absent and treatment regimen = 0.85

BCVA by regimen: Baseline RAP present

Comparison groups

Continuous: Baseline RAP present v Discontinuous: Baseline RAP present

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.41 ^[20]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.86

Confidence interval

level

95%

sides

2-sided

lower limit

-9.67

upper limit

3.95

Notes
[20] - p-value for interaction between baseline RAP present/absent and treatment regimen = 0.85

BCVA by drug: Sensitivity analysis 1

Statistical analysis description

Sensitivity analysis of the primary outcome: excluding measurements taken 1 month later, when the main study visit was missed.

Comparison groups

Bevacizumab v Ranibizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.26

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.35

Confidence interval

level

95%

sides

2-sided

lower limit

-3.73

upper limit

1.03

BCVA by treatment regimen: Sensitivity analysis 1

Statistical analysis description

Sensitivity analysis of the primary outcome: excluding measurements taken 1 month later, when the main study visit was missed.

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.19

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.98

upper limit

0.78

BCVA by drug: Sensitivity analysis 2

Statistical analysis description

Sensitivity analysis of the primary outcome: including data only for the study visits at which all functional outcomes were assessed (visits 0, 3, 6, 12, 18 and 24).

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.16

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-4.08

upper limit

0.68

BCVA by treatment regimen: Sensitivity analysis 2

Statistical analysis description

Sensitivity analysis of the primary outcome: including data only for the study visits at which all functional outcomes were assessed (visits 0, 3, 6, 12, 18 and 24).

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.19

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.59

Confidence interval

level

95%

sides

2-sided

lower limit

-3.97

upper limit

0.79

Secondary: Frequencies of adverse events: Death from any cause

Top of page

End point title

Frequencies of adverse events: Death from any cause

End point description

Death from any cause

End point type

Secondary

End point timeframe

Duration of trial follow-up (maximum 2 years)

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Patients
Yes	15	15	10	20
No	299	281	298	182

Death from any cause, by drug

Statistical analysis description

ORs < 1 reflect fewer deaths during the 2 years of follow-up in the ranibizumab arm.

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.91

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

2.02

Death from any cause, by treatment regimen

Statistical analysis description

ORs < 1 reflect fewer deaths during the 2 years of follow-up in the continuous arm.

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.05

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

1.03

Secondary: Frequencies of adverse events: Arteriothrombotic event or heart failure

Top of page

End point title

Frequencies of adverse events: Arteriothrombotic event or heart failure

End point description

Arteriothrombotic event (MI, stroke, death from a vascular cause) or heart failure

End point type

Secondary

End point timeframe

Duration of trial follow-up (maximum 2 years)

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Patients
Yes	20	12	12	20
No	294	284	296	282

Arteriothrombotic or heart failure, by drug

Statistical analysis description

ORs < 1 reflect fewer events during the 2 years of follow-up in the ranibizumab arm.

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.16

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

3.57

Arteriothrombotic or heart failure, by regimen

Statistical analysis description

ORs < 1 reflect fewer events during the 2 years of follow-up in the continuous arm.

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.13

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

1.19

Secondary: Frequencies of adverse events: Any vascular event

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End point title

Frequencies of adverse events: Any vascular event

End point description

Vascular events include arteriothrombotic events, heart failure, deep-vein thrombosis, pulmonary embolism, transient ischaemic attack, hospitalisation for angina, and non-ocular haemorrhage

End point type

Secondary

End point timeframe

Duration of trial follow-up (maximum 2 years)

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Patients
Yes	31	19	21	29
No	283	277	287	273

Any vascular event, by drug

Statistical analysis description

ORs < 1 reflect fewer events during the 2 years of follow-up in the ranibizumab arm.

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

3.01

Any vascular event, by treatment regimen

Statistical analysis description

ORs < 1 reflect fewer events during the 2 years of follow-up in the continuous arm.

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.21

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.38

upper limit

1.24

Secondary: Frequencies of adverse events: Any vascular event or death

Top of page

End point title

Frequencies of adverse events: Any vascular event or death

End point description

End point type

Secondary

End point timeframe

Duration of trial follow-up (maximum 2 years)

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Patients
Yes	38	28	27	39
No	276	268	281	263

Any vascular event or death, by drug

Statistical analysis description

ORs < 1 reflect fewer events during the 2 years of follow-up in the ranibizumab arm.

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.25

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

2.29

Any vascular event or death, by treatment regimen

Statistical analysis description

ORs < 1 reflect fewer events during the 2 years of follow-up in the continuous arm.

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

0.38

upper limit

1.09

Secondary: Frequencies of adverse events: Any systemic event

Top of page

End point title

Frequencies of adverse events: Any systemic event

End point description

≥1 serious systemic event (includes any non-ocular serious adverse event)

End point type

Secondary

End point timeframe

Duration of trial follow-up (maximum 2 years)

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Patients
Yes	81	80	74	87
No	233	216	234	215

Any systemic event, by drug

Statistical analysis description

ORs < 1 reflect fewer events during the 2 years of follow-up in the ranibizumab arm

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.82

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

1.39

Any systemic event, by treatment regimen

Statistical analysis description

ORs < 1 reflect fewer events during the 2 years of follow-up in the continuous arm

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.16

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.11

Secondary: Health-related quality of life: EQ-5D

Top of page

End point title

Health-related quality of life: EQ-5D

End point description

For the EQ-5D utility index, higher summary scores represent better utility.

End point type

Secondary

End point timeframe

Participants completed the EQ-5D at visits 0, 3, 12 and 24

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Score
median (inter-quartile range (Q1-Q3))	0.85 (0.73 to 1.00)	0.85 (0.73 to 1.00)	0.85 (0.73 to 1.00)	0.85 (0.73 to 1.00)

EQ-5D score, by drug

Statistical analysis description

For EQ-5D no suitable transformation could be found and so data were dichotomized as ‘perfect health’ (EQ-5D score of 1) compared with less than perfect health. ORs <1 reflect higher quality of life during the 2 years of follow-up in the ranibizumab arm.

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.51

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

1.25

EQ-5D score, by treatment regimen

Statistical analysis description

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.64

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

1.29

Secondary: Health-related quality of life: MacDQol

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End point title

Health-related quality of life: MacDQol

End point description

MacDQol (Macular disease Dependent Quality of Life) is an instrument designed to assess macular disease-specific quality of life. Lower scores represent less impact of nAMD on quality of life.

End point type

Secondary

End point timeframe

Administered by telephone after visits 3, 12 and 24.

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Score
median (inter-quartile range (Q1-Q3))	-1.5 (-2.8 to -0.3)	-1.4 (-2.7 to -0.4)	-1.3 (-2.7 to -0.3)	-1.6 (-3.0 to -0.4)

MacDQol, by drug

Statistical analysis description

For MacDQoL, the outcome was transformed from original scale of –9 to +3 to a scale of –3 to +9, and analysed using a log transformation. The GMR is, therefore, interpreted as the GMR of the MacDQoL score, and not of the MacDQoL score directly. GMR <1 reflect higher quality of life during the 2 years of follow-up in the ranibizumab arm

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.74

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

1.42

MacDQol, by treatment regimen

Statistical analysis description

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.73

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.28

Secondary: Treatment satisfaction: MacTSQ

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End point title

Treatment satisfaction: MacTSQ

End point description

MacTSQ (Macular disease Treatment Satisfaction Questionnaire) is an instrument designed to assess patients’ satisfaction with treatment for nAMD. Higher summary scores represent a higher treatment satisfaction.

End point type

Secondary

End point timeframe

Administered by telephone after visits 3, 12 and 24.

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Score
median (inter-quartile range (Q1-Q3))	66 (61.5 to 70)	65 (60 to 69)	65.5 (61 to 69)	66 (60 to 69)

MacTSQ, by drug

Statistical analysis description

For MacTSQ at 2 years, no suitable transformation could be found and so data were dichotomized (MacTSQ < median TSQ score over all time points vs. ≥ median TSQ score over all time points). ORs <1 reflect higher quality of life during the 2 years of follow-up in the ranibizumab arm.

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.23

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.16

MacTSQ, by treatment regimen

Statistical analysis description

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.47

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.68

Secondary: Resource use: Injection consultation

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End point title

Resource use: Injection consultation

End point description

Measured as the number of episodes of injection consultations.

End point type

Secondary

End point timeframe

Resource use used by the average patient during 2-year study period

End point values	Discontinuous bevacizumab	Continuous bevacizumab	Discontinuous ranibizumab	Continuous ranibizumab
Number of subjects analysed	146	150	156	158
Units: Number of consultations
arithmetic mean (confidence interval 95%)	13.0 (12.3 to 13.8)	22.0 (21.6 to 22.4)	12.7 (12.0 to 13.4)	21.7 (21.2 to 22.1)

Injection consultations, by drug

Statistical analysis description

Ranibizumab vs. bevacizumab

Comparison groups

Discontinuous bevacizumab v Continuous bevacizumab v Discontinuous ranibizumab v Continuous ranibizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.4

Injection consultations, by treatment regimen

Statistical analysis description

Continuous vs. discontinuous

Comparison groups

Discontinuous bevacizumab v Continuous bevacizumab v Discontinuous ranibizumab v Continuous ranibizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

8.3

upper limit

9.7

Secondary: Resource use: Monitoring consultations

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End point title

Resource use: Monitoring consultations

End point description

Measured as the number of episodes of monitoring consultations.

End point type

Secondary

End point timeframe

Resource use used by the average patient during 2-year study period

End point values	Discontinuous bevacizumab	Continuous bevacizumab	Discontinuous ranibizumab	Continuous ranibizumab
Number of subjects analysed	146	150	156	158
Units: Number of consultations
arithmetic mean (confidence interval 95%)	13.2 (12.7 to 13.8)	7.1 (6.9 to 7.4)	13.7 (13.1 to 14.2)	7.6 (7.4 to 7.9)

Monitoring consultations, by drug

Statistical analysis description

Ranibizumab vs. bevacizumab

Comparison groups

Continuous bevacizumab v Discontinuous ranibizumab v Discontinuous bevacizumab v Continuous ranibizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.9

Monitoring consultations, by treatment regimen

Statistical analysis description

Continuous vs. discontinuous

Comparison groups

Discontinuous bevacizumab v Continuous bevacizumab v Discontinuous ranibizumab v Continuous ranibizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-6.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.5

upper limit

-5.6

Secondary: Resource use: Bed-days linked to expected SAEs

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End point title

Resource use: Bed-days linked to expected SAEs

End point description

Measured as the number of episodes of bed-days linked to expected SAEs.

End point type

Secondary

End point timeframe

Resource use used by the average patient during 2-year study period

End point values	Discontinuous bevacizumab	Continuous bevacizumab	Discontinuous ranibizumab	Continuous ranibizumab
Number of subjects analysed	146	150	156	158
Units: Days
arithmetic mean (confidence interval 95%)	1.0 (-0.2 to 2.1)	0.8 (0.1 to 1.4)	0.7 (0.2 to 1.2)	0.3 (0.0 to 0.6)

Bed-days, by drug (continuous arm)

Statistical analysis description

Continuous arm: Ranibizumab vs. bevacizumab

Comparison groups

Continuous bevacizumab v Continuous ranibizumab

Number of subjects included in analysis

308

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

0.3

Bed-days, by drug (discontinuous arm)

Statistical analysis description

Discontinuous arm: Ranibizumab vs. bevacizumab

Comparison groups

Discontinuous bevacizumab v Discontinuous ranibizumab

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

Bed-days, by treatment regimen (ranibizumab arm)

Statistical analysis description

Ranibizumab arm: Continuous vs. discontinuous

Comparison groups

Discontinuous ranibizumab v Continuous ranibizumab

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.3

Bed-days, by treatment regimen (bevacizumab)

Statistical analysis description

Bevacizumab arm: Continuous vs. discontinuous

Comparison groups

Discontinuous bevacizumab v Continuous bevacizumab

Number of subjects included in analysis

296

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

1.1

Secondary: Resource use: Ambulatory consultations

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End point title

Resource use: Ambulatory consultations

End point description

Measured as the number of episodes of ambulatory resource use, when an ‘episode’ encompasses all contacts with medical professionals on the same date. For example, seeing a GP and a practice nurse on the same date is counted as one ambulatory consultation in this analysis.

End point type

Secondary

End point timeframe

Resource use used by the average patient during 2-year study period. Consultations within 30 days of expected (S)AEs.

End point values	Discontinuous bevacizumab	Continuous bevacizumab	Discontinuous ranibizumab	Continuous ranibizumab
Number of subjects analysed	146	150	156	158
Units: Number of consultations
arithmetic mean (confidence interval 95%)	2.8 (2.2 to 3.5)	3.1 (2.4 to 3.7)	2.8 (2.3 to 3.3)	3.1 (2.4 to 3.9)

Ambulatory consultations, by drug (continuous)

Statistical analysis description

Continuous arm: Ranibizumab vs. bevacizumab

Comparison groups

Continuous bevacizumab v Continuous ranibizumab

Number of subjects included in analysis

308

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

1.1

Ambulatory consultations, by drug (discontinuous)

Statistical analysis description

Discontinuous arm: Ranibizumab vs. bevacizumab

Comparison groups

Discontinuous bevacizumab v Discontinuous ranibizumab

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

0.8

Ambulatory consultations, by regimen (ranibizumab)

Statistical analysis description

Ranibizumab arm: Continuous vs. discontinuous

Comparison groups

Discontinuous ranibizumab v Continuous ranibizumab

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

1.2

Ambulatory consultations, by regimen (bevacizumab)

Statistical analysis description

Bevacizumab arm: Continuous vs. discontinuous

Comparison groups

Discontinuous bevacizumab v Continuous bevacizumab

Number of subjects included in analysis

296

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.1

Secondary: Resource use: Changes in medications

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End point title

Resource use: Changes in medications

End point description

Changes in medications associated with expected (S)AEs.

End point type

Secondary

End point timeframe

Resource use used by the average patient during 2-year study period.

End point values	Discontinuous bevacizumab	Continuous bevacizumab	Discontinuous ranibizumab	Continuous ranibizumab
Number of subjects analysed	146	150	156	158
Units: Number of changes
arithmetic mean (confidence interval 95%)	3.0 (2.5 to 3.6)	2.6 (2.2 to 3.1)	2.8 (2.2 to 3.4)	3.0 (2.4 to 3.6)

Changes in medication, by drug (continuous)

Statistical analysis description

Continuous arm: Ranibizumab vs. bevacizumab

Comparison groups

Continuous bevacizumab v Continuous ranibizumab

Number of subjects included in analysis

308

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.1

Changes in medication, by drug (discontinuous)

Statistical analysis description

Discontinuous arm: Ranibizumab vs. bevacizumab

Comparison groups

Discontinuous bevacizumab v Discontinuous ranibizumab

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.6

Changes in medication, by regimen (ranibizumab)

Statistical analysis description

Ranibizumab arm: Continuous vs. discontinuous

Comparison groups

Discontinuous ranibizumab v Continuous ranibizumab

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

Changes in medication, by regimen (bevacizumab)

Statistical analysis description

Bevacizumab arm: Continuous vs. discontinuous

Comparison groups

Continuous bevacizumab v Discontinuous bevacizumab

Number of subjects included in analysis

296

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

0.3

Secondary: Cost effectiveness: QALYs

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End point title

Cost effectiveness: QALYs

End point description

End point type

Secondary

End point timeframe

Mean QUALYs per patient over the 2-year trial period.

End point values	Discontinuous bevacizumab	Continuous bevacizumab	Discontinuous ranibizumab	Continuous ranibizumab
Number of subjects analysed	146	150	156	158
Units: QUALY
arithmetic mean (confidence interval 95%)	1.584 (1.583 to 1.630)	1.604 (1.563 to 1.645)	1.582 (1.530 to 1.634)	1.608 (1.565 to 1.651)

QALY, by drug (continuous)

Statistical analysis description

Continuous arm: Ranibizumab vs. bevacizumab

Comparison groups

Continuous bevacizumab v Continuous ranibizumab

Number of subjects included in analysis

308

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.004

Confidence interval

level

95%

sides

2-sided

lower limit

-0.046

upper limit

0.054

QALY, by drug (discontinuous)

Statistical analysis description

Discontinuous arm: Ranibizumab vs. bevacizumab

Comparison groups

Discontinuous bevacizumab v Discontinuous ranibizumab

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

-0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-0.064

upper limit

0.06

QALY, by treatment regimen (ranibizumab)

Statistical analysis description

Ranibizumab arm: Continuous vs. discontinuous

Comparison groups

Discontinuous ranibizumab v Continuous ranibizumab

Number of subjects included in analysis

314

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.032

upper limit

0.085

QALY, by treatment regimen (bevacizumab)

Statistical analysis description

Bevacizumab arm: Continuous vs. discontinuous

Comparison groups

Discontinuous bevacizumab v Continuous bevacizumab

Number of subjects included in analysis

296

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mean difference (final values)

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.032

upper limit

0.071

Secondary: Clinical measures of vision: Near visual acuity

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End point title

Clinical measures of vision: Near visual acuity

End point description

Near visual acuity (NVA) is measured in logMAR units using charts that utilise words of specific character sizes and lengths.

End point type

Secondary

End point timeframe

Measured at 0, 3, 6, 12, 18 and 24 months

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: logMAR
arithmetic mean (standard deviation)	0.55 ± 0.39	0.61 ± 0.42	0.58 ± 0.40	0.58 ± 0.41

Near visual acuity, by drug

Statistical analysis description

Difference in NVA at 2 years, by drug allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. GMR values of < 1 reflect a better outcome in the ranibizumab group.

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.23

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.04

Near visual acuity, by treatment regimen

Statistical analysis description

Difference in NVA at 2 years, by treatment regimen allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. GMR values of < 1 reflect a better outcome in the continuous group.

Comparison groups

Discontinuous v Continuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.04

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

0.99

Secondary: Clinical measures of vision: Reading index

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End point title

Clinical measures of vision: Reading index

End point description

Reading index is a derivative of reading speed. Reading speed is a psychophysical test, which measures ability to read a string of words without reference to context. It tests the ability of the eye to scan along a line of words, and this function is impaired if visual deficits are present in the parafoveal retina. Reading speed is measured using a print size subtending a visual angle that is 0.1 logMAR larger than the threshold NVA and expressed in units of words read per minute. The reading index is the reading speed divided by the size of print read and thus makes allowance for the visual angle.

End point type

Secondary

End point timeframe

Measured at 0, 3, 6, 12, 18 and 24 months

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Words read
median (inter-quartile range (Q1-Q3))	50.9 (22.8 to 93.7)	52.5 (9.7 to 90.6)	46.3 (11.4 to 84.0)	55.4 (19.0 to 97.6)

Reading index, by drug

Statistical analysis description

Difference in reading index at 2 years, by drug allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. Negative values reflect a better outcome in the ranibizumab group.

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.7

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.34

Confidence interval

level

95%

sides

2-sided

lower limit

-8.29

upper limit

5.61

Reading index, by treatment regimen

Statistical analysis description

Difference in reading index at 2 years, by treatment regimen allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. Negative values reflect a better outcome in the continuous group.

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.93

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-7.27

upper limit

6.62

Secondary: Clinical measures of vision: Contrast sensitivity

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End point title

Clinical measures of vision: Contrast sensitivity

End point description

Contrast sensitivity is a global measure of macular function. It has been suggested that it represents a better surrogate marker for visual function than BCVA by virtue of the fact that some studies have observed better correlation with patient-reported outcomes.

End point type

Secondary

End point timeframe

Measured at 0, 3, 6, 12, 18 and 24 months

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Letters
arithmetic mean (standard deviation)	28.1 ± 6.0	28.3 ± 5.8	28.7 ± 5.4	27.7 ± 6.3

Contrast sensitivity, by drug

Statistical analysis description

Difference in contrast sensitivity at 2 years, by drug allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. Negative values reflect a better outcome in the ranibizumab group.

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.62

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.62

upper limit

1.04

Contrast sensitivity, by treatment regimen

Statistical analysis description

Difference in contrast sensitivity at 2 years, by treatment regimen allocation. Difference is estimated using data from visits 0, 3, 6, 12, 18 and 24, adjusted for center size. Negative values reflect a better outcome in the continuous group.

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.011

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.07

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

-0.25

Secondary: Lesion morphology: Geographic atrophy

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End point title

Lesion morphology: Geographic atrophy

End point description

New GA during follow-up in trial. Assessed from colour and FFA. Area ≥ 175 μm greatest linear dimension with two or more relevant features in colour images (well-defined margins; visibility of choroidal vessels; scalloped edges) and consistent finding on FFA (early hyperfluorescence, persisting through the FFA sequence and fading in late images)

End point type

Secondary

End point timeframe

During follow-up in trial. Measured at baseline, 12 and 24 months.

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Patients	86	91	101	76

Geographic atrophy, by drug

Statistical analysis description

Ratios of < 1 reflect better outcomes in the ranibizumab group

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.46

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

1.25

Geographic atrophy, by treatment regimen

Statistical analysis description

Ratios of < 1 reflect better outcomes in the continuous group

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.033

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.47

Confidence interval

level

95%

sides

2-sided

lower limit

1.03

upper limit

2.11

Secondary: Lesion morphology: Dye leakage

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End point title

Lesion morphology: Dye leakage

End point description

Dye leakage on angiogram (assesed from FFA). Areas of featureless hyperfluorescence that increase in the late frames and which may also exhibit well delineated hyperfluorescence in the early frames.

End point type

Secondary

End point timeframe

Measured at baseline, 12 and 24 months.

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Patients	101	89	86	104

Dye leakage, by drug

Statistical analysis description

Ratios of < 1 reflect better outcomes in the ranibizumab group

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.46

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.67

Dye leakage, by treatment regimen

Statistical analysis description

Ratios of < 1 reflect better outcomes in the continuous group

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.11

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.74

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.07

Secondary: Lesion morphology: Fluid

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End point title

Lesion morphology: Fluid

End point description

Any fluid on OCT

End point type

Secondary

End point timeframe

Measured at 0, 3, 6, 9, 12, 15, 18, 21 and 24 months

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Patients	127	141	112	156

Fluid, by drug

Statistical analysis description

Ratios of < 1 reflect better outcomes in the ranibizumab group

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.065

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

1.02

Fluid, by treatment regimen

Statistical analysis description

Ratios of < 1 reflect better outcomes in the continuous group

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

0.67

Secondary: Lesion morphology: Lesion present

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End point title

Lesion morphology: Lesion present

End point description

Assessed from FFA

End point type

Secondary

End point timeframe

Measured at baseline, 12 and 24 months.

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Patients	142	127	123	146

Lesion present, by drug

Statistical analysis description

Ratios of < 1 reflect better outcomes in the ranibizumab group

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.44

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.67

Lesion present, by treatment regimen

Statistical analysis description

Ratios of < 1 reflect better outcomes in the continuous group

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.024

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

0.95

Secondary: Lesion morphology: Retinal plus subretinal fluid thickness at fovea

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End point title

Lesion morphology: Retinal plus subretinal fluid thickness at fovea

End point description

Assessed from OCT. Foveal neuroretinal thickness (a linear measurement of the distance between the inner and outer boundary of the neurosensory retina at the foveal centre) plus SRF thickness at fovea (height of hyporeflective region separating the RPE band from the outer boundary of the neurosensory retina at the foveal centre).

End point type

Secondary

End point timeframe

Measured at 0, 3, 6, 9, 12, 15, 18, 21 and 24 months.

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: µm
arithmetic mean (standard deviation)	163.5 ± 77.7	172.7 ± 95.7	161.7 ± 84.2	174.4 ± 89.4

Retinal plus SRF thickness, by drug

Statistical analysis description

Ratios of < 1 reflect better outcomes in the ranibizumab group

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.75

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.08

Retinal plus SRF thickness, by treament regimen

Statistical analysis description

Ratios of < 1 reflect better outcomes in the continuous group

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.046

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

Secondary: Lesion morphology: Total lesion thickness at the fovea

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End point title

Lesion morphology: Total lesion thickness at the fovea

End point description

Assessed from OCT. Sum of foveal neuroretinal thickness (a linear measurement of the distance between the inner and outer boundary of the neurosensory retina at the foveal centre), SRF thickness at fovea (height of hyporeflective region separating the RPE band from the outer boundary of the neurosensory retina at the foveal centre) and PED (Elevation of the hyper-reflective band corresponding to the RPE and or scar at the foveal centre).

End point type

Secondary

End point timeframe

Measured at 0, 3, 6, 9, 12, 15, 18, 21 and 24 months.

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: µM
arithmetic mean (standard deviation)	322.4 ± 137.3	331 ± 144.2	314.7 ± 137.1	338.5 ± 143.3

Total lesion thickness, by drug

Statistical analysis description

Ratios of < 1 reflect better outcomes in the ranibizumab group

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.24

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.03

Total lesion thickness, by treatment regimen

Statistical analysis description

Ratios of < 1 reflect better outcomes in the continuous group

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0035

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

0.97

Secondary: Best corrected visual acuity at 1 year

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End point title

Best corrected visual acuity at 1 year

End point description

Results of interim analysis: BCVA after all patients have been followed for 1 year after starting treatment.

End point type

Secondary

End point timeframe

Measured at 0, 3, 6, and 12 months

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308	302
Units: Letters
arithmetic mean (standard deviation)	69.0 ± 16.0	66.1 ± 17.4	66.8 ± 17.4	68.4 ± 16.1

BCVA at 1 year, by drug

Statistical analysis description

Difference in BCVA at 1 year, by drug allocation. Difference is estimated using data from visits 0, 3, 6 and 12, adjusted for center size. Negative values reflect a better mean VA in the ranibizumab group. Non-inferiority limit = -3.5 letters

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.056

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.99

Confidence interval

level

95%

sides

2-sided

lower limit

-4.04

upper limit

0.06

BCVA at 1 year, by treatment regimen

Statistical analysis description

Difference in BCVA at 1 year, by treatment regimen allocation. Difference is estimated using data from visits 0, 3, 6 and 12, adjusted for center size. Negative values reflect a better mean VA in the continuous group. Non-inferiority limit = -3.5 letters

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.74

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

1.7

Secondary: Survival free from treatment failure

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End point title

Survival free from treatment failure

End point description

Treatment failure: Satisfying one or more of the criteria for re-treatment.

End point type

Secondary

End point timeframe

Re-treatment criteria collected monthly from month 3-24.

End point values	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Number of subjects analysed	314	296	308 ^[21]	302
Units: Months
median (inter-quartile range (Q1-Q3))	5.1 (3.7 to 16.8)	4.9 (3.2 to 14.0)	7.6 (3.2 to 24.0)	4.4 (3.2 to 6.9)

Notes
[21] - 75th percentile (Q3) not reached. Maximum duration (24 months) entered.

Time to treatment failure, by drug

Statistical analysis description

Hazard ratio (bevacizumab–ranibizumab)

Comparison groups

Ranibizumab v Bevacizumab

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.18

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.36

Time to treatment failure, by regimen

Statistical analysis description

Hazard ratio (discontinuous–continuous)

Comparison groups

Continuous v Discontinuous

Number of subjects included in analysis

610

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.95

Confidence interval

level

95%

sides

2-sided

lower limit

1.61

upper limit

2.35

Adverse events

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Timeframe for reporting adverse events

Adverse events, both serious and non-serious, were recorded at each visit.

Adverse event reporting additional description

All expected adverse events and unexpected adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA, McLean, VA, USA). All SAEs were reviewed by senior clinicians masked to treatment allocation.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

14.1

Reporting group title

Ranibizumab

Reporting group description

Intravitreal injections of ranibizumab (0.5mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

Reporting group title

Bevacizumab

Reporting group description

Intravitreal injections of bevacizumab (1.25mg), either monthly (if randomised to continuous treatment regimen) or as-needed (if randomised to discontinuous treatment regimen).

Reporting group title

Continuous

Reporting group description

Monthly treatment.

Reporting group title

Discontinuous

Reporting group description

Treated if pre specified clinical and OCT criteria for active disease were met. If re-treatment was needed, a further cycle of three doses was given monthly.

Serious adverse events	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Total subjects affected by serious adverse events
subjects affected / exposed	87 / 314 (27.71%)	84 / 296 (28.38%)	79 / 308 (25.65%)	92 / 302 (30.46%)
number of deaths (all causes)	15	15	10	20
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
Breast cancer
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
Gallbladder cancer
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal carcinoma
subjects affected / exposed	0 / 314 (0.00%)	2 / 296 (0.68%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic neoplasm malignant
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Lung neoplasm malignant
subjects affected / exposed	5 / 314 (1.59%)	2 / 296 (0.68%)	3 / 308 (0.97%)	4 / 302 (1.32%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
Mantle cell lymphoma
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Mesothelioma
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	3 / 308 (0.97%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0
Oesophageal carcinoma
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cancer
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
Pancreatic carcinoma
subjects affected / exposed	0 / 314 (0.00%)	2 / 296 (0.68%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer metastatic
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Vascular disorders
Circulatory collapse
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	3 / 314 (0.96%)	1 / 296 (0.34%)	2 / 308 (0.65%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	2 / 3	0 / 1	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Orthostatic hypotension
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Poor peripheral circulation
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vasculitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Analgesic therapy
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic aneurysm repair
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac pacemaker insertion
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cataract operation
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chemotherapy
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystectomy
subjects affected / exposed	0 / 314 (0.00%)	2 / 296 (0.68%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithotomy
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cochlea implant
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery bypass
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterostomy
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrostomy tube insertion
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hip arthroplasty
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hospitalisation
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hysterectomy
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Knee arthroplasty
subjects affected / exposed	1 / 314 (0.32%)	2 / 296 (0.68%)	1 / 308 (0.32%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Knee operation
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung lobectomy
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mastectomy
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral nerve operation
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sebaceous cyst excision
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin neoplasm excision
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgery
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transurethral bladder resection
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transurethral prostatectomy
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vulval operation
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	15 / 314 (4.78%)	15 / 296 (5.07%)	10 / 308 (3.25%)	20 / 302 (6.62%)
occurrences causally related to treatment / all	4 / 15	3 / 15	2 / 10	5 / 20
deaths causally related to treatment / all	4 / 15	3 / 15	2 / 10	5 / 20
Multi-organ failure
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Swelling
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Social circumstances
Convalescent
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postmenopausal haemorrhage
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Chronic obstructive pulmonary disease
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	2 / 308 (0.65%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Emphysema
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 314 (0.96%)	3 / 296 (1.01%)	3 / 308 (0.97%)	3 / 302 (0.99%)
occurrences causally related to treatment / all	1 / 3	1 / 3	1 / 3	1 / 3
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
Investigations
Biopsy
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biopsy vulva
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endoscopy upper gastrointestinal tract
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
IOP increased
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	7 / 314 (2.23%)	2 / 296 (0.68%)	3 / 308 (0.97%)	6 / 302 (1.99%)
occurrences causally related to treatment / all	0 / 7	0 / 2	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal stoma complication
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 314 (0.32%)	3 / 296 (1.01%)	2 / 308 (0.65%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
Upper limb fracture
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	7 / 314 (2.23%)	3 / 296 (1.01%)	6 / 308 (1.95%)	4 / 302 (1.32%)
occurrences causally related to treatment / all	4 / 7	2 / 3	3 / 6	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 314 (0.32%)	2 / 296 (0.68%)	1 / 308 (0.32%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 314 (0.00%)	3 / 296 (1.01%)	0 / 308 (0.00%)	3 / 302 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	1 / 2	0 / 0	1 / 2
Cardiac failure
subjects affected / exposed	7 / 314 (2.23%)	2 / 296 (0.68%)	5 / 308 (1.62%)	4 / 302 (1.32%)
occurrences causally related to treatment / all	0 / 7	0 / 2	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Cor pulmonale
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Left ventricular failure
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
Mitral valve incompetence
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
MI
subjects affected / exposed	4 / 314 (1.27%)	4 / 296 (1.35%)	2 / 308 (0.65%)	6 / 302 (1.99%)
occurrences causally related to treatment / all	4 / 4	3 / 5	2 / 2	5 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial haemorrhage
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
Supraventricular tachycardia
subjects affected / exposed	0 / 314 (0.00%)	2 / 296 (0.68%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	7 / 314 (2.23%)	3 / 296 (1.01%)	4 / 308 (1.30%)	6 / 302 (1.99%)
occurrences causally related to treatment / all	6 / 7	2 / 3	3 / 4	5 / 6
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
Facial paresis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Frontotemporal dementia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Unresponsive to stimuli
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Microcytic anaemia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Meniere's disease
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden hearing loss
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Amaurosis fugax
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blindness
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cataract traumatic
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diplopia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Keratitis
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal haemorrhage
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
RPE tear
subjects affected / exposed	3 / 314 (0.96%)	1 / 296 (0.34%)	2 / 308 (0.65%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal vein occlusion
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uveitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vitreous haemorrhage
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-study eye: AMD
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-study eye: Cataract
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-study eye: Endophthalmitis
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-study eye: Herpes zoster
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-study eye: Wound evisceration
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	2 / 308 (0.65%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis chronic
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary bladder polyp
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	0 / 308 (0.00%)	3 / 302 (0.99%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	4 / 314 (1.27%)	5 / 296 (1.69%)	5 / 308 (1.62%)	4 / 302 (1.32%)
occurrences causally related to treatment / all	0 / 5	0 / 5	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Pneumonia
subjects affected / exposed	3 / 314 (0.96%)	5 / 296 (1.69%)	3 / 308 (0.97%)	5 / 302 (1.66%)
occurrences causally related to treatment / all	1 / 3	0 / 5	0 / 3	1 / 5
deaths causally related to treatment / all	1 / 1	0 / 1	0 / 1	1 / 1
Upper respiratory tract infection
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 314 (0.32%)	2 / 296 (0.68%)	3 / 308 (0.97%)	0 / 302 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Ranibizumab	Bevacizumab	Continuous	Discontinuous
Total subjects affected by non serious adverse events
subjects affected / exposed	294 / 314 (93.63%)	276 / 296 (93.24%)	289 / 308 (93.83%)	281 / 302 (93.05%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified
subjects affected / exposed	15 / 314 (4.78%)	9 / 296 (3.04%)	11 / 308 (3.57%)	13 / 302 (4.30%)
occurrences all number	15	10	12	13
Vascular disorders
Vascular disorders
subjects affected / exposed	55 / 314 (17.52%)	51 / 296 (17.23%)	58 / 308 (18.83%)	48 / 302 (15.89%)
occurrences all number	72	66	79	59
Surgical and medical procedures
Surgical and medical procedures
subjects affected / exposed	19 / 314 (6.05%)	15 / 296 (5.07%)	13 / 308 (4.22%)	21 / 302 (6.95%)
occurrences all number	23	16	14	25
General disorders and administration site conditions
General disorders and administration site conditions
subjects affected / exposed	40 / 314 (12.74%)	49 / 296 (16.55%)	46 / 308 (14.94%)	43 / 302 (14.24%)
occurrences all number	52	61	56	57
Immune system disorders
Immune system disorders
subjects affected / exposed	10 / 314 (3.18%)	7 / 296 (2.36%)	9 / 308 (2.92%)	8 / 302 (2.65%)
occurrences all number	10	8	10	8
Social circumstances
Social circumstances
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Reproductive system and breast disorders
Reproductive system and breast disorders
subjects affected / exposed	6 / 314 (1.91%)	7 / 296 (2.36%)	3 / 308 (0.97%)	10 / 302 (3.31%)
occurrences all number	7	7	3	11
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
subjects affected / exposed	125 / 314 (39.81%)	122 / 296 (41.22%)	119 / 308 (38.64%)	128 / 302 (42.38%)
occurrences all number	218	199	199	218
Psychiatric disorders
Psychiatric disorders
subjects affected / exposed	10 / 314 (3.18%)	10 / 296 (3.38%)	13 / 308 (4.22%)	7 / 302 (2.32%)
occurrences all number	14	11	17	8
Hepatobiliary disorders
Hepatobiliary disorders
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	1 / 308 (0.32%)	2 / 302 (0.66%)
occurrences all number	3	1	1	3
Investigations
Investigation
subjects affected / exposed	18 / 314 (5.73%)	24 / 296 (8.11%)	19 / 308 (6.17%)	23 / 302 (7.62%)
occurrences all number	21	28	22	27
Injury, poisoning and procedural complications
Accident
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	1	1	1	1
Animal bite
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	2 / 308 (0.65%)	1 / 302 (0.33%)
occurrences all number	2	1	2	1
Ankle fracture
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Arthropod bite
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	2 / 308 (0.65%)	0 / 302 (0.00%)
occurrences all number	1	2	3	0
Cartilage injury
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Contusion
subjects affected / exposed	11 / 314 (3.50%)	3 / 296 (1.01%)	10 / 308 (3.25%)	4 / 302 (1.32%)
occurrences all number	13	3	12	4
Epicondylitis
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Excoriation
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Eye injury
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Face injury
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Fall
subjects affected / exposed	31 / 314 (9.87%)	27 / 296 (9.12%)	31 / 308 (10.06%)	27 / 302 (8.94%)
occurrences all number	40	37	40	37
Foot fracture
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Foreign body
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Fracture
subjects affected / exposed	2 / 314 (0.64%)	6 / 296 (2.03%)	2 / 308 (0.65%)	6 / 302 (1.99%)
occurrences all number	3	6	2	7
Hand fracture
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
injury
subjects affected / exposed	2 / 314 (0.64%)	3 / 296 (1.01%)	2 / 308 (0.65%)	3 / 302 (0.99%)
occurrences all number	2	3	2	3
Joint dislocation
subjects affected / exposed	2 / 314 (0.64%)	2 / 296 (0.68%)	2 / 308 (0.65%)	2 / 302 (0.66%)
occurrences all number	2	2	2	2
Joint injury
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	2	0	1	1
Joint sprain
subjects affected / exposed	4 / 314 (1.27%)	3 / 296 (1.01%)	2 / 308 (0.65%)	5 / 302 (1.66%)
occurrences all number	4	3	2	5
Laceration
subjects affected / exposed	5 / 314 (1.59%)	3 / 296 (1.01%)	4 / 308 (1.30%)	4 / 302 (1.32%)
occurrences all number	6	3	5	4
Ligament sprain
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Limb injury
subjects affected / exposed	7 / 314 (2.23%)	5 / 296 (1.69%)	9 / 308 (2.92%)	3 / 302 (0.99%)
occurrences all number	7	5	9	3
Mouth injury
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Muscle strain
subjects affected / exposed	4 / 314 (1.27%)	3 / 296 (1.01%)	4 / 308 (1.30%)	3 / 302 (0.99%)
occurrences all number	4	3	4	3
Rib fracture
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Road traffic accident
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Thermal burn
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences all number	3	0	0	3
Vascular injury
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	2 / 308 (0.65%)	0 / 302 (0.00%)
occurrences all number	2	0	2	0
Congenital, familial and genetic disorders
Congenital, familial and genetic disorders
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Cardiac disorders
Angina pectoris
subjects affected / exposed	4 / 314 (1.27%)	4 / 296 (1.35%)	4 / 308 (1.30%)	4 / 302 (1.32%)
occurrences all number	5	4	4	5
Arrhythmia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Atrial fibrillation
subjects affected / exposed	4 / 314 (1.27%)	4 / 296 (1.35%)	4 / 308 (1.30%)	4 / 302 (1.32%)
occurrences all number	4	4	4	4
Bradycardia
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Cardiac disorder
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Cardiac flutter
subjects affected / exposed	0 / 314 (0.00%)	2 / 296 (0.68%)	2 / 308 (0.65%)	0 / 302 (0.00%)
occurrences all number	0	2	2	0
Cardiac valve disease
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Mitral valve incompetence
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences all number	1	1	0	2
Palpitations
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	2 / 308 (0.65%)	0 / 302 (0.00%)
occurrences all number	4	0	4	0
Supraventricular tachycardia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Tachycardia
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences all number	1	1	0	2
Nervous system disorders
Nervous system disorders
subjects affected / exposed	90 / 314 (28.66%)	77 / 296 (26.01%)	76 / 308 (24.68%)	91 / 302 (30.13%)
occurrences all number	157	108	121	144
Blood and lymphatic system disorders
Blood and lymphatic system disorders
subjects affected / exposed	5 / 314 (1.59%)	10 / 296 (3.38%)	12 / 308 (3.90%)	3 / 302 (0.99%)
occurrences all number	5	11	13	3
Ear and labyrinth disorders
Ear and labyrinth disorders
subjects affected / exposed	18 / 314 (5.73%)	20 / 296 (6.76%)	21 / 308 (6.82%)	17 / 302 (5.63%)
occurrences all number	23	23	26	20
Eye disorders
Abnormal sensation in eye
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Blepharitis
subjects affected / exposed	9 / 314 (2.87%)	10 / 296 (3.38%)	10 / 308 (3.25%)	9 / 302 (2.98%)
occurrences all number	9	15	12	12
Blepharoplasty
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Blepharospasm
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	1 / 308 (0.32%)	2 / 302 (0.66%)
occurrences all number	2	1	1	2
Cataract
subjects affected / exposed	7 / 314 (2.23%)	7 / 296 (2.36%)	8 / 308 (2.60%)	6 / 302 (1.99%)
occurrences all number	7	7	8	6
Cataract cortical
subjects affected / exposed	3 / 314 (0.96%)	1 / 296 (0.34%)	3 / 308 (0.97%)	1 / 302 (0.33%)
occurrences all number	3	1	3	1
Cataract nuclear
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Cataract operation
subjects affected / exposed	3 / 314 (0.96%)	5 / 296 (1.69%)	7 / 308 (2.27%)	1 / 302 (0.33%)
occurrences all number	3	6	8	1
Cataract traumatic
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Chalazion
subjects affected / exposed	2 / 314 (0.64%)	4 / 296 (1.35%)	3 / 308 (0.97%)	3 / 302 (0.99%)
occurrences all number	2	5	3	4
Colour blindness acquired
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Conjunctival cyst
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Conjunctival haemorrhage
subjects affected / exposed	59 / 314 (18.79%)	56 / 296 (18.92%)	67 / 308 (21.75%)	48 / 302 (15.89%)
occurrences all number	77	72	86	63
Conjunctival hyperaemia
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Conjunctivitis
subjects affected / exposed	8 / 314 (2.55%)	8 / 296 (2.70%)	9 / 308 (2.92%)	7 / 302 (2.32%)
occurrences all number	9	9	11	7
Conjunctivitis allergic
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Corneal abrasion
subjects affected / exposed	8 / 314 (2.55%)	10 / 296 (3.38%)	12 / 308 (3.90%)	6 / 302 (1.99%)
occurrences all number	13	11	16	8
Corneal deposits
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Corneal disorder
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Corneal dystrophy
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	2	0	1	1
Corneal erosion
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Corneal perforation
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Dacryocystitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Diplopia
subjects affected / exposed	4 / 314 (1.27%)	2 / 296 (0.68%)	1 / 308 (0.32%)	5 / 302 (1.66%)
occurrences all number	4	2	1	5
Dry eye
subjects affected / exposed	10 / 314 (3.18%)	4 / 296 (1.35%)	8 / 308 (2.60%)	6 / 302 (1.99%)
occurrences all number	13	5	9	9
Episcleritis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Exophthalmos
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Eye discharge
subjects affected / exposed	8 / 314 (2.55%)	2 / 296 (0.68%)	5 / 308 (1.62%)	5 / 302 (1.66%)
occurrences all number	9	4	7	6
Eye haemorrhage
subjects affected / exposed	0 / 314 (0.00%)	2 / 296 (0.68%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	0	2	1	1
Eye infection
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Eye inflammation
subjects affected / exposed	3 / 314 (0.96%)	6 / 296 (2.03%)	3 / 308 (0.97%)	6 / 302 (1.99%)
occurrences all number	3	9	3	9
Eye irritation
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Eye pain
subjects affected / exposed	91 / 314 (28.98%)	91 / 296 (30.74%)	97 / 308 (31.49%)	85 / 302 (28.15%)
occurrences all number	146	150	166	130
Eye pruritus
subjects affected / exposed	2 / 314 (0.64%)	2 / 296 (0.68%)	2 / 308 (0.65%)	2 / 302 (0.66%)
occurrences all number	2	3	2	3
Eye swelling
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Eyelid cyst
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	2 / 308 (0.65%)	0 / 302 (0.00%)
occurrences all number	1	1	2	0
Eyelid irritation
subjects affected / exposed	0 / 314 (0.00%)	2 / 296 (0.68%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences all number	0	2	0	2
Eyelid oedema
subjects affected / exposed	0 / 314 (0.00%)	4 / 296 (1.35%)	1 / 308 (0.32%)	3 / 302 (0.99%)
occurrences all number	0	4	1	3
Eyelid pain
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Eyelid ptosis
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Fibrosis
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Foreign body sensation in eyes
subjects affected / exposed	3 / 314 (0.96%)	0 / 296 (0.00%)	1 / 308 (0.32%)	2 / 302 (0.66%)
occurrences all number	3	0	1	2
Glaucoma
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	1	1	1	1
Glaucomatous optic disc atrophy
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Hallucination, visual
subjects affected / exposed	8 / 314 (2.55%)	2 / 296 (0.68%)	5 / 308 (1.62%)	5 / 302 (1.66%)
occurrences all number	8	2	5	5
Hordeolum
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	1	1	1	1
Intraocular lens implant
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
IOP increased
subjects affected / exposed	79 / 314 (25.16%)	66 / 296 (22.30%)	87 / 308 (28.25%)	58 / 302 (19.21%)
occurrences all number	154	130	188	96
Iridocyclitis
subjects affected / exposed	0 / 314 (0.00%)	2 / 296 (0.68%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences all number	0	2	0	2
Iridotomy
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Keratitis
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	2	1	2	1
Lacrimal mucocoele
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Lacrimation increased
subjects affected / exposed	30 / 314 (9.55%)	41 / 296 (13.85%)	35 / 308 (11.36%)	36 / 302 (11.92%)
occurrences all number	37	53	43	47
Laser therapy
subjects affected / exposed	2 / 314 (0.64%)	2 / 296 (0.68%)	2 / 308 (0.65%)	2 / 302 (0.66%)
occurrences all number	2	2	2	2
Lenticular opacities
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	2 / 308 (0.65%)	1 / 302 (0.33%)
occurrences all number	2	1	2	1
Macular oedema
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Maculopathy
subjects affected / exposed	0 / 314 (0.00%)	2 / 296 (0.68%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences all number	0	2	0	2
Metamorphopsia
subjects affected / exposed	2 / 314 (0.64%)	3 / 296 (1.01%)	2 / 308 (0.65%)	3 / 302 (0.99%)
occurrences all number	3	3	2	4
Mydriasis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Optic disc haemorrhage
subjects affected / exposed	3 / 314 (0.96%)	1 / 296 (0.34%)	3 / 308 (0.97%)	1 / 302 (0.33%)
occurrences all number	3	1	3	1
Paracentesis eye
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Periorbital haematoma
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Photophobia
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	2 / 308 (0.65%)	0 / 302 (0.00%)
occurrences all number	1	1	2	0
Photopsia
subjects affected / exposed	2 / 314 (0.64%)	3 / 296 (1.01%)	5 / 308 (1.62%)	0 / 302 (0.00%)
occurrences all number	2	3	5	0
Pigment dispersion syndrome
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Posterior capsule opacification
subjects affected / exposed	1 / 314 (0.32%)	2 / 296 (0.68%)	1 / 308 (0.32%)	2 / 302 (0.66%)
occurrences all number	1	2	1	2
Posterior capsulotomy
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	0 / 308 (0.00%)	3 / 302 (0.99%)
occurrences all number	2	1	0	3
Punctate keratitis
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences all number	1	1	0	2
Pupillary reflex impaired
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	2	0	2	0
Retinal artery embolism
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Retinal artery occlusion
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Retinal artery spasm
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Retinal detachment
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Retinal haemorrhage
subjects affected / exposed	8 / 314 (2.55%)	15 / 296 (5.07%)	10 / 308 (3.25%)	13 / 302 (4.30%)
occurrences all number	10	16	12	14
Retinal oedema
subjects affected / exposed	2 / 314 (0.64%)	3 / 296 (1.01%)	0 / 308 (0.00%)	5 / 302 (1.66%)
occurrences all number	2	3	0	5
RPE tear
subjects affected / exposed	5 / 314 (1.59%)	2 / 296 (0.68%)	3 / 308 (0.97%)	4 / 302 (1.32%)
occurrences all number	5	2	3	4
Retinal tear
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Retinal vein occlusion
subjects affected / exposed	3 / 314 (0.96%)	3 / 296 (1.01%)	3 / 308 (0.97%)	3 / 302 (0.99%)
occurrences all number	3	3	3	3
Skin lesion excision
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Superficial injury of eye
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Uveitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Vascular occlusion
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Vision blurred
subjects affected / exposed	5 / 314 (1.59%)	6 / 296 (2.03%)	6 / 308 (1.95%)	5 / 302 (1.66%)
occurrences all number	5	6	6	5
Visual acuity reduced
subjects affected / exposed	4 / 314 (1.27%)	3 / 296 (1.01%)	1 / 308 (0.32%)	6 / 302 (1.99%)
occurrences all number	5	3	1	7
Visual field defect
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Visual impairment
subjects affected / exposed	14 / 314 (4.46%)	17 / 296 (5.74%)	14 / 308 (4.55%)	17 / 302 (5.63%)
occurrences all number	17	17	14	20
Vitreal cells
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Vitreous adhesions
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Vitreous detachment
subjects affected / exposed	19 / 314 (6.05%)	14 / 296 (4.73%)	16 / 308 (5.19%)	17 / 302 (5.63%)
occurrences all number	19	15	17	17
Vitreous disorder
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Vitreous floaters
subjects affected / exposed	65 / 314 (20.70%)	60 / 296 (20.27%)	71 / 308 (23.05%)	54 / 302 (17.88%)
occurrences all number	81	74	88	67
Vitreous haemorrhage
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Non-study eye: Cataract
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Non-study eye: Cataract operation
subjects affected / exposed	0 / 314 (0.00%)	4 / 296 (1.35%)	1 / 308 (0.32%)	3 / 302 (0.99%)
occurrences all number	0	4	1	3
Non-study eye: CNV
subjects affected / exposed	1 / 314 (0.32%)	2 / 296 (0.68%)	1 / 308 (0.32%)	2 / 302 (0.66%)
occurrences all number	1	2	1	2
Non-study eye: Conjunctivitis
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	2	0	1	1
Non-study eye: Corneal abrasion
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Non-study eye: Eye inflammation
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Non-study eye: Eye irritation
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Non-study eye: Macular degeneration
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Non-study eye: Metamorphopsia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Non-study eye: Ocular hyperaemia
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Non-study eye: Retinal artery embolism
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Non-study eye: Retinal haemorrhage
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	2 / 308 (0.65%)	1 / 302 (0.33%)
occurrences all number	2	1	2	1
Non-study eye: RPE tear
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Non-study eye: Venous stasis retinopathy
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Non-study eye: Vision blurred
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Non-study eye: Visual acuity reduced
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences all number	1	1	0	2
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	2 / 314 (0.64%)	4 / 296 (1.35%)	2 / 308 (0.65%)	4 / 302 (1.32%)
occurrences all number	2	4	2	4
Abdominal distension
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	2	0	1	1
Abdominal hernia
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Abdominal pain
subjects affected / exposed	2 / 314 (0.64%)	5 / 296 (1.69%)	5 / 308 (1.62%)	2 / 302 (0.66%)
occurrences all number	2	5	5	2
Abdominal pain upper
subjects affected / exposed	5 / 314 (1.59%)	3 / 296 (1.01%)	6 / 308 (1.95%)	2 / 302 (0.66%)
occurrences all number	7	3	8	2
Abdominal symptom
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Anal fissure
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Anorectal discomfort
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Change of bowel habit
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	2	0	1	1
Colitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Colitis ulcerative
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Constipation
subjects affected / exposed	4 / 314 (1.27%)	7 / 296 (2.36%)	6 / 308 (1.95%)	5 / 302 (1.66%)
occurrences all number	4	7	6	5
Crohn's disease
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Diarrhoea
subjects affected / exposed	23 / 314 (7.32%)	13 / 296 (4.39%)	15 / 308 (4.87%)	21 / 302 (6.95%)
occurrences all number	28	13	17	24
Dry mouth
subjects affected / exposed	1 / 314 (0.32%)	2 / 296 (0.68%)	1 / 308 (0.32%)	2 / 302 (0.66%)
occurrences all number	1	2	1	2
Dyspepsia
subjects affected / exposed	3 / 314 (0.96%)	5 / 296 (1.69%)	4 / 308 (1.30%)	4 / 302 (1.32%)
occurrences all number	3	5	4	4
Dysphagia lusoria
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	1	1	1	1
Faecal incontinence
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Faecal vomiting
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Food poisoning
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	1	1	1	1
Gastric disorder
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	1	1	1	1
Gastritis
subjects affected / exposed	1 / 314 (0.32%)	1 / 296 (0.34%)	1 / 308 (0.32%)	1 / 302 (0.33%)
occurrences all number	1	1	1	1
Gastro-oesophageal reflux disease
subjects affected / exposed	0 / 314 (0.00%)	3 / 296 (1.01%)	2 / 308 (0.65%)	1 / 302 (0.33%)
occurrences all number	0	3	2	1
Gingival disorder
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Gingival pain
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Glossitis
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Haemorrhoids
subjects affected / exposed	2 / 314 (0.64%)	1 / 296 (0.34%)	0 / 308 (0.00%)	3 / 302 (0.99%)
occurrences all number	2	1	0	3
Hiatus hernia
subjects affected / exposed	2 / 314 (0.64%)	3 / 296 (1.01%)	4 / 308 (1.30%)	1 / 302 (0.33%)
occurrences all number	2	3	4	1
Intestinal obstruction
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Irritable bowel syndrome
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	3	0	3	0
Lip swelling
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Mouth ulceration
subjects affected / exposed	4 / 314 (1.27%)	2 / 296 (0.68%)	4 / 308 (1.30%)	2 / 302 (0.66%)
occurrences all number	4	2	4	2
Nausea
subjects affected / exposed	38 / 314 (12.10%)	27 / 296 (9.12%)	31 / 308 (10.06%)	34 / 302 (11.26%)
occurrences all number	51	36	46	41
Oedema mouth
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Oesophagitis
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	1	0	0	1
Pancreatic cyst
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	0	1	1	0
Pancreatitis acute
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Rectal haemorrhage
subjects affected / exposed	1 / 314 (0.32%)	2 / 296 (0.68%)	1 / 308 (0.32%)	2 / 302 (0.66%)
occurrences all number	1	2	1	2
Rectal lesion
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Rectal prolapse
subjects affected / exposed	2 / 314 (0.64%)	0 / 296 (0.00%)	0 / 308 (0.00%)	2 / 302 (0.66%)
occurrences all number	2	0	0	2
Regurgitation
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Sensitivity of teeth
subjects affected / exposed	1 / 314 (0.32%)	0 / 296 (0.00%)	1 / 308 (0.32%)	0 / 302 (0.00%)
occurrences all number	1	0	1	0
Toothache
subjects affected / exposed	3 / 314 (0.96%)	1 / 296 (0.34%)	2 / 308 (0.65%)	2 / 302 (0.66%)
occurrences all number	3	1	2	2
Vomiting
subjects affected / exposed	8 / 314 (2.55%)	5 / 296 (1.69%)	9 / 308 (2.92%)	4 / 302 (1.32%)
occurrences all number	11	5	12	4
Gingivitis
subjects affected / exposed	0 / 314 (0.00%)	1 / 296 (0.34%)	0 / 308 (0.00%)	1 / 302 (0.33%)
occurrences all number	0	1	0	1
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
subjects affected / exposed	38 / 314 (12.10%)	41 / 296 (13.85%)	38 / 308 (12.34%)	41 / 302 (13.58%)
occurrences all number	46	47	43	50
Renal and urinary disorders
Renal and urinary disorders
subjects affected / exposed	9 / 314 (2.87%)	12 / 296 (4.05%)	8 / 308 (2.60%)	13 / 302 (4.30%)
occurrences all number	10	15	11	14
Endocrine disorders
Endocrine discorders
subjects affected / exposed	1 / 314 (0.32%)	6 / 296 (2.03%)	3 / 308 (0.97%)	4 / 302 (1.32%)
occurrences all number	1	7	4	4
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
subjects affected / exposed	91 / 314 (28.98%)	99 / 296 (33.45%)	88 / 308 (28.57%)	102 / 302 (33.77%)
occurrences all number	124	144	118	150
Infections and infestations
Infections and infestations
subjects affected / exposed	194 / 314 (61.78%)	165 / 296 (55.74%)	167 / 308 (54.22%)	192 / 302 (63.58%)
occurrences all number	448	389	401	436
Metabolism and nutrition disorders
Metabolism and nutrition disorders
subjects affected / exposed	14 / 314 (4.46%)	8 / 296 (2.70%)	12 / 308 (3.90%)	10 / 302 (3.31%)
occurrences all number	20	8	15	13

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Oct 2007

Amendment to study protocol: • Method of masking updated.

27 Mar 2008

Amendments to study protocol: • Clarified that the injector will be an ophthalmologist. • Footnote added to figure 3 for clarity • Patients with 8 or more dioptres of myopia added as a exclusion criteria. • Heart failure added as a serious adverse event. • Exploratory analysis to investigate the association between serum markers and cardiovascular SAEs added. • Typographical errors in the list of systemic adverse events corrected. • The reference to feeding patient responses to the MacDQoL and the MacTSQ back to the clinic staff removed.

03 Aug 2010

Amendment to study protocol: • Additional blood samples to be taken for genetic analysis • Retinal pigment epithelial tear added as an ocular adverse event.

24 Feb 2011

Amendments to study protocol: • Additional blood samples 6 & 18 months.

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

http://www.ncbi.nlm.nih.gov/pubmed/22578446
http://www.ncbi.nlm.nih.gov/pubmed/23870813
http://www.ncbi.nlm.nih.gov/pubmed/25220133
http://www.ncbi.nlm.nih.gov/pubmed/24070809
http://www.ncbi.nlm.nih.gov/pubmed/25079928
http://www.ncbi.nlm.nih.gov/pubmed/26445075
http://www.ncbi.nlm.nih.gov/pubmed/25489638
http://www.ncbi.nlm.nih.gov/pubmed/27073205
http://www.ncbi.nlm.nih.gov/pubmed/29038796
http://www.ncbi.nlm.nih.gov/pubmed/30555977
http://www.ncbi.nlm.nih.gov/pubmed/30301555

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Clinical trials

Clinical Trial Results: A randomised control trial of alternative treatments to Inhibit VEGf in Age-related choroidal Neovascularisation (IVAN)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Best corrected visual acuity

Primary: Best corrected visual acuity

Secondary: Frequencies of adverse events: Death from any cause

Secondary: Frequencies of adverse events: Death from any cause

Secondary: Frequencies of adverse events: Arteriothrombotic event or heart failure

Secondary: Frequencies of adverse events: Arteriothrombotic event or heart failure

Secondary: Frequencies of adverse events: Any vascular event

Secondary: Frequencies of adverse events: Any vascular event

Secondary: Frequencies of adverse events: Any vascular event or death

Secondary: Frequencies of adverse events: Any vascular event or death

Secondary: Frequencies of adverse events: Any systemic event

Secondary: Frequencies of adverse events: Any systemic event

Secondary: Health-related quality of life: EQ-5D

Secondary: Health-related quality of life: EQ-5D

Secondary: Health-related quality of life: MacDQol

Secondary: Health-related quality of life: MacDQol

Secondary: Treatment satisfaction: MacTSQ

Secondary: Treatment satisfaction: MacTSQ

Secondary: Resource use: Injection consultation

Secondary: Resource use: Injection consultation

Secondary: Resource use: Monitoring consultations

Secondary: Resource use: Monitoring consultations

Secondary: Resource use: Bed-days linked to expected SAEs

Secondary: Resource use: Bed-days linked to expected SAEs

Secondary: Resource use: Ambulatory consultations

Secondary: Resource use: Ambulatory consultations

Secondary: Resource use: Changes in medications

Secondary: Resource use: Changes in medications

Secondary: Cost effectiveness: QALYs

Secondary: Cost effectiveness: QALYs

Secondary: Clinical measures of vision: Near visual acuity

Secondary: Clinical measures of vision: Near visual acuity

Secondary: Clinical measures of vision: Reading index

Secondary: Clinical measures of vision: Reading index

Secondary: Clinical measures of vision: Contrast sensitivity

Secondary: Clinical measures of vision: Contrast sensitivity

Secondary: Lesion morphology: Geographic atrophy

Secondary: Lesion morphology: Geographic atrophy

Secondary: Lesion morphology: Dye leakage

Secondary: Lesion morphology: Dye leakage

Secondary: Lesion morphology: Fluid

Secondary: Lesion morphology: Fluid

Secondary: Lesion morphology: Lesion present

Secondary: Lesion morphology: Lesion present

Secondary: Lesion morphology: Retinal plus subretinal fluid thickness at fovea

Secondary: Lesion morphology: Retinal plus subretinal fluid thickness at fovea

Secondary: Lesion morphology: Total lesion thickness at the fovea

Secondary: Lesion morphology: Total lesion thickness at the fovea

Secondary: Best corrected visual acuity at 1 year

Secondary: Best corrected visual acuity at 1 year

Secondary: Survival free from treatment failure

Secondary: Survival free from treatment failure

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A randomised control trial of alternative treatments to Inhibit VEGf in Age-related choroidal Neovascularisation (IVAN)