RIVAL: A Comparison of Ranibizumab and Aflibercept for the Development of Geographic Atrophy in (Wet) AMD Patients

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02130024
• Collaborator: (none)
• Enrollment: 281
• Locations: 22
• Arms: 2
• Actual Duration (Months): 43.2
• Patients Per Site: 12.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study was to compare the development of new geographic atrophy in patients with wet Age-related Macular Degeneration (AMD) when treated with either ranibizumab or aflibercept over 24 months. Geographic atrophy is an advanced form of AMD that can result in the progressive and irreversible loss of visual function over time.

Condition or Disease	Intervention/Treatment	Phase
Age-Related Macular Degeneration	Drug: Ranibizumab 0.5 mg; Drug: Aflibercept 2.0 mg	Phase 4

Detailed Description

In each arm, patients underwent three monthly loading doses (at Baseline, Week 4, and Week 8). From Week 8, after the patient had received their third injection of study treatment, the visit intervals were determined by the patient's disease activity. If any of the protocol-specified signs of disease activity were present in the study eye, the subsequent injection visit interval was kept at 4 weeks. If none of the signs were present, the subsequent injection interval was extended by 2-week increments up until a maximum of 12-weekly intervals was reached. If there were any signs of disease activity in the study eye, the treatment interval was reduced as specified in the protocol. The planned individual duration of study participation was 24 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 281 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Masking Description: Investigators were not masked. The patients, the BCVA assessors, and the Central Reading Center (who set the treatment intervals) were masked.
• Primary Purpose: Treatment
• Official Title: Development of New Geographic Atrophy in Patients With Neovascular (Wet) Age-related Macular Degeneration: a Comparison of Ranibizumab and Aflibercept
• Actual Study Start Date: Apr 11, 2014
• Actual Primary Completion Date: Nov 15, 2017
• Actual Study Completion Date: Nov 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranibizumab 0.5 mg 3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	Drug: Ranibizumab 0.5 mg; Administered as an intravitreal injection; Other Names: Lucentis
Active Comparator: Aflibercept 2.0 mg 3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	Drug: Aflibercept 2.0 mg; Administered as an intravitreal injection; Other Names: Eylea

Outcome Measures

Primary Outcome Measures

1. Mean Change in Square-root Area of Geographic Atrophy (GA) From Baseline to Month 24 [Baseline, Month 24]

   Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis.

Secondary Outcome Measures

1. Mean Change in Square-root Area of Geographic Atrophy From Baseline to Month 12 [Baseline, Month 12]

   Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis.

2. Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study [Baseline, Month 12, Month 24]

   Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center. A patient was considered to have developed new GA if they did not have any GA at the start of the study period and were subsequently diagnosed with GA during the study period (diagnosis of GA change from "No" to "Yes)." The analysis of new GA development was restricted to only those subjects without GA reported at baseline. One eye (study eye) contributed to the analysis.

3. Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24 [Baseline, Month 12, Month 24]

   The number of intravitreal injections was calculated. One eye (study eye) contributed to the analysis.

4. Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24 [Baseline, Month 12, Month 24]

   Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. BCVA change was defined as a change in letters correctly identified from the baseline assessment. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis

5. Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24 [Baseline, Month 12, Month 24]

   CSFT (the average retinal thickness of the circular area within 1 millimeter diameter around the foveal center) was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. A negative change value indicates an improvement, while a positive change value indicates a worsening. One eye (study eye) contributed to the analysis

6. Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF) [Month 2, Month 12, Month 24]

   Intraretinal fluid and subretinal fluid was assessed using Optical Coherence Tomography (OCT) and recorded as Present/Absent. One eye (study eye) contributed to the analysis.

7. Percentage of Patients Showing Greater Than and Equal to 15 Letters Gain for BCVA From Baseline to Month 12 and to Month 24 [Baseline, Month 12, Month 24]

   Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis.

8. Percentage of Patients Showing Less Than and Equal to 15 Letters Loss for BCVA From Baseline to Month 12 and to Month 24 [Baseline, Month 12, Month 24]

   Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis.

9. Mean Number of Times a Patient Needed to Return to Monthly Intravitreal Injections Over 24 Months [Month 24]

   The number of times the patient returned to a monthly injection interval (from an extended interval) at least once during the 24-month study was calculated. One eye (study eye) contributed to the analysis.

10. Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment [Baseline, Week 5, Week 9]

    Blood for VEGF plasma concentration analysis was collected at Baseline and again at 7 days after the injection at Week 4 and 7 days after the injection at Week 8.

11. Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 [Baseline, Month 12, Month 24]

    Retinal nerve fibre thickness was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. A negative change in value (i.e. thinner nerve fibre) indicates nerve damage. One eye (study eye) contributed to the analysis.

12. Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells [Baseline, Week 9]

    Anterior cell grade was assessed by the Investigator during slit lamp examination and graded on a 5-point scale: Grade 0=0 cells; Grade 1=1 to 10 cells; Grade 2=11 to 20 cells; Grade 3=21 to 50 cells; Grade 4=>50 cells. The presence of blood cells (red and white) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. One eye (study eye) contributed to the analysis.

13. Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare [Baseline, Week 9]

    Anterior chamber flare was assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = none; 1 = mild (trace to clearly noticeable, visible); 2 = moderate; 3 = marked; and 4 = severe. The presence of flare (increased protein levels) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. Proportion of patients is reported as a percentage. One eye (study eye) contributed to the analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Written informed consent.

Inclusion criteria specific to the study eye:

• Diagnosis of active subfoveal Choroidal Neovascularisation (CNV) secondary to wet Age-related Macular Degeneration (AMD);

• Best Corrected Visual Acuity (BCVA) score of 23 letters or more as measured by 3-metre Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts.

Exclusion criteria:

• Pregnant, nursing, or at risk of becoming pregnant during the study;

• Inability to comply with the study or follow-up procedures;

• Recent (3 months) stroke or myocardial infarction; uncontrolled hypertension; hypersensitivity to the study treatments or to fluorescein;

• In either eye: active periocular or ocular infection or inflammation; iris neovascularisation; uncontrolled or neovascular glaucoma; or one or more patch of geographic atrophy (GA) as specified in the protocol.

Exclusion criteria specific to the study eye:

• Prior or current treatment with anti-angiogenic drugs or corticosteroids;

• Other eye conditions as specified in the protocol;

• Any intraocular procedure carried out within 2 months before baseline or anticipated within 6 months following baseline.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Albury	New South Wales	Australia	2640
2	Novartis Investigative Site	Brookvale	New South Wales	Australia	2100
3	Novartis Investigative Site	Chatswood	New South Wales	Australia	2067
4	Novartis Investigative Site	Hurtsville	New South Wales	Australia	2220
5	Novartis Investigative Site	Mona Vale	New South Wales	Australia
6	Novartis Investigative Site	Parramatta	New South Wales	Australia	2150
7	Novartis Investigative Site	Strathfield	New South Wales	Australia	2035
8	Novartis Investigative Site	Strathfield	New South Wales	Australia	2135
9	Novartis Investigative Site	Sydney	New South Wales	Australia	2000
10	Novartis Investigative Site	Sydney	New South Wales	Australia	AUSTRALIA
11	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
12	Novartis Investigative Site	Caboolture	Queensland	Australia	4510
13	Novartis Investigative Site	Redcliffe	Queensland	Australia	4020
14	Novartis Investigative Site	South Brisbane	Queensland	Australia	4101
15	Novartis Investigative Site	Southport	Queensland	Australia	4215
16	Novartis Investigative Site	Adelaide	South Australia	Australia	5000
17	Novartis Investigative Site	South Launceston	Tasmania	Australia	7249
18	Novartis Investigative Site	Clayton	Victoria	Australia	3168
19	Novartis Investigative Site	Malvern	Victoria	Australia	3144
20	Novartis Investigative Site	Parkville,	Victoria	Australia	3065
21	Novartis Investigative Site	Nedlands	Western Australia	Australia	6009
22	Novartis Investigative Site	Subiaco	Western Australia	Australia	6008

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jan 19, 2015
• Statistical Analysis Plan - May 4, 2018

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02130024
• Other Study ID Numbers: CRFB002AAU17
• First Posted: May 2, 2014
• Last Update Posted: Jun 5, 2019
• Last Verified: Oct 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Age-related macular degeneration; AMD; wet AMD; ranibizumab; aflibercept; geographic atrophy; inject and extend
• Additional relevant MeSH terms: Macular Degeneration; Geographic Atrophy; Atrophy; Ranibizumab; Aflibercept

Study Results

Participant Flow

Recruitment Details	Patients were recruited and enrolled from 24 sites located in Australia.
Pre-assignment Detail	This reporting group includes all patients randomized to treatment.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Period Title: Overall Study
STARTED	142	139
Safety Set	141	139
Full Analysis Set (FAS)	141	137
COMPLETED	117	108
NOT COMPLETED	25	31

Baseline Characteristics

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg	Total
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	Total of all reporting groups
Overall Participants	142	139	281
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	76.6 (8.5)	78.7 (7.45)	77.7 (8.06)
Sex: Female, Male (Count of Participants)
Female	72 50.7%	76 54.7%	148 52.7%
Male	70 49.3%	63 45.3%	133 47.3%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	132 93%	130 93.5%	262 93.2%
Black African	0 0%	1 0.7%	1 0.4%
Asian	8 5.6%	7 5%	15 5.3%
Other	2 1.4%	1 0.7%	3 1.1%

Outcome Measures

1. Primary Outcome

Title	Mean Change in Square-root Area of Geographic Atrophy (GA) From Baseline to Month 24
Description	Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis.
Time Frame	Baseline, Month 24

Outcome Measure Data

Analysis Population Description

All randomized patients with at least one post-baseline efficacy value for the primary endpoint (FAS). Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Baseline	0.024 (0.0988)	0.050 (0.2345)
Change from Baseline at Month 24	0.363 (0.7105)	0.285 (0.5392)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.236
	Comments
	Method	Mixed Models Analysis
	Comments	Fixed effects: Baseline GA area, treatment, visit, treatment by visit. Random effect: Subject
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Change in Square-root Area of Geographic Atrophy From Baseline to Month 12
Description	Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Baseline	0.024 (0.0988)	0.050 (0.2345)
Change from Baseline at Month 12	0.155 (0.4272)	0.145 (0.3179)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.769
	Comments
	Method	Mixed Models Analysis
	Comments	Fixed effects: Baseline GA area, treatment, visit, treatment by visit. Random effect: Subject
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study
Description	Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center. A patient was considered to have developed new GA if they did not have any GA at the start of the study period and were subsequently diagnosed with GA during the study period (diagnosis of GA change from "No" to "Yes)." The analysis of new GA development was restricted to only those subjects without GA reported at baseline. One eye (study eye) contributed to the analysis.
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Baseline to Month 12	17.6	20.3
Month 12 to Month 24	15.1	7.2
Baseline to Month 24	28.8	25.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 12 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.586
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.44 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio of 'Newly Developed GA (Yes)' at between the two treatment groups at study visit

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Month 12 to Month 24 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.110
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.27
	Confidence Interval	(2-Sided) 95%; 0.83 to 6.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio of 'Newly Developed GA (Yes)' at between the two treatment groups at study visit

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 24 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.554
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.67 to 2.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24
Description	The number of intravitreal injections was calculated. One eye (study eye) contributed to the analysis.
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Baseline to Month 12	9.7 (2.78)	9.7 (2.54)
Month 12 to Month 24	8.9 (3.24)	8.3 (3.56)
Baseline to Month 24	17.7 (6.44)	17.0 (6.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to <Month 12 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.733
	Comments
	Method	Negative Binomial Regression Model
	Comments	Log (number of injections) = treatment + log (year of follow-up) (offset)
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment effect: Injection frequency (rate) ratio of Ranibizumab vs. Aflibercept

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 24 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.745
	Comments
	Method	Negative Binomial Regression Model
	Comments	Log (number of injections) = treatment + log (year of follow-up) (offset)
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment effect: Injection frequency (rate) ratio of Ranibizumab vs. Aflibercept

5. Secondary Outcome

Title	Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24
Description	Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. BCVA change was defined as a change in letters correctly identified from the baseline assessment. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Baseline	65.3 (15.10)	65.1 (12.53)
Change from Baseline at Month 12	6.9 (12.25)	5.2 (12.83)
Change from Baseline at Month 24	6.5 (14.38)	5.3 (13.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 12 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.079
	Comments
	Method	Mixed Models Analysis
	Comments	Fixed effects: Baseline BCVA, treatment, visit, and treatment by visit. Random effect: Subject. Response variable: Change from baseline in BCVA
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	2.32
	Confidence Interval	(2-Sided) 95%; -0.27 to 4.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Effect: Ranibizumab minus Aflibercept

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 24 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.151
	Comments
	Method	Mixed Models Analysis
	Comments	Fixed effects: Baseline BCVA, treatment, visit, and treatment by visit. Random effect: Subject. Response variable: Change from baseline in BCVA
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	1.95
	Confidence Interval	(2-Sided) 95%; -0.71 to 4.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Effect: Ranibizumab minus Aflibercept

6. Secondary Outcome

Title	Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24
Description	CSFT (the average retinal thickness of the circular area within 1 millimeter diameter around the foveal center) was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. A negative change value indicates an improvement, while a positive change value indicates a worsening. One eye (study eye) contributed to the analysis
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Baseline	468.2 (150.82)	483.5 (168.05)
Change from Baseline at Month 12	-147.2 (128.38)	-171.6 (150.12)
Change from Baseline at Month 24	-151.3 (133.37)	-181.7 (155.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 12 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.294
	Comments
	Method	Mixed Models Analysis
	Comments	Fixed effects: Baseline CSFT, treatment, visit, and treatment by visit. Random effect: Subject. Response variable: Change from baseline in CSFT
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	10.12
	Confidence Interval	(2-Sided) 95%; -8.82 to 29.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Effect: Ranibizumab minus Aflibercept

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 24 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.225
	Comments
	Method	Mixed Models Analysis
	Comments	Fixed effects: Baseline CSFT, treatment, visit, and treatment by visit. Random effect: Subject. Response variable: Change from baseline in CSFT
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	11.86
	Confidence Interval	(2-Sided) 95%; -7.35 to 31.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Effect: Ranibizumab minus Aflibercept

7. Secondary Outcome

Title	Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF)
Description	Intraretinal fluid and subretinal fluid was assessed using Optical Coherence Tomography (OCT) and recorded as Present/Absent. One eye (study eye) contributed to the analysis.
Time Frame	Month 2, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Month 2	56.9	61.3
Month 12	55.9	63.6
Month 24	57.3	60.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Month 2 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.461
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio of no IRF/SRF present between the two treatment groups at study visit

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Month 12 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.215
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.44 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio of no IRF/SRF present between the two treatment groups at study visit

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Month 24 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.616
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio of no IRF/SRF present between the two treatment groups at study visit

8. Secondary Outcome

Title	Percentage of Patients Showing Greater Than and Equal to 15 Letters Gain for BCVA From Baseline to Month 12 and to Month 24
Description	Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis.
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Change from Baseline at Month 12	22.0	20.7
Change from Baseline at Month 24	24.8	18.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 12 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.891
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor and baseline BCVA as covariate. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.53 to 2.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio of BCVA change from baseline ≥15 letters between the two treatment groups at study visit

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 24 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.206
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor and baseline BCVA as covariate. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 0.77 to 3.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio of BCVA change from baseline ≥15 letters between the two treatment groups at study visit

9. Secondary Outcome

Title	Percentage of Patients Showing Less Than and Equal to 15 Letters Loss for BCVA From Baseline to Month 12 and to Month 24
Description	Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis.
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Change from Baseline at Month 12	96.9	95.0
Change from Baseline at Month 24	94.0	94.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 12 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.460
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor and baseline BCVA as covariate. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.63
	Confidence Interval	(2-Sided) 95%; 0.45 to 5.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio of BCVA change from baseline ≥ -15 letters between the two treatment groups at study visit

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Month 24 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.913
	Comments
	Method	Regression, Logistic
	Comments	Includes treatment as factor and baseline BCVA as covariate. Model: log(p/1-p) =Treatment
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.30 to 2.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio of BCVA change from baseline ≥ -15 letters between the two treatment groups at study visit

10. Secondary Outcome

Title	Mean Number of Times a Patient Needed to Return to Monthly Intravitreal Injections Over 24 Months
Description	The number of times the patient returned to a monthly injection interval (from an extended interval) at least once during the 24-month study was calculated. One eye (study eye) contributed to the analysis.
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data. Descriptive statistics only.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	134	134
Mean (Standard Deviation) [occurrences]	2.3 (1.28)	2.3 (1.15)

11. Secondary Outcome

Title	Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment
Description	Blood for VEGF plasma concentration analysis was collected at Baseline and again at 7 days after the injection at Week 4 and 7 days after the injection at Week 8.
Time Frame	Baseline, Week 5, Week 9

Outcome Measure Data

Analysis Population Description

FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	137
Baseline	44.29 (43.369)	41.88 (35.236)
Change from Baseline at Week 5	-0.48 (30.299)	-26.37 (36.220)
Change from Baseline at Week 9	0.48 (35.125)	-25.14 (32.525)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Week 5 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Fixed: BL Plasma VEGF, treatment, visit, and treatment by visit. Random effect: Subject. Response variable: Change from BL in Plasma VEGF
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	27.20
	Confidence Interval	(2-Sided) 95%; 21.44 to 32.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Effect: Ranibizumab minus Aflibercept

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Aflibercept 2.0 mg
	Comments	Baseline to Week 9 Analysis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Fixed: BL Plasma VEGF, treatment, visit, and treatment by visit. Random effect: Subject. Response variable: Change from BL in Plasma VEGF
Method of Estimation	Estimation Parameter	Treatment Effect
	Estimated Value	28.88
	Confidence Interval	(2-Sided) 95%; 23.08 to 34.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Effect: Ranibizumab minus Aflibercept

12. Secondary Outcome

Title	Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24
Description	Retinal nerve fibre thickness was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. A negative change in value (i.e. thinner nerve fibre) indicates nerve damage. One eye (study eye) contributed to the analysis.
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

Safety Set. All patients who received at least one application of study treatment and had at least one post-baseline safety assessment, as treated. Descriptive statistics only.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	139
Month 12: Decrease from Baseline	2.5	2.7
Month 12: No Change from Baseline	96.7	97.3
Month 12: Increase from Baseline	0.8	0
Month 24: Decrease from Baseline	3.6	1.0
Month 24: No Change from Baseline	96.4	97.9
Month 24: Increase from Baseline	0	1.0

13. Secondary Outcome

Title	Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells
Description	Anterior cell grade was assessed by the Investigator during slit lamp examination and graded on a 5-point scale: Grade 0=0 cells; Grade 1=1 to 10 cells; Grade 2=11 to 20 cells; Grade 3=21 to 50 cells; Grade 4=>50 cells. The presence of blood cells (red and white) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. One eye (study eye) contributed to the analysis.
Time Frame	Baseline, Week 9

Outcome Measure Data

Analysis Population Description

Safety Set. All patients who received at least one application of study treatment and had at least one post-baseline safety assessment, as treated. Descriptive statistics only.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	138
Baseline: Grade 0	99.3	98.5
Baseline: Grade 1+	0.7	1.5
Baseline: Grade 2+	0	0
Baseline: Grade 3+	0	0
Baseline: Grade 4+	0	0
Week 9: Grade 0	95.1	92.7
Week 9: Grade 1+	4.9	7.3
Week 9: Grade 2+	0	0
Week 9: Grade 3+	0	0
Week 9: Grade 4+	0	0

14. Secondary Outcome

Title	Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare
Description	Anterior chamber flare was assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = none; 1 = mild (trace to clearly noticeable, visible); 2 = moderate; 3 = marked; and 4 = severe. The presence of flare (increased protein levels) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. Proportion of patients is reported as a percentage. One eye (study eye) contributed to the analysis.
Time Frame	Baseline, Week 9

Outcome Measure Data

Analysis Population Description

Safety Set. All patients who received at least one application of study treatment and had at least one post-baseline safety assessment, as treated. Descriptive statistics only.

Arm/Group Title	Ranibizumab 0.5 mg	Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
Measure Participants	141	138
Baseline: Grade 0	97.8	99.3
Baseline: Grade 1+	2.2	0.7
Baseline: Grade 2+	0	0
Baseline: Grade 3+	0	0
Baseline: Grade 4+	0	0
Week 9: Grade 0	94.3	92.7
Week 9: Grade 1+	5.7	7.3
Week 9: Grade 2+	0	0
Week 9: Grade 3+	0	0
Week 9: Grade 4+	0	0

Adverse Events

Time Frame	Adverse events were collected for the duration of the individual's participation in the study (approximately 24 months).
Adverse Event Reporting Description	This analysis population includes all patients who received at least one application of study treatment and had at least one post-baseline safety assessment (Safety Analysis Set).
Arm/Group Title	Ranibizumab 0.5 mg		Aflibercept 2.0 mg
Arm/Group Description	3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]		3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity [treat and extend]
All Cause Mortality
	Ranibizumab 0.5 mg		Aflibercept 2.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/141 (2.1%)		6/139 (4.3%)
Serious Adverse Events
	Ranibizumab 0.5 mg		Aflibercept 2.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/141 (35.5%)		58/139 (41.7%)
Blood and lymphatic system disorders
Anaemia (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Iron deficiency anaemia (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Platelet dysfunction (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Cardiac disorders
Acute myocardial infarction (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Aortic valve incompetence (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Atrial fibrillation (Non-ocular)	7/141 (5%)		0/139 (0%)
Atrioventricular block complete (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Cardiac arrest (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Cardiac failure (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Cardiac failure chronic (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Cardiac failure congestive (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Coronary artery disease (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Left ventricular failure (Non-ocular)	0/141 (0%)		2/139 (1.4%)
Myocardial infarction (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Palpitations (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Tachycardia (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Ventricular tachycardia (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Ear and labyrinth disorders
Meniere's disease (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Eye disorders
Retinal artery embolism (Right eye)	1/141 (0.7%)		0/139 (0%)
Retinal artery occlusion (Right eye)	1/141 (0.7%)		0/139 (0%)
Retinal detachment (Left eye)	0/141 (0%)		2/139 (1.4%)
Gastrointestinal disorders
Constipation (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Diarrhoea (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Diverticulum (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Gastritis (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Gastrointestinal haemorrhage (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Intestinal obstruction (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Localised intraabdominal fluid collection (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Nausea (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Oesophageal food impaction (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Peritoneal adhesions (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Pharyngo-oesophageal diverticulum (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Rectal haemorrhage (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Small intestinal obstruction (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Volvulus (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Vomiting (Non-ocular)	1/141 (0.7%)		0/139 (0%)
General disorders
Chest pain (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Condition aggravated (Non-ocular)	0/141 (0%)		2/139 (1.4%)
Death (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Disease progression (Non-ocular)	0/141 (0%)		1/139 (0.7%)
General physical health deterioration (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Hernia (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Pyrexia (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Hepatobiliary disorders
Bile duct stone (Non-ocular)	0/141 (0%)		2/139 (1.4%)
Cholecystitis (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Infections and infestations
Blastocystis infection (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Cellulitis (Non-ocular)	1/141 (0.7%)		2/139 (1.4%)
Clostridium difficile colitis (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Cystitis (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Endophthalmitis (Left eye)	0/141 (0%)		1/139 (0.7%)
Endophthalmitis (Right eye)	0/141 (0%)		1/139 (0.7%)
Escherichia infection (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Gallbladder empyema (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Gastroenteritis (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Gastroenteritis viral (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Herpes zoster (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Infective exacerbation of chronic obstructive airways disease (Non-ocular)	2/141 (1.4%)		0/139 (0%)
Influenza (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Localised infection (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Lower respiratory tract infection (Non-ocular)	2/141 (1.4%)		0/139 (0%)
Onychomycosis (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Pneumonia (Non-ocular)	4/141 (2.8%)		4/139 (2.9%)
Pneumonia bacterial (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Rhinovirus infection (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Sepsis (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Septic shock (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Subcutaneous abscess (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Urinary tract infection (Non-ocular)	2/141 (1.4%)		4/139 (2.9%)
Urinary tract infection bacterial (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Injury, poisoning and procedural complications
Ankle fracture (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Back injury (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Cataract traumatic (Right eye)	1/141 (0.7%)		0/139 (0%)
Contusion (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Facial bones fracture (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Fall (Non-ocular)	3/141 (2.1%)		1/139 (0.7%)
Femoral neck fracture (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Femur fracture (Non-ocular)	0/141 (0%)		2/139 (1.4%)
Fibula fracture (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Foot fracture (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Forearm fracture (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Hip fracture (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Humerus fracture (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Jaw fracture (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Joint injury (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Laceration (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Limb injury (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Radius fracture (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Rib fracture (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Spinal column injury (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Subdural haematoma (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Subdural haemorrhage (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Tibia fracture (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Metabolism and nutrition disorders
Hypercalcaemia (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Hypoglycaemia (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Hypokalaemia (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Hyponatraemia (Non-ocular)	0/141 (0%)		2/139 (1.4%)
Malnutrition (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Metabolic acidosis (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Musculoskeletal and connective tissue disorders
Arthritis (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Back pain (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Intervertebral disc space narrowing (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Mobility decreased (Non-ocular)	2/141 (1.4%)		0/139 (0%)
Muscular weakness (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Osteoarthritis (Non-ocular)	2/141 (1.4%)		1/139 (0.7%)
Spinal column stenosis (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adrenal gland cancer (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Angioimmunoblastic T-cell lymphoma (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Basal cell carcinoma (Non-ocular)	7/141 (5%)		2/139 (1.4%)
Benign ovarian tumour (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Benign uterine neoplasm (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Bladder cancer (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Bladder cancer recurrent (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Bladder neoplasm (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Gastrointestinal carcinoma (Non-ocular)	0/141 (0%)		2/139 (1.4%)
Malignant melanoma (Non-ocular)	0/141 (0%)		2/139 (1.4%)
Malignant neoplasm progression (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Mesothelioma (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Myeloproliferative disorder (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Oesophageal cancer metastatic (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Pancreatic carcinoma (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Prostate cancer (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Sinonasal papilloma (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Small cell lung cancer metastatic (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Squamous cell carcinoma (Non-ocular)	4/141 (2.8%)		4/139 (2.9%)
Tonsil cancer (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Nervous system disorders
Amnesia (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Aphasia (Non-ocular)	3/141 (2.1%)		0/139 (0%)
Basal ganglia haemorrhage (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Cerebral artery thrombosis (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Cerebrovascular accident (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Dementia (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Dizziness (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Dysarthria (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Ischaemic stroke (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Lacunar infarction (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Neuralgia (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Presyncope (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Subarachnoid haemorrhage (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Syncope (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Transient ischaemic attack (Non-ocular)	2/141 (1.4%)		1/139 (0.7%)
Psychiatric disorders
Delirium (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Depression (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Renal and urinary disorders
Haematuria (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Nephrolithiasis (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Obstructive uropathy (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Renal failure acute (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Urethral haemorrhage (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Urinary bladder haemorrhage (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Urinary retention (Non-ocular)	0/141 (0%)		2/139 (1.4%)
Reproductive system and breast disorders
Ovarian cyst (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Prostatomegaly (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Uterovaginal prolapse (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Vaginal ulceration (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease (Non-ocular)	1/141 (0.7%)		2/139 (1.4%)
Dyspnoea (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Epistaxis (Non-ocular)	1/141 (0.7%)		1/139 (0.7%)
Pleural effusion (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Pulmonary embolism (Non-ocular)	0/141 (0%)		2/139 (1.4%)
Pulmonary hypertension (Non-ocular)	0/141 (0%)		1/139 (0.7%)
Pulmonary oedema (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Respiratory failure (Non-ocular)	2/141 (1.4%)		1/139 (0.7%)
Surgical and medical procedures
Open reduction of fracture (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Vascular disorders
Aortic dilatation (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Aortic embolus (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Aortic stenosis (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Hypertension (Non-ocular)	1/141 (0.7%)		0/139 (0%)
Hypotension (Non-ocular)	2/141 (1.4%)		1/139 (0.7%)
Other (Not Including Serious) Adverse Events
	Ranibizumab 0.5 mg		Aflibercept 2.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	122/141 (86.5%)		123/139 (88.5%)
Blood and lymphatic system disorders
Anaemia (Non-ocular)	4/141 (2.8%)		4/139 (2.9%)
Cardiac disorders
Angina pectoris (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Atrial fibrillation (Non-ocular)	3/141 (2.1%)		4/139 (2.9%)
Bundle branch block left (Non-ocular)	0/141 (0%)		3/139 (2.2%)
Tachycardia (Non-ocular)	2/141 (1.4%)		3/139 (2.2%)
Ear and labyrinth disorders
Vertigo (Non-ocular)	0/141 (0%)		5/139 (3.6%)
Eye disorders
Age-related macular degeneration (Left eye)	6/141 (4.3%)		8/139 (5.8%)
Age-related macular degeneration (Right eye)	10/141 (7.1%)		14/139 (10.1%)
Blepharitis (Both eyes)	3/141 (2.1%)		2/139 (1.4%)
Cataract (Both eyes)	1/141 (0.7%)		3/139 (2.2%)
Cataract (Left eye)	3/141 (2.1%)		14/139 (10.1%)
Cataract (Right eye)	6/141 (4.3%)		8/139 (5.8%)
Chalazion (Left eye)	2/141 (1.4%)		4/139 (2.9%)
Chalazion (Right eye)	1/141 (0.7%)		3/139 (2.2%)
Choroidal neovascularisation (Left eye)	2/141 (1.4%)		3/139 (2.2%)
Choroidal neovascularisation (Right eye)	6/141 (4.3%)		5/139 (3.6%)
Conjunctival haemorrhage (Left eye)	6/141 (4.3%)		3/139 (2.2%)
Dry eye (Both eyes)	13/141 (9.2%)		9/139 (6.5%)
Dry eye (Left eye)	1/141 (0.7%)		3/139 (2.2%)
Eye discharge (Both eyes)	0/141 (0%)		3/139 (2.2%)
Eye discharge (Left eye)	3/141 (2.1%)		0/139 (0%)
Eye discharge (Right eye)	2/141 (1.4%)		3/139 (2.2%)
Eye irritation (Both eyes)	2/141 (1.4%)		3/139 (2.2%)
Eye irritation (Left eye)	5/141 (3.5%)		3/139 (2.2%)
Eye irritation (Right eye)	2/141 (1.4%)		4/139 (2.9%)
Eye pain (Both eyes)	6/141 (4.3%)		0/139 (0%)
Eye pain (Left eye)	10/141 (7.1%)		15/139 (10.8%)
Eye pain (Right eye)	14/141 (9.9%)		13/139 (9.4%)
Eye pruritus (Both eyes)	1/141 (0.7%)		4/139 (2.9%)
Lacrimation increased (Both eyes)	4/141 (2.8%)		5/139 (3.6%)
Lacrimation increased (Left eye)	5/141 (3.5%)		3/139 (2.2%)
Lacrimation increased (Right eye)	3/141 (2.1%)		3/139 (2.2%)
Macular degeneration (Right eye)	3/141 (2.1%)		3/139 (2.2%)
Metamorphopsia (Left eye)	1/141 (0.7%)		3/139 (2.2%)
Metamorphopsia (Right eye)	0/141 (0%)		3/139 (2.2%)
Ocular hyperaemia (Left eye)	3/141 (2.1%)		7/139 (5%)
Ocular hyperaemia (Right eye)	4/141 (2.8%)		4/139 (2.9%)
Posterior capsule opacification (Right eye)	2/141 (1.4%)		4/139 (2.9%)
Retinal haemorrhage (Left eye)	3/141 (2.1%)		5/139 (3.6%)
Retinal haemorrhage (Right eye)	5/141 (3.5%)		3/139 (2.2%)
Retinal pigment epithelial tear (Left eye)	5/141 (3.5%)		3/139 (2.2%)
Vision blurred (Both eyes)	4/141 (2.8%)		1/139 (0.7%)
Vision blurred (Left eye)	2/141 (1.4%)		5/139 (3.6%)
Vision blurred (Right eye)	3/141 (2.1%)		6/139 (4.3%)
Visual acuity reduced (Right eye)	6/141 (4.3%)		2/139 (1.4%)
Vitreous detachment (Both eyes)	4/141 (2.8%)		2/139 (1.4%)
Vitreous detachment (Left eye)	3/141 (2.1%)		12/139 (8.6%)
Vitreous detachment (Right eye)	2/141 (1.4%)		11/139 (7.9%)
Vitreous floaters (Both eyes)	4/141 (2.8%)		2/139 (1.4%)
Vitreous floaters (Left eye)	7/141 (5%)		7/139 (5%)
Vitreous floaters (Right eye)	7/141 (5%)		9/139 (6.5%)
Gastrointestinal disorders
Abdominal pain (Non-ocular)	0/141 (0%)		5/139 (3.6%)
Constipation (Non-ocular)	6/141 (4.3%)		13/139 (9.4%)
Diarrhoea (Non-ocular)	7/141 (5%)		5/139 (3.6%)
Gastrooesophageal reflux disease (Non-ocular)	3/141 (2.1%)		10/139 (7.2%)
Nausea (Non-ocular)	12/141 (8.5%)		6/139 (4.3%)
Vomiting (Non-ocular)	4/141 (2.8%)		5/139 (3.6%)
General disorders
Asthenia (Non-ocular)	3/141 (2.1%)		0/139 (0%)
Chest pain (Non-ocular)	4/141 (2.8%)		4/139 (2.9%)
Influenza like illness (Non-ocular)	8/141 (5.7%)		3/139 (2.2%)
Malaise (Non-ocular)	1/141 (0.7%)		4/139 (2.9%)
Oedema peripheral (Non-ocular)	2/141 (1.4%)		3/139 (2.2%)
Pain (Right eye)	0/141 (0%)		3/139 (2.2%)
Pyrexia (Non-ocular)	4/141 (2.8%)		2/139 (1.4%)
Immune system disorders
Drug hypersensitivity (Both eyes)	3/141 (2.1%)		0/139 (0%)
Drug hypersensitivity (Non-ocular)	4/141 (2.8%)		3/139 (2.2%)
Seasonal allergy (Non-ocular)	6/141 (4.3%)		1/139 (0.7%)
Infections and infestations
Bronchitis (Non-ocular)	4/141 (2.8%)		1/139 (0.7%)
Cellulitis (Non-ocular)	0/141 (0%)		3/139 (2.2%)
Diverticulitis (Non-ocular)	3/141 (2.1%)		1/139 (0.7%)
Gastroenteritis (Non-ocular)	2/141 (1.4%)		3/139 (2.2%)
Herpes zoster (Non-ocular)	4/141 (2.8%)		4/139 (2.9%)
Influenza (Non-ocular)	11/141 (7.8%)		6/139 (4.3%)
Lower respiratory tract infection (Non-ocular)	11/141 (7.8%)		6/139 (4.3%)
Nasopharyngitis (Non-ocular)	15/141 (10.6%)		8/139 (5.8%)
Pneumonia (Non-ocular)	2/141 (1.4%)		4/139 (2.9%)
Sinusitis (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Upper respiratory tract infection (Non-ocular)	8/141 (5.7%)		11/139 (7.9%)
Urinary tract infection (Non-ocular)	11/141 (7.8%)		15/139 (10.8%)
Injury, poisoning and procedural complications
Contusion (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Corneal abrasion (Right eye)	4/141 (2.8%)		2/139 (1.4%)
Fall (Non-ocular)	11/141 (7.8%)		15/139 (10.8%)
Head injury (Non-ocular)	0/141 (0%)		3/139 (2.2%)
Investigations
Abdominal X-ray (Non-ocular)	1/141 (0.7%)		4/139 (2.9%)
Angiogram (Non-ocular)	4/141 (2.8%)		3/139 (2.2%)
Arteriogram coronary (Non-ocular)	3/141 (2.1%)		4/139 (2.9%)
Biopsy (Non-ocular)	0/141 (0%)		4/139 (2.9%)
Blood alkaline phosphatase increased (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Blood chloride decreased (Non-ocular)	3/141 (2.1%)		3/139 (2.2%)
Blood cholesterol increased (Non-ocular)	3/141 (2.1%)		0/139 (0%)
Blood creatinine increased (Non-ocular)	1/141 (0.7%)		4/139 (2.9%)
Blood sodium decreased (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Blood urea increased (Non-ocular)	2/141 (1.4%)		4/139 (2.9%)
C-reactive protein increased (Non-ocular)	3/141 (2.1%)		6/139 (4.3%)
Chest X-ray (Non-ocular)	14/141 (9.9%)		20/139 (14.4%)
Colonoscopy (Non-ocular)	6/141 (4.3%)		6/139 (4.3%)
Computerised tomogram (Non-ocular)	6/141 (4.3%)		18/139 (12.9%)
Computerised tomogram abdomen (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Computerised tomogram head (Non-ocular)	11/141 (7.8%)		11/139 (7.9%)
Cystoscopy (Non-ocular)	2/141 (1.4%)		3/139 (2.2%)
Echocardiogram (Non-ocular)	9/141 (6.4%)		13/139 (9.4%)
Electrocardiogram (Non-ocular)	7/141 (5%)		5/139 (3.6%)
Electrocardiogram ambulatory (Non-ocular)	0/141 (0%)		3/139 (2.2%)
Full blood count (Non-ocular)	3/141 (2.1%)		1/139 (0.7%)
Gamma-glutamyltransferase increased (Non-ocular)	0/141 (0%)		4/139 (2.9%)
Glomerular filtration rate decreased (Non-ocular)	2/141 (1.4%)		3/139 (2.2%)
Haematocrit decreased (Non-ocular)	0/141 (0%)		4/139 (2.9%)
Haemoglobin decreased (Non-ocular)	2/141 (1.4%)		4/139 (2.9%)
International normalised ratio increased (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Intraocular pressure increased (Left eye)	1/141 (0.7%)		3/139 (2.2%)
Lymphocyte count decreased (Non-ocular)	2/141 (1.4%)		4/139 (2.9%)
Neutrophil count increased (Non-ocular)	2/141 (1.4%)		5/139 (3.6%)
Nuclear magnetic resonance imaging (Non-ocular)	2/141 (1.4%)		4/139 (2.9%)
Nuclear magnetic resonance imaging brain (Non-ocular)	5/141 (3.5%)		3/139 (2.2%)
Red blood cell count decreased (Non-ocular)	0/141 (0%)		3/139 (2.2%)
Ultrasound Doppler (Non-ocular)	5/141 (3.5%)		4/139 (2.9%)
Ultrasound abdomen (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Ultrasound kidney (Non-ocular)	2/141 (1.4%)		3/139 (2.2%)
Weight decreased (Non-ocular)	0/141 (0%)		3/139 (2.2%)
White blood cell count increased (Non-ocular)	2/141 (1.4%)		5/139 (3.6%)
X-ray (Non-ocular)	5/141 (3.5%)		1/139 (0.7%)
X-ray limb (Non-ocular)	3/141 (2.1%)		1/139 (0.7%)
X-ray of pelvis and hip (Non-ocular)	2/141 (1.4%)		5/139 (3.6%)
Metabolism and nutrition disorders
Hypercholesterolaemia (Non-ocular)	5/141 (3.5%)		1/139 (0.7%)
Hypokalaemia (Non-ocular)	3/141 (2.1%)		4/139 (2.9%)
Vitamin D deficiency (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Musculoskeletal and connective tissue disorders
Arthralgia (Non-ocular)	6/141 (4.3%)		7/139 (5%)
Arthritis (Non-ocular)	4/141 (2.8%)		2/139 (1.4%)
Back pain (Non-ocular)	9/141 (6.4%)		8/139 (5.8%)
Muscular weakness (Non-ocular)	3/141 (2.1%)		0/139 (0%)
Musculoskeletal pain (Non-ocular)	5/141 (3.5%)		1/139 (0.7%)
Osteoarthritis (Non-ocular)	4/141 (2.8%)		2/139 (1.4%)
Osteoporosis (Non-ocular)	1/141 (0.7%)		4/139 (2.9%)
Pain in extremity (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Nervous system disorders
Dizziness (Non-ocular)	5/141 (3.5%)		7/139 (5%)
Headache (Non-ocular)	6/141 (4.3%)		12/139 (8.6%)
Lethargy (Non-ocular)	3/141 (2.1%)		3/139 (2.2%)
Migraine (Non-ocular)	3/141 (2.1%)		0/139 (0%)
Neuralgia (Non-ocular)	3/141 (2.1%)		1/139 (0.7%)
Sciatica (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Psychiatric disorders
Anxiety (Non-ocular)	0/141 (0%)		4/139 (2.9%)
Delirium (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Insomnia (Non-ocular)	1/141 (0.7%)		7/139 (5%)
Renal and urinary disorders
Haematuria (Non-ocular)	2/141 (1.4%)		6/139 (4.3%)
Renal cyst (Non-ocular)	2/141 (1.4%)		3/139 (2.2%)
Renal impairment (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Urinary incontinence (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Respiratory, thoracic and mediastinal disorders
Asthma (Non-ocular)	3/141 (2.1%)		1/139 (0.7%)
Cough (Non-ocular)	11/141 (7.8%)		7/139 (5%)
Dyspnoea (Non-ocular)	8/141 (5.7%)		5/139 (3.6%)
Oropharyngeal pain (Non-ocular)	2/141 (1.4%)		3/139 (2.2%)
Productive cough (Non-ocular)	4/141 (2.8%)		1/139 (0.7%)
Skin and subcutaneous tissue disorders
Rash (Non-ocular)	4/141 (2.8%)		6/139 (4.3%)
Skin lesion (Non-ocular)	3/141 (2.1%)		0/139 (0%)
Surgical and medical procedures
Cancer surgery (Non-ocular)	6/141 (4.3%)		5/139 (3.6%)
Cardiac pacemaker insertion (Non-ocular)	1/141 (0.7%)		3/139 (2.2%)
Cataract operation (Left eye)	4/141 (2.8%)		11/139 (7.9%)
Cataract operation (Right eye)	10/141 (7.1%)		7/139 (5%)
Hip arthroplasty (Non-ocular)	5/141 (3.5%)		6/139 (4.3%)
Inguinal hernia repair (Non-ocular)	0/141 (0%)		3/139 (2.2%)
Intraocular lens implant (Right eye)	2/141 (1.4%)		4/139 (2.9%)
Radiotherapy (Non-ocular)	3/141 (2.1%)		2/139 (1.4%)
Skin neoplasm excision (Non-ocular)	9/141 (6.4%)		6/139 (4.3%)
Transfusion (Non-ocular)	3/141 (2.1%)		0/139 (0%)
Vascular disorders
Hypertension (Non-ocular)	8/141 (5.7%)		12/139 (8.6%)
Hypotension (Non-ocular)	5/141 (3.5%)		4/139 (2.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.