Clinical trial NCT01972789
Conditions: Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMD
Keywords: Subfoveal choroidal neovascularization (CNV) wet age-related macular degeneration(AMD) inject and extend retinal fluid
Sponsor: Novartis Pharmaceuticals
Start date: 2013-10-31; Completion date: 2017-02-28
Enrollment: 349 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate and compare two individualised ranibizumab treatment regimens, differentiated by the definition of disease activity, which determines the treatment interval until the next injection. The results will be used to generate recommendations about ranibizumab treatment when using an 'inject and extend' approach to maximise patient outcomes, while reducing the need for potentially unnecessary intravitreal injections. This study will also investigate if genotypic expression influences response to intravitreal injections of ranibizumab between the two treatment arms.

The study hypothesis is that intravitreal ranibizumab when administered to resolve IRF (and/or SRF \>200 μm at the foveal centre) results in visual acuity benefit that is not clinically worse than intravitreal ranibizumab when administered to completely resolve both IRF and SRF in patients with wet AMD

Detailed description:

Arms: arm 1: Ranibizumab 0.5mg is given monthly for the first 3 months followed by an individualised treatment regimen as determined by disease activity defined by a loss of ≥5 letters, new retinal haemorrhage, presence of any IRF or SRF on OCT. arm 2: Ranibizumab 0.5mg is given monthly for the first 3 months followed by an individualised treatment regimen as determined by disease activity defined by a loss of ≥5 letters, new retinal haemorrhage, presence of IRF or SRF \>200 um on OCT.
Interventions: intervention 1: Ranibizumab
Intervention descriptions: intervention 1: Ranibizumab solution for injection is commercially supplied in two presentations: as a pre-filled syringe (containing 1.65 mg of ranibizumab in 0.165 mL solution) and as a vial (containing 2.3 mg of ranibizumab in 0.23 mL solution) corresponding to a recommended dose of 0.5 mg (0.05 mL) given as a single intravitreal injection. It will be prescribed and administered by the investigator or designee

Protocol documents:
Prot_000.pdf: 
Clinical Development 
RFB002/ranibizumab / NCT01972789
A Phase IV, randomised, controlled, single masked study 
investigating the efficacy and safety of ranibizumab “inject 
and extend” using an intensive retinal fluid retreatment 
regimen compared to a relaxed retinal fluid retreatment 
regimen in patients with wet age-related macular 
degeneration (AMD). 
Project standard In-text and Post-text and appendix 
deliverables 
AUTHOR(S): 
 
DOCUMENT TYPE: 
MAP Documentation 
DOCUMENT STATUS: 
Final version 2.0 
RELEASE DATE: 
19 June 2017 
NUMBER OF PAGES: 
218 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template version 3.1 July 2014 


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Deliverables Approval 
 
By my signature, I confirm that this deliverables document has been reviewed by 
Novartis Australia, and has been approved for use on the CRFB002AAU15 study: 
 
Name 
Title / Company 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents 3 
General guidance .................................................................................................. 5 
1.1 
General guidance on shells in this document ............................................. 5 
1.1.1 
Document headers .................................................................... 5 
1.1.2 
Presentation of table numbering and titles within this document
 5 
1.2 
General strategies of data presentation ...................................................... 5 
1.2.1 
Treatment group labels and ordering ......................................... 5 
1.2.2 
Missing treatment columns ........................................................ 5 
1.2.3 
Order of entries in listings .......................................................... 6 
1.2.4 
Decimal places .......................................................................... 6 
1.2.5 
Baseline Definition ..................................................................... 6 
Overall table of contents for IIS outputs ...................................................................... 7 
2 
Shells and specifications ......................................................... 14 
2.1 
Shells and specifications for Sections 10, 11 and 12 of a standard CSR 
(Text tables and figures) ........................................................................... 14 
Section 10 Study patients ............................................................................... 14 
Section 11 Efficacy ......................................................................................... 16 
Section 12 Safety evaluation .......................................................................... 33 
2.2 
Shells and specifications for Sections 14 and 16 of a standard CSR ....... 38 
Section 14 – Tables, figures referred to but not included in the text ............... 38 
Section 14.1 – Demographic data ................................................................... 38 
Section 14.2 – Efficacy and other non-safety data (e.g. PK, PK/PD, health 
economics, QoL) ..................................................................... 84 
Section 14.3 – Safety data ............................................................................ 145 
Section 14.3.1 – Displays of adverse events ................................................ 152 
Section 14.3.2 – Listings of deaths, other serious and significant adverse 
events .................................................................................... 170 
Section 14.3.3 – Narratives of deaths, other serious and significant adverse 
events (non Biometric deliverables) ....................................... 175 
Section 14.3.4 – Abnormal laboratory value listings ..................................... 175 
Section 16.2 – Patient data listings ............................................................... 178 
Section 16.2.1 – Discontinued patients ......................................................... 178 
Section 16.2.2 – Protocol deviations ............................................................. 180 
Section 16.2.3 – Patients excluded from the efficacy analysis ...................... 181 
Section 16.2.4 – Demographic data .............................................................. 182 


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Section 16.2.5  Compliance and/or drug concentration data ........................ 190 
Section 16.2.6 – Individual efficacy response data and other non-safety data
 196 
Section 16.2.7 – Adverse event listings ........................................................ 207 
Section 16.2.8 – Laboratory measurements ................................................. 213 
Section 16.2.9 – Vital signs, physical findings and other observations related 
to safety listings ..................................................................... 214 
Section 16.2.10 – Listing of subject numbers who reported at least one safety 
event of special interest by event and treatment ................... 218 
Section 16.2.11 – Case retrieval strategy listing ........................................... 218 


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General guidance 
1.1 
General guidance on shells in this document 
1.1.1 
Document headers 
The following header will be used for all Section 14 and Section 16 tables, listings and 
figures outlined in this document:  CRFB002AAU15/RFB002/Ranibizumab. 
1.1.2 
Presentation of table numbering and titles within this document 
In order to facilitate the inclusion of a table of contents for all output, the format of the 
number and title for each layout should be in the Novstyle format “Non-TOC Heading” 
and therefore does not exactly match the layout that is intended for the final deliverable. 
In practice, the numbering and title for all Section 14 and Section 16 tables and listings 
defined in this document will be of the following formats respectively: 
 
Table XX.X-X.X 
Title Title Title Title Title Title 
Analysis set 
 
Listing XX.X-X.X 
Title Title Title Title Title Title 
Analysis set 
1.2 
General strategies of data presentation 
1.2.1 
Treatment group labels and ordering 
The following treatment labels will be used for all tables, listings and figures in the order 
provided here: 
• Intensive 
• Relaxed 
• Total (where applicable) 
1.2.2 
Missing treatment columns 
All treatment columns should be presented as long as data is available for at least one 
treatment group. When information is not available for any treatment groups then “No 
observations available” will be used to reflect that observations are not available for a 
specific table/figure/listing. 
In the case where treatment columns are automatically dropped due to lack of 
events/data etc. output the following footnote will be added: 
Note:  Treatment groups which do not contribute events are not displayed. 


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1.2.3 
Order of entries in listings 
All listings should be sorted by treatment group, site, patient, visit date/event date (in 
the case of multiple observations per visit date/event date, the observations should be 
sorted alphabetically within visit date/event date). 
1.2.4 
Decimal places 
Decimal places for demographic, background and duration of exposure variables will 
be as follows: 
• 3 decimal places for p-values; if p-value is less than 0.001, display <0.001. 
• 2 decimal places for standard errors and standard deviations. 
• 1 decimal place for means and medians. 
• 1 decimal place for min and max. 
• 1 decimal place for percentages. 
• If percentage = 100, no decimal is required. 
Decimal places for efficacy and other safety summary tables and listings will be as 
follows: 
• p-value: 3 decimal places; if p-value is less than 0.001, display <0.001. 
• Standard errors and standard deviations: data precision + 2 decimal places  
• Means and medians: data precision + 1 decimal place  
• Minimums and maximums: same as data precision  
• Percentages: 1 decimal place 
• If percentage = 100, no decimal is required. 
Please ignore current examples of precision in shells. 
1.2.5 
Baseline Definition 
For statistical purposes, baseline will be defined as the last available non-missing value 
collected just prior to the start of treatment in the study eye. 


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Overall table of contents for IIS outputs 
Deliverables Approval ................................................................................................. 2 
Table 10-1 
Patient disposition – n (%) of patients...................................... 14 
Table 10-2 
Protocol Deviations – n (%) of patients and total counts.......... 15 
Table 11.1-1 
Analysis sets – n (%) of patients .............................................. 16 
Table 11.2-1 
Demographic summary by treatment group ............................. 17 
Table 11.2-2 
Baseline Medical History Questions by treatment group ......... 19 
Table 11.2-3 
Medical History - Arterial Thomboembolic Events ................... 20 
Table 11.2-4 
Baseline AMD characteristics (STUDY EYE) by treatment group
 ................................................................................................ 21 
Table 11.4-1.1 
Mean absolute change in BCVA from baseline to months 2, 12 
and 24 ...................................................................................... 29 
Table 11.4-1.2 
Mean absolute change in BCVA from baseline to months 2, 12 
and 24 ...................................................................................... 30 
Table 11.4-2 
Mean change in Central Retinal Thickness from baseline to 
months 2, 12 and 24 (STUDY EYE) ........................................ 31 
Table 11.4-3 
Number of Injections from baseline to month 12 and 24.......... 32 
Table 12.1-1 
Overall exposure ..................................................................... 33 
Table 12.1-2 
Treatment Frequency and Intervals at 12 and 24 months ....... 34 
Table 12.2-1 
Number (%) of patients with AEs by primary system organ class
 ................................................................................................ 35 
Table 14.1-1 
Patient disposition, by treatment .............................................. 39 
Table 14.1-2 
Screening phase subject disposition........................................ 40 
Table 14.1-3 
Protocol deviations, by treatment ............................................ 41 
Table 14.1-4 
Protocol deviations leading to exclusion from analysis sets .... 42 
Table 14.1-5 
Out of Window visits ................................................................ 43 
Table 14.1-6 
Under and Over Treatment due to treatment interval error ...... 44 
Table 14.1-7 
Analysis sets, by treatment ...................................................... 45 
Table 14.1-8 
Randomisation by Site ............................................................. 46 
Table 14.1-9 
Demographics, by treatment .................................................... 47 
Table 14.1-10 
Baseline characteristics by Treatment Group .......................... 49 
Table 14.1-11 
Baseline characteristics by genotyping status ......................... 60 
Table 14.1-12 
Baseline Medical History Questions by treatment group ......... 71 
Table 14.1-13 
Medical History, by primary system organ class, preferred terms 
and treatment .......................................................................... 72 
Table 14.1-14 
Ocular Medical History, by primary system organ class, 
preferred terms ........................................................................ 73 
Table 14.1-15 
Medical History - Arterial Thomboembolic Events ................... 74 


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Table 14.1-16  
Baseline AMD characteristics (STUDY EYE) by treatment group
 ................................................................................................ 75 
Table 14.1-17 
Baseline AMD characteristics (FELLOW EYE) by treatment 
group ....................................................................................... 83 
Figure 14.2-1 
Absolute BCVA over time by treatment ................................... 85 
Figure 14.2-2 
Absolute change in BCVA over time by treatment ................... 86 
Figure 14.2-3 
Visual Acuity over time, stratified by baseline acuity ............... 87 
Figure 14.2-4 
Visual Acuity over time, stratified by baseline acuity ............... 88 
Figure 14.2-5 
Change in BCVA from baseline stratified by visual acuity ....... 89 
Figure 14.2-6 
Change in BCVA from baseline stratified by visual acuity ....... 90 
Figure 14.2-7 
Proportion of Patients with >= 15 letter increase in BCVA from 
baseline, over time by treatment .............................................. 91 
Figure 14.2-8 
Proportion of Patients with >= 15 letter increase in BCVA from 
baseline at Month 12 and 24 ................................................... 92 
Figure 14.2-9 
Proportion of patients achieving >=6/12 vision, over time by 
treatment ................................................................................. 93 
Figure 14.2-10 
Proportion of of patients achieving >=6/12 vision at Month 12 
and 24 ...................................................................................... 94 
Figure 14.2-11 
Proportion of patients showing worse than 6/60 vision, over time 
by treatment ............................................................................. 95 
Figure 14.2-12 
Proportion of of patients showing worse than 6/60 vision at 
Month 12 and 24 ...................................................................... 96 
Figure 14.2-13 
Proportion of patients with IRF and BCVA, over time by 
treatment ................................................................................. 97 
Figure 14.2-14 
Proportion of patients with SRF and BCVA, over time by 
treatment ................................................................................. 98 
Figure 14.2-15 
Proportion of patients with IRF and SRF, and BCVA, over time 
by treatment ............................................................................. 99 
Figure 14.2-16 
Proportion of patients with neither IRF or SRF, and BCVA, over 
time by treatment ................................................................... 100 
Figure 14.2-17 
Proportion of patients with Geographic Atrophy and BCVA, over 
time by treatment ................................................................... 101 
Figure 14.2-18 
Proportion of Patients with IRF over time by treatment ......... 102 
Figure 14.2-19 
Proportion of Patients with SRF over time by treatment ........ 103 
Figure 14.2-20 
Proportion of Patients with IRF and SRF over time by treatment
 .............................................................................................. 104 
Figure 14.2-21 
Proportion of Patients with neither IRF or SRF over time by 
treatment ............................................................................... 105 
Figure 14.2-22 
Proportion of Patients with Geographic Atrophy over time by 
treatment ............................................................................... 106 


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Figure 14.2-23 
Change in geographic atrophy area from baseline over time by 
treatment ............................................................................... 107 
Figure 14.2-24 
Change in Central Subfield Foveal Thickness from baseline, 
over time by treatment ........................................................... 108 
Figure 14.2-25 
Number of injections by treatment at 12 and 24 months........ 109 
Table 14.2-1 
Visual Acuity – Summary and Change from Baseline ........... 110 
Table 14.2-2 
Visual Acuity – Mixed Model Analysis.................................... 111 
Table 14.2-3 
Visual Acuity – Mixed Model Analysis.................................... 111 
Table 14.2-4 
Proportion of Patients with >=15 letters change from baseline – 
Logistic Regression ............................................................... 112 
Table 14.2-4 
Proportion of Patients with less than 15 letters lost change from 
baseline – Logistic Regression .............................................. 114 
Table 14.2-5 
Proportion of Patients who achieve >=6/12 visual acuity – 
Logistic Regression ............................................................... 116 
Table 14.2-6 
Proportion of Patients who achieve <=6/60 visual acuity – 
Logistic Regression ............................................................... 117 
Table 14.2-7 
Interval Decision Summary Table .......................................... 118 
Table 14.2-8 
Number of Injections .............................................................. 119 
Table 14.2-9 
Number of Injections from Baseline to Months 12 and 24 – 
Negative Binomial Regression ............................................... 120 
Table 14.2-10 
Treatment Interval Summary (Based on Interval Decision) ... 121 
Table 14.2-11 
Treatment Interval Summary (Based on Actual Intervals 
between Visits) ...................................................................... 122 
Table 14.2-12 
Treatment Interval Visit Summary (Based on Interval Decision)
 .............................................................................................. 123 
Table 14.2-13 
Treatment Interval Visit Summary (Based on Actual Intervals 
between Visits) ...................................................................... 124 
Table 14.2-14 
Breakpoint Set Interval - Summary ........................................ 125 
Table 14.2-15 
Post-Breakpoint Maximum Inteval - Summary ....................... 126 
Table 14.2-16 
Time to Breakpoint - Summary .............................................. 127 
Table 14.2-17 
Time to Breakpoint – Survival Analysis .................................. 128 
Table 14.2-18 
Geographic Atrophy Area – Summary and Change from 
Baseline (Central Reading Center Data) ............................... 129 
Table 14.2-19 
Geographic Atrophy – Categorical Summary ........................ 130 
Table 14.2-20 
Geographic Atrophy – Survival Analysis ................................ 131 
Table 14.2-21 
Geographic Atrophy – Mixed Model Analysis ........................ 132 
Table 14.2-22 
Geographic Atrophy – Mixed Model Analysis ........................ 133 
Table 14.2-23 
Proportion of Patients with Geographic Atrophy from Baseline to 
Month 24 – Logistic Regression ............................................ 134 


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Table 14.2-24 
Proportion of Patients showing intra-retinal /  sub-retinal fluid, by 
visit ........................................................................................ 135 
Table 14.2-25 
Proportion of patients with SRF at baseline who never resolve 
their SRF (irrespective of their IRF) – Logistic Regression .... 136 
Table 14.2-26 
Proportion of patients with IRF at baseline who never resolve 
their IRF (irrespective of their SRF) – Logistic Regression .... 137 
Table 14.2-27 
Proportion of patients with IRF and SRF at baseline who never 
resolve either their IRF or SRF – Logistic Regression ........... 138 
Table 14.2-28 
Intra-Retinal and Sub-Retinal Fluid – Generalized Estimating 
Equation ................................................................................ 139 
Table 14.2-29 
Central Retinal Thickness – Summary and Change from 
Baseline, by treatment ........................................................... 140 
Table 14.2-30 
Central Retinal Thickness – Mixed Model Analysis ............... 141 
Table 14.2-31 
Genotyping by Treatment ...................................................... 142 
Table 14.2-32 
Genotyping by Race .............................................................. 143 
Table 14.3-1 
Number (%) of patients receiving each dose and regimen of 
study medication by treatment and visit ................................. 145 
Table 14.3-2 
Duration of exposure to study drug, by treatment .................. 146 
Table 14.3-3 
Medications and significant non-drug therapies taken prior to 
the start of study drug by ATC class, preferred term and 
treatment ............................................................................... 147 
Table 14.3-4 
Forbidden concomitant medications and significant non-drug 
therapies after start of study drug by ATC class, preferred term 
and treatment ........................................................................ 148 
Table 14.3-5 
Vital signs by visit and treatment ........................................... 149 
Table 14.3-6 
Ophthalmic Examination – Intraocular Pressure (IOP) by 
treatment ............................................................................... 150 
Listing 14.3-1 
Patients with notably abnormal vital signs ............................. 151 
Table 14.3.1-1 
Incidence of adverse events, regardless of study drug 
relationship, by primary system organ class, preferred term and 
treatment ............................................................................... 153 
Table 14.3.1-2 
Incidence of ocular adverse events, regardless of study drug 
relationship, by primary system organ class, preferred term and 
treatment ............................................................................... 154 
Table 14.3.1-3 
Incidence of adverse events, regardless of study drug 
relationship by primary system organ class, preferred term, 
maximum severity and treatment ........................................... 155 
Table 14.3.1-4 
Incidence of ocular adverse events, regardless of study drug 
relationship by primary system organ class, preferred term, 
maximum severity and treatment ........................................... 156 


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Table 14.3.1-5 
Incidence of adverse events, by primary system organ class, 
preferred term, maximum relationship to study drug and 
treatment ............................................................................... 157 
Table 14.3.1-6 
Incidence of adverse events suspected to be related to study 
drug, by primary system organ class, preferred term and 
treatment ............................................................................... 158 
Table 14.3.1-7 
Incidence of ocular adverse events suspected to be related to 
study drug, by primary system organ class, preferred term and 
treatment ............................................................................... 159 
Table 14.3.1-8 
Incidence of serious adverse events, regardless of study drug 
relationship, by primary system organ class, preferred term and 
treatment ............................................................................... 160 
Table 14.3.1-9 
Incidence of ocular serious adverse events, regardless of study 
drug relationship, by primary system organ class, preferred term 
and treatment ........................................................................ 161 
Table 14.3.1-10 
Incidence of adverse events leading to treatment withdrawal, 
regardless of study drug relationship, by primary system organ 
class, preferred term and treatment ....................................... 162 
Table 14.3.1-11 
Incidence of ocular adverse events leading to treatment 
withdrawal, regardless of study drug relationship, by primary 
system organ class, preferred term and treatment ................ 163 
Table 14.3.1-12 
Incidence of adverse events leading to study drug interruption, 
regardless of study drug relationship, by primary system organ 
class, preferred term and treatment ....................................... 164 
Table 14.3.1-13 
Incidence of ocular adverse events leading to study drug 
interruption, regardless of study drug relationship, by primary 
system organ class, preferred term and treatment ................ 165 
Table 14.3.1-14 
Incidence of adverse events requiring significant additional 
therapy, regardless of study drug relationship, by primary 
system organ class, preferred term and treatment ................ 166 
Table 14.3.1-15 
Incidence of ocular adverse events requiring significant 
additional therapy, regardless of study drug relationship, by 
primary system organ class, preferred term and treatment ... 167 
Table 14.3.1-16 
Deaths, by primary system organ class, preferred term and 
treatment ............................................................................... 168 
Table 14.3.1-17 
Arterial Thomboembolic Events ............................................. 169 
Listing 14.3.2-1 
Deaths, by treatment ............................................................. 170 
Listing 14.3.2-2 
Serious adverse events, by treatment ................................... 171 
Listing 14.3.2-3 
Adverse events causing study drug discontinuation by treatment
 .............................................................................................. 172 
Listing 14.3.2-4 
Adverse events requiring interruption by treatment ............... 173 


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Listing 14.3.2-5 
Adverse events requiring significant additional therapy ......... 174 
Listing 16.1.7-1 
Randomized allocation to treatment ...................................... 176 
Listing 16.2.1-1 
Study phase completion by treatment.................................... 178 
Listing 16.2.1-2 
Screened subjects discontinued from study prior to 
randomization ........................................................................ 179 
Listing 16.2.2-1.1 
Protocol deviations by treatment ........................................... 180 
Listing 16.2.3-1 
Patients excluded from Per-Protocol efficacy analysis by 
treatment ............................................................................... 181 
Listing 16.2.4-1 
Patient Disposition ................................................................. 182 
Listing 16.2.4-2 
Eligibility Criteria .................................................................... 183 
Listing 16.2.4-3 
Patient demographics by treatment ....................................... 184 
Listing 16.2.4-4 
Patient demographic questions by treatment ......................... 185 
Listing 16.2.4-5 
Relevant medical history and current medical conditions by 
treatment ............................................................................... 186 
Listing 16.2.4-6 
AMD Treatment History (STUDY eye) ................................... 187 
Listing 16.2.4-7 
AMD Treatment History (FELLOW eye) ................................ 188 
Listing 16.2.4-8 
AMD Treatment at Baseline ................................................... 189 
Listing 16.2.5-1 
Dose administration record by treatment (STUDY eye) ......... 190 
Listing 16.2.5-2 
Dose administration record by treatment (FELLOW eye) ...... 191 
Listing 16.2.5-3 
Medications and significant non-drug therapies prior to start of 
study drug by treatment ......................................................... 192 
Listing 16.2.5-4 
Medications and significant non-drug therapies after start of 
study drug by treatment ......................................................... 193 
Listing 16.2.5-5 
Medications and significant non-drug therapies after start of 
study drug by treatment (STUDY EYE) ................................. 194 
Listing 16.2.5-6 
Medications and significant non-drug therapies after start of 
study drug by treatment (FELLOW EYE) ............................... 195 
Listing 16.2.6-1 
CF/FA/AF by treatment (STUDY EYE) (CRF Data) ............... 196 
Listing 16.2.6-2 
CF/FA/AF by treatment (FELLOW EYE) ................................ 197 
Listing 16.2.6-3 
Fluorescein Angiography Assessments by treatment (STUDY 
EYE) (Central Reading Center Data) ..................................... 198 
Listing 16.2.6-4 
Colour Fundus Assessments by treatment (STUDY EYE) 
(Central Reading Center Data) .............................................. 199 
Listing 16.2.6-5 
Visual Acuity by Treatment (STUDY EYE) ............................ 200 
Listing 16.2.6-6 
Visual Acuity by Treatment (FELLOW EYE) .......................... 201 
Listing 16.2.6-7 
Optical Coherence Tomography (OCT) by Treatment (STUDY 
EYE) (CRF Data) ................................................................... 202 


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Listing 16.2.6-8 
Optical Coherence Tomography (OCT) by Treatment (FELLOW 
EYE) (CRF Data) ................................................................... 203 
Listing 16.2.6-9 
Optical Coherence Tomography (OCT) by treatment (STUDY 
EYE) (Central Reading Center Data) ..................................... 204 
Listing 16.2.6-10 
Genotyping Sampling ............................................................ 205 
Listing 16.2.6-11 
Genotyping SNPs .................................................................. 206 
Listing 16.2.7-1 
Adverse events ...................................................................... 207 
Listing 16.2.7-2 
Ocular adverse events ........................................................... 208 
Listing 16.2.7-3 
Adverse events suspect to be related to study drug and/or 
ocular injection ....................................................................... 209 
Listing 16.2.7-4 
Serious adverse events ......................................................... 210 
Listing 16.2.7-5 
Adverse events leading to treatment withdrawal ................... 211 
Listing 16.2.7-6 
Adverse events leading to treatment interruption .................. 212 
Listing 16.2.9-1 
Vital signs by treatment ......................................................... 214 
Listing 16.2.9-2 
Ophthalmic Examinations by treatment (STUDY EYE).......... 215 
Listing 16.2.9-3 
Ophthalmic Examinations by treatment (FELLOW EYE) ....... 216 
Listing 16.2.9-4 
Pregnancy test data by treatment .......................................... 217 
 


 
 
 
2 
Shells and specifications 
2.1 
Shells and specifications for Sections 10, 11 and 12 of a standard CSR (Text tables and figures) 
Section 10 Study patients 
PATIENT DISPOSITION 
Table 10-1 
Patient disposition – n (%) of patients  
Randomised Set 
 
n(%) 
Intensive 
(N=X) 
 Relaxed  
(N=X) 
 Total  
(N=X) 
 
All Enrolled 
 
x (xx.x) 
 
x (xx.x) 
 
x (xx.x) 
Number of Subjects Started Treatment 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Number of Subjects Completed Treatment 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Number of Subjects Discontinued Early  
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
Primary Reason for Early Discontinuation 
 
 
 
Adverse Event  
x (xx.x) 
x (xx.x) 
x (xx.x) 
Subject withdrew consent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Lost to follow-up 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Site administrative problems 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Death 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Protocol deviation 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Physician’s decision 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Source: Table 14.1-1 


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PROTOCOL DEVIATIONS 
Table 10-2 
Protocol Deviations – n (%) of patients and total counts 
Full Analysis Set 
 
Population n (%) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Total  
(N=X) 
 
 
 
 
Subjects with at least one protocol deviation 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Number of deviations 
x 
x 
x 
 
Type of Deviation 
 
 
 
 
I (inclusion criteria) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
E (Exclusion criteria) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
M (Medication) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
O (other)  
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
Source: Table 14.1-3 


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Section 11 Efficacy  
ANALYSIS SETS 
Table 11.1-1 
Analysis sets – n (%) of patients 
Randomised Set 
 
Population n(%) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Total  
(N=X) 
 
 
 
 
Randomised Set 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Full Analysis Set 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Safety Set  
x (xx.x) 
x (xx.x) 
x (xx.x) 
Per-Protocol Set* 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
* Includes all patients who contributed at least one data point to per-protocol analyses. Individual data points or visits may have been excluded from per-
protocol analyses based on protocol deviation assessments. 
Source: Table 14.1-7 
Note to Programmer: Table needs to include all analysis sets used in the output. This includes any 
derived analysis sets used for sensitivity analyses 


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MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Table 11.2-1 
Demographic summary by treatment group 
Randomised Set 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Study Eye 
 
 
Left 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Right 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Age (years)* 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Gender n(%) 
 
 
 
Female 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Male 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Predominate Race n(%) 
 
 
 
Caucasian: Afghan, Caucasian, 
Egypt, Egyptian, El Salvadore, Greek, 
Hispanic, Israeli, Italian, Maltese, 
Middle East, Middle Eastern, South 
American, Turkish, Yugoslavian  
x (xx.x) 
x (xx.x) 
x (xx.x) 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
Black African 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Asian: Asian and Indian 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Aboriginal and Torres Strait Islander 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Pacific Islander 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Sure 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Ethnicity n(%) 
 
 
 
Anglo Saxon 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Northern European 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Southern European 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Asian Indian 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Sure 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Do you have a family history of AMD? 
 
 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Is there any history of arterial thromboembolic events? 
 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Has the participant ever smoked cigarettes, pipes or cigars? 
 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
*Age calculated at date of informed consent 
SD: Standard Deviation 
Source: Table 14.1-6 


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CRFB002AAU15/RFB002/Ranibizumab 
 
Table 11.2-2 
Baseline Medical History Questions by treatment group  
Randomised Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Medical history/Current medical conditions to be reported* 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
* Refer to Table 14.1-9 and 14.1-10 for further details 
Source: Table 14.1-7 
 
 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
Table 11.2-3 Medical History - Arterial Thomboembolic Events 
Randomised Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
Arterial Thomboembolic Events (ATEs)* 
xx.x 
x 
xx.x 
x 
xx.x 
x 
Nonfatal myocardial infarction 
xx.x 
x 
xx.x 
x 
xx.x 
x 
Nonfatal stroke 
xx.x 
x 
xx.x 
x 
xx.x 
x 
 
 
 
 
 
 
 
* ATEs defined as nonfatal myocardial infarction, nonfatal stroke, vascular death and death of unknown cause 
AE: Adverse Event 
Note: Some patients may have experienced multiple events 
 
 
 
 
 
 
 
 
 
 
 


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Table 11.2-4 
Baseline AMD characteristics (STUDY EYE) by treatment group  
Randomised Set 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Was any treatment ever given to the fellow eye prior to Screening? 
 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Lucentis 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Eylea 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Visudyne 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Avastin 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Steroids 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Total BCVA Score (ETDRS letters) 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Visual Acuity - Categorical (20/40) 
 
 
 
 
>=70 letters 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
<70 letters 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Central Subfield Foveal Thickness (µm)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Central Subfield Volume (mm3)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Area of Lesion (mm2)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Intra-Retinal Fluid Status 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Intra-Retinal Fluid Status* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Intra-Retinal Fluid Centre Involvement* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Intra-Retinal Cysts* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Intra-Retinal Cysts Centre Involvement* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Sub-Retinal Fluid Status 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
 
 
 
 
Sub-Retinal Fluid Status* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Sub-Retinal Fluid Centre Involvement* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Sub-Retinal Fluid at Centrepoint* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Sub-Retinal Fluid Height at Centrepoint 
 
 
 
 
<=200μm 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
>200 μm 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Applicable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Sub-Retinal Fluid Height at Centrepoint* 
 
 
 
 
<=200μm 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
>200 μm 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Applicable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Morphologic Changes* 
 
 
 
 
Epiretinal Membrane 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Vitreoretinal Traction 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Macular Hole 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Atrophy 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 


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MAP Module 7.1 
 
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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Area of CNV (mm2)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
CNV Complex (lesion) 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Definite 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Questionable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…… 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
CNV Complex (lesion)* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Definite 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Questionable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…… 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
CNV Complex (lesion) Location 
 
 
 
 
Subfoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal with centre 
involvement 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal with centre 
involvement 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 


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MAP Module 7.1 
 
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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
CNV Location 
 
 
 
 
Subfoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
CNV Location* 
 
 
 
 
Subfoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal with centre 
involvement 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal with centre 
involvement 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
CNV Secondary to …..* 
 
 
 
 
AMD 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Angioid Streaks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Idiopathic 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Pathologic Myopia 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Type of CNV* 
 
 
 
 
Predominantly classic 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Occult 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Fibrovascular PED 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Serous PED 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
CNV Leakage* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Lesion Components* 
 
 
 
 
Blood 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
CNV 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Serous PED 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
RPE Tear 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Geographic Atrophy (Status)* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Definite 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Applicable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Geographic Atrophy Location* 
 
 
 
 
Central Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Inner Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Outer Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Geographic Atrophy Area (mm2)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Haemorrhage* 
 
 
 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Haemorrhage Location* 
 
 
 
 
Central Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Inner Subfield  
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Outer Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Retinal Abnormality* 
 
 
 
 
Drusen 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Atrophy 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Fibrosis 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PED 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Retinal Abnormality Location* 
 
 
 
 
Central 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Periphery 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
* Source: 
 
Source: Table 14.1-8 
Note to Programmer: Footnote is to appear on all pages 


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CRFB002AAU15/RFB002/Ranibizumab 
 
ANALYSIS OF EFFICACY 
Table 11.4-1.1 
Mean absolute change in BCVA from baseline to months 2, 12 and 24  
Full analysis set 
 
Visit 
Statistic 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Actual Value 
Absolute 
Change from 
Baseline* 
Actual Value 
Absolute 
Change from 
Baseline 
Actual Value 
Absolute 
Change from 
Baseline 
 
 
 
 
 
 
 
 
Baseline 
n 
x 
- 
x 
- 
x 
- 
 
Mean (SD) 
x.x (x.x) 
- 
x.x (x.x) 
- 
x.x (x.x) 
- 
 
Min; Max 
x;x 
- 
x;x 
- 
x;x 
- 
 
 
 
 
 
 
 
 
Month 2 
n 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
x;x 
x;x 
x;x 
 
 
 
 
 
 
 
 
Month 12 
n 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
x;x 
x;x 
x;x 
 
 
 
 
 
 
 
 
Month 24 
n 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
x;x 
x;x 
x;x 
 
 
*Baseline: The last available non-missing value collected just prior to the start of treatment in the study eye 
SD: Standard Deviation 
Source: Table 14.2-1 


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Table 11.4-1.2 
Mean absolute change in BCVA from baseline to months 2, 12 and 24  
Per Protocol Set 
 
Visit 
Statistic 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Actual Value 
Absolute 
Change from 
Baseline* 
Actual Value 
Absolute 
Change from 
Baseline 
Actual Value 
Absolute 
Change from 
Baseline 
 
 
 
 
 
 
 
 
Baseline 
n 
x 
- 
x 
- 
x 
- 
 
Mean (SD) 
x.x (x.x) 
- 
x.x (x.x) 
- 
x.x (x.x) 
- 
 
Min; Max 
x;x 
- 
x;x 
- 
x;x 
- 
 
 
 
 
 
 
 
 
Month 2 
n 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
x;x 
x;x 
x;x 
 
 
 
 
 
 
 
 
Month 12 
n 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
x;x 
x;x 
x;x 
 
 
 
 
 
 
 
 
Month 24 
n 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
x;x 
x;x 
x;x 
 
 
*Baseline: The last available non-missing value collected just prior to the start of treatment in the study eye 
SD: Standard Deviation 
Source: Table 14.2-1 
 
 
 
 


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Table 11.4-2 
Mean change in Central Retinal Thickness from baseline to months 2, 12 and 24 (STUDY EYE) 
Full Analysis Set 
 
Visit 
Statistic 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Actual Value 
Absolute 
Change from 
Baseline* 
Actual Value 
Absolute 
Change from 
Baseline 
Actual Value 
Absolute 
Change from 
Baseline 
 
 
 
 
 
 
 
 
Baseline 
n 
x 
- 
x 
- 
x 
- 
 
Mean (SD) 
x.x (x.x) 
- 
x.x (x.x) 
- 
x.x (x.x) 
- 
 
Min; Max 
x;x 
- 
x;x 
- 
x;x 
- 
 
 
 
 
 
 
 
 
Month 2 
n 
x 
- 
x 
- 
x 
- 
 
Mean (SD) 
x.x (x.x) 
- 
x.x (x.x) 
- 
x.x (x.x) 
- 
 
Min; Max 
x;x 
- 
x;x 
- 
x;x 
- 
 
 
 
 
 
 
 
 
Month 12 
n 
x 
- 
x 
- 
x 
- 
 
Mean (SD) 
x.x (x.x) 
- 
x.x (x.x) 
- 
x.x (x.x) 
- 
 
Min; Max 
x;x 
- 
x;x 
- 
x;x 
- 
 
 
 
 
 
 
 
 
Month 24 
n 
x 
- 
x 
- 
x 
- 
 
Mean (SD) 
x.x (x.x) 
- 
x.x (x.x) 
- 
x.x (x.x) 
- 
 
Min; Max 
x;x 
- 
x;x 
- 
x;x 
- 
 
 
*Baseline: The last available non-missing value collected just prior to the start of treatment in the study eye 
SD: Standard Deviation 
NOTE: Data based on Central Reading Center data 
Source: Table 14.2-5 
 
 
 
 


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Table 11.4-3 
Number of Injections from baseline to month 12 and 24  
Full Analysis Set 
 
Visit 
 
Intensive 
(N=X)  
 Relaxed 
(N=X)  
Total 
(N=X) 
 
 
 
 
 
Number of Injections 
(First Year) 
n 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
 
 
 
 
 
Number of Injections 
(Second Year) 
n 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
 
 
 
 
 
Number of Injections 
(Total) 
n 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
 
 
 
 
 
Exposure (year) 
n 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
 
 
 
 
 
Injections per year* 
 
xx 
xx 
xx 
 
 
 
 
 
* Injections per year = Total number of injections / total exposure to treatment (years) 
Source: Table 14.2-8 
 


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Section 12 Safety evaluation 
EXTENT OF EXPOSURE 
Table 12.1-1 
Overall exposure 
Safety Set 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Duration of Exposure (days)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
SD: Standard Deviation 
*Duration of Exposure = Date of first treatment to date of End of Treatment + 1 
Source:  Table 14.3-2 
 
 
 
 
 
 
 


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Table 12.1-2 
Treatment Frequency and Intervals at 12 and 24 months 
Safety set 
 
Visit 
Interval 
n (%) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Month 12 
4 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
6 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
8 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
10 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
12 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Month 24 
4 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
6 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
8 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
10 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
12 weeks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Source: Table 14.3-1 
 
 Note to Programmer: This table counts what interval schedule each patient is on at the static 
timepoints of Month 12 and Month 24. Knowing the Month 12 date, look at the injection visit immediately 
prior to that date and use the Interval Decision value. If the patient’s injection visit was held at the same 
time as the Month 12 visit then use the Interval leading up to the visit rather than the Injection Decision. 


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ADVERSE EVENTS 
Table 12.2-1 
Number (%) of patients with AEs by primary system organ class  
Safety set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive 
(N=X) 
Relaxed 
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x) 
x 
x (xx.x) 
x 
x (xx.x) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x) 
x 
x (xx.x) 
x 
x (xx.x) 
x 
 
PT1 
x (xx.x) 
x 
x (xx.x) 
x 
x (xx.x) 
x 
 
PT2 
x (xx.x) 
x 
x (xx.x) 
x 
x (xx.x) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x) 
x 
x (xx.x) 
x 
x (xx.x) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x) 
x 
x (xx.x) 
x 
x (xx.x) 
x 
 
PT1 
x (xx.x) 
x 
x (xx.x) 
x 
x (xx.x) 
x 
 
PT2 
x (xx.x) 
x 
x (xx.x) 
x 
x (xx.x) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x) 
x 
x (xx.x) 
x 
x (xx.x) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
A patient with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment. 
A patient with multiple adverse events within a primary system organ class is counted only once in the total row. 
Source: Table 14.3.1-1 
 
 


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DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS 
 
None 


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CRFB002AAU15/RFB002/Ranibizumab 
 
LABORATORY EVALUATIONS 
 
None 
 
LIVER TOXICITY 
 
None 
 
VITAL SIGNS, PHYSICAL FINDING, OTHER OBSERVATION RELATED TO SAFETY 
 
None 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
2.2 
Shells and specifications for Sections 14 and 16 of a standard CSR 
Section 14 – Tables, figures referred to but not included in the text 
Section 14.1 – Demographic data 
Figures (Section 14.1) 
No Output 
 
 


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Tables (Section 14.1) 
Table 14.1-1 
Patient disposition, by treatment     
Randomised Set 
 
Disposition 
               Reason 
Intensive 
(N=X) 
n (%) 
 Relaxed  
(N=X) 
n (%) 
 Total  
(N=X) 
n (%) 
 
All Enrolled 
 
x (xx.x) 
 
x (xx.x) 
 
x (xx.x) 
 
 
 
 
Number of Subjects Started Treatment 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Number of Subjects Completed Treatment 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Number of Subjects Terminated Early  
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
Primary Reason for Termination 
 
 
 
Adverse Event  
x (xx.x) 
x (xx.x) 
x (xx.x) 
Subject withdrew consent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Lost to follow-up 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Site administrative problems 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Death 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Protocol deviation 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Physician’s decision 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.1-2 
Screening phase subject disposition 
Randomised Set 
 
Disposition 
               Reason 
 Total  
(N=X) 
n (%) 
 
Completed Screening phase 
 
x (xx.x) 
Discontinued prior to screening phase completion 
x (xx.x) 
 
 
Primary Reason for Termination 
 
Adverse Event  
x (xx.x) 
Lost to follow-up 
x (xx.x) 
Physician’s decision 
x (xx.x) 
Screen failure 
x (xx.x) 
Study terminated by Sponsor 
x (xx.x) 
Technical problems 
x (xx.x) 
Subject/guardian decision 
x (xx.x) 
Death 
x (xx.x) 
 
 
Note: Percentage is out of total number screened 


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Table 14.1-3 
Protocol deviations, by treatment 
Full Analysis Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Total  
(N=X) 
 
 
 
 
Subjects with at least one protocol deviation 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Number of deviations 
x 
x 
x 
 
 
 
 
Category 1 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Category 2 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Category 3 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Category 4 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Category n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
Note: Patients with multiple occurrences of a protocol deviation category are counted only once in the protocol deviation category. 
Note: Patients may have protocol deviations in more than one protocol deviation category. 


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Table 14.1-4 
Protocol deviations leading to exclusion from analysis sets 
Full Analysis Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Total  
(N=X) 
 
 
 
 
Excluded from Full Analysis Set (FAS) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
Total 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Category 1 
x (xx.x) 
x (xx.x) 
x (xx.x) 
PD term 1 
 
 
 
PD term 2 
 
 
 
…. 
 
 
 
Category 2 
x (xx.x) 
x (xx.x) 
x (xx.x) 
PD term 1 
 
 
 
PD term 2 
 
 
 
…. 
 
 
 
Category 3 
x (xx.x) 
x (xx.x) 
x (xx.x) 
PD term 1 
 
 
 
PD term 2 
 
 
 
…. 
 
 
 
Category 4 
x (xx.x) 
x (xx.x) 
x (xx.x) 
PD term 1 
 
 
 
PD term 2 
 
 
 
…. 
 
 
 
Category n 
 
 
 
…. 
 
 
 
 
 
 
 
Excluded from …… Set 
 
 
 
…. 
 
 
 
 
 
 
 
Note: Patients with multiple occurrences of a protocol deviation category are counted only once for that specific protocol deviation criterion. 
Note: Patients may have multiple protocol deviations. 


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Table 14.1-5 
Out of Window visits 
Full Analysis Set 
 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Total  
(N=X) 
 
 
 
 
 
Number of days 
earlier than planned 
1 - 7 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
8 – 14 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
15 - 28 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
29 - 42 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
>42 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Number of days later 
than planned 
1 - 7 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
8 – 14 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
15 - 28 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
29 - 42 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
>42 days 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
 
 


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Table 14.1-6 
Under and Over Treatment due to treatment interval error 
Full Analysis Set 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Total  
(N=X) 
 
 
 
 
 
Under-Treated at least once 
n(%) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Number of Times Under-Treated 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Over-Treated at least once 
n(%) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Number of Times Over-Treated 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
X 
 
 
 
 
 
SD: Standard Deviation 
 
 
 


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Table 14.1-7 
Analysis sets, by treatment 
All Enrolled 
 
Analysis Set 
Intensive  
(N=X) 
n (%) 
 Relaxed  
(N=X) 
n (%) 
 Total  
(N=X) 
n (%) 
 
 
 
 
Randomized Set 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Full Analysis Set 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Safety Set  
x (xx.x) 
x (xx.x) 
x (xx.x) 
Per-Protocol Set* 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
Note: Percentages are based on the number of patients in the Randomized set. 
* Includes all patients who contributed at least one data point to per-protocol analyses. Individual data points or visits may have been excluded from per-
protocol analyses based on protocol deviation assessments. 
 
Randomized Set: The Randomised Population will consist of all randomised patients. 
Full Analysis Set (FAS): The Full Analysis Set (FAS) compromises all subjects randomised and whom have at least one post-baseline efficacy value for the primary 
endpoint. 
Safety Set: The Safety Set will consist of all patients who received at least one application of study treatment and had at least one post-baseline safety assessment. The 
statement that a patient had no adverse events also constitutes a safety assessment.  
Per-Protocol Set: The Per-Protocol Set (PPS) will consist of all patients in the FAS who followed the treatment regimen as randomised and completed the study without 
clinically significant protocol deviations.  Clinically significant protocol deviations will be identified and documented prior to the database lock.  Refer to “Protocol 
Deviations” study document for further details. 
 
 
 
 
 
 
 
 
Note to Programmer: Table needs to include all analysis sets used in the output. This includes any 
derived analysis sets used for sensitivity analyses 


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Table 14.1-8 
Randomisation by Site 
All Enrolled 
 
Site 
Intensive  
(N=X) 
n (%) 
 Relaxed  
(N=X) 
n (%) 
P Value 
 Total  
(N=X) 
n (%) 
 
 
 
 
 
 
 
 
x.xxxx 
 
Site A 
x (xx.x) 
x (xx.x) 
 
x (xx.x) 
Site B 
x (xx.x) 
x (xx.x) 
 
x (xx.x) 
Site C  
x (xx.x) 
x (xx.x) 
 
x (xx.x) 
Site D 
x (xx.x) 
x (xx.x) 
 
x (xx.x) 
 
 
 
 
 
 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.1-9 
Demographics, by treatment 
Randomised Set 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Study Eye 
 
 
Left 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Right 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Age (years)* 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Gender n(%) 
 
 
 
Female 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Male 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Predominate Race n(%) 
 
 
 
Caucasian: Afghan, Caucasian, 
Egypt, Egyptian, El Salvadore, Greek, 
Hispanic, Israeli, Italian, Maltese, 
Middle East, Middle Eastern, South 
American, Turkish, Yugoslavian 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Black African 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Asian: Asian and Indian 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Aboriginal and Torres Strait Islander 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Pacific Islander 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Sure 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Ethnicity n(%) 
 
 
 
Anglo Saxon 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Northern European 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Southern European 
x (xx.x) 
x (xx.x) 
x (xx.x) 


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Asian Indian 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Sure 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Do you have a family history of AMD? 
 
 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Is there any history of arterial thromboembolic events? 
 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Has the participant ever smoked cigarettes, pipes or cigars? 
 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
*Age calculated at date of informed consent 
SD: Standard Deviation 
 
 


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Table 14.1-10 
Baseline characteristics by Treatment Group 
Randomised Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
Age (years)* 
     - 
 
 
x.xxxx 
 
     n 
xxx 
xxx 
 
xxx 
     Mean 
xx.x 
xx.x 
 
xx.x 
     Median 
xx.x 
xx.x 
 
xx.x 
     SD 
x.x 
x.x 
 
x.x 
     Minimum 
xx 
xx 
 
xx 
     Maximum 
xx 
xx 
 
xx 
Gender 
     - 
 
 
x.xxxx 
 
     Female 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
     Male 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Race 
     - 
 
 
0.5840 
 
     AFGHAN 
1 (0.4%) 
 
 
xxx (xx.x%) 
     ……………… 
1 (0.4%) 
 
 
xxx (xx.x%) 
 
Race (Grouped) 
     - 
 
 
x.xxxx 
 
Caucasian: Afghan, Caucasian, 
Egypt, Egyptian, El Salvadore, 
Greek, Hispanic, Israeli, Italian, 
Maltese, Middle East, Middle 
Eastern, South American, Turkish, 
Yugoslavian 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Black African 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Asian: Asian and Indian 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Aboriginal and Torres Strait 
Islander 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Pacific Islander 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Not Sure 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
Ethnicity 
     - 
  
 
x.xxxx 
  
     ABORIGINAL 
xxx (xx.x%) 
 
 
xxx (xx.x%) 
     ……………… 
 
 
     WELSH 
xxx (xx.x%) 
 
 
xxx (xx.x%) 
 
 
Family history of AMD 
     - 
  
 
x.xxxx 
  
     No 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
     Yes 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
 
 
 
History of arterial thromboembolic events 
     - 
  
 
0.2342 
  
     No 
216 (85.7%) 
86 (90.5%) 
 
302 (87.0%) 
     Yes 
36 (14.3%) 
9 (9.5%) 
 
45 (13.0%) 
Smoking History 
 
 
     - 
  
 
0.2612 
  
     Current smoker 
24 (9.5%) 
8 (8.4%) 
 
32 (9.2%) 
     Never smoked 
108 (42.9%) 
50 (52.6%) 
 
158 (45.5%) 
     Smoked in the past 
120 (47.6%) 
37 (38.9%) 
 
157 (45.2%) 
Smoking History (Grouped) 
 
 
     - 
  
 
0.7516 
  
     Current smoker 
24 (9.5%) 
8 (8.4%) 
 
32 (9.2%) 
     Non-Smoker 
228 (90.5%) 
87 (91.6%) 
 
315 (90.8%) 
Previous exposure of non-study eye 
 
 
     - 
  
 
0.0246 
  
     No 
183 (72.6%) 
80 (84.2%) 
 
263 (75.8%) 
     Yes 
69 (27.4%) 
15 (15.8%) 
 
84 (24.2%) 
Previous exposure - treatment 
 
 
     - 
  
 
0.3904 
  
     Avastin 
10 (14.5%) 
3 (20.0%) 
 
13 (15.5%) 
     Eylea 
15 (21.7%) 
5 (33.3%) 
 
20 (23.8%) 
     Lucentis 
50 (72.5%) 
7 (46.7%) 
 
57 (67.9%) 
     Visudyne 
7 (10.1%) 
 
 
7 (8.3%) 
     Other 
2 (2.9%) 
 
 
2 (2.4%) 


Novartis 
Confidential 
Page 51 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
Study Eye 
 
 
     - 
  
 
0.0149 
  
     Left eye 
109 (43.3%) 
55 (57.9%) 
 
164 (47.3%) 
     Right eye 
143 (56.7%) 
40 (42.1%) 
 
183 (52.7%) 
Best Corrective Visual Acuity 
 
 
     - 
  
 
0.2503 
  
     n 
252 
95 
 
347 
     Mean 
63.8 
61.8 
 
63.2 
     Median 
67.0 
63.0 
 
66.0 
     SD 
13.7 
14.7 
 
14.0 
     Minimum 
23 
23 
 
23 
     Maximum 
90 
85 
 
90 
BCVA (Categorical) 
     - 
  
 
0.1910 
  
     <70 
145 (57.5%) 
62 (65.3%) 
  
207 (59.7%) 
     >=70 
107 (42.5%) 
33 (34.7%) 
  
140 (40.3%) 
Central Subfield Foveal Thickness 
 
 
     - 
  
 
0.4227 
  
     n 
252 
95 
  
347 
     Mean 
445.0 
461.6 
  
449.5 
     Median 
405.0 
409.0 
  
406.0 
     SD 
175.6 
162.6 
 
172.1 
     Minimum 
169 
256 
  
169 
     Maximum 
1309 
1123 
 
1309 
Central Subfield Foveal Volume 
 
 
 
     - 
  
 
0.3304 
  
     n 
252 
95 
  
347 
     Mean 
0.4 
0.4 
 
0.4 
     Median 
0.3 
0.3 
 
0.3 
     SD 
0.2 
0.3 
 
0.2 
     Minimum 
0 
0 
  
0 
     Maximum 
3 
3 
 
3 
Intraretinal Fluid 
 
 
 
     - 
  
  
0.7260 
  
     Absent 
159 (63.1%) 
58 (61.1%) 
 
217 (62.5%) 
     Present 
93 (36.9%) 
37 (38.9%) 
 
130 (37.5%) 


Novartis 
Confidential 
Page 52 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
Intraretinal Fluid - Center Involvement 
 
 
     - 
  
 
0.6946 
  
     Absent 
8 (3.2%) 
4 (4.2%) 
 
12 (3.5%) 
     Present 
85 (33.7%) 
33 (34.7%) 
 
118 (34.0%) 
Intraretinal Cysts 
     - 
  
 
0.8995 
  
     Absent 
108 (42.9%) 
40 (42.1%) 
  
148 (42.7%) 
     Definite 
144 (57.1%) 
55 (57.9%) 
  
199 (57.3%) 
Intraretinal Cysts - Center Involvement 
 
 
     - 
  
 
0.3667 
  
     Absent 
8 (3.2%) 
5 (5.3%) 
  
13 (3.7%) 
     Definite 
136 (54.0%) 
50 (52.6%) 
  
186 (53.6%) 
Any Subretinal Fluid 
 
 
 
 
     - 
  
 
0.0341 
  
     Absent 
51 (20.2%) 
10 (10.5%) 
 
61 (17.6%) 
     Present 
201 (79.8%) 
85 (89.5%) 
 
286 (82.4%) 
Any Subretinal Fluid - Center Involvement 
 
 
 
 
     - 
  
 
0.1079 
  
     Absent 
18 (7.1%) 
3 (3.2%) 
 
21 (6.1%) 
     Present 
183 (72.6%) 
82 (86.3%) 
 
265 (76.4%) 
Morphological Changes 
 
 
 
 
     - 
  
 
0.3693 
  
     Absent 
176 (69.8%) 
71 (74.7%) 
  
247 (71.2%) 
     Definite 
76 (30.2%) 
24 (25.3%) 
 
100 (28.8%) 
Morphological Change - Epiretinal Membrane 
     - 
  
  
0.4748 
  
     No 
48 (19.0%) 
13 (13.7%) 
 
61 (17.6%) 
     Yes 
29 (11.5%) 
11 (11.6%) 
 
40 (11.5%) 
 
 


Novartis 
Confidential 
Page 53 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
No Intraretinal Fluid or Cysts (derived) 
 
 
     - 
  
 
0.7266 
  
     IRF or IR Cyst or both (IRF and Cyst) 
154 (61.1%) 
60 (63.2%) 
 
214 (61.7%) 
     No IRF nor IR Cyst 
98 (38.9%) 
35 (36.8%) 
 
133 (38.3%) 
 
 
 
Morphological Change - Vitreo-Retinal Traction 
 
     - 
  
  
0.7219 
  
     No 
38 (15.1%) 
13 (13.7%) 
 
51 (14.7%) 
     Yes 
38 (15.1%) 
11 (11.6%) 
 
49 (14.1%) 
Morphological Change - Macular Hole 
 
 
 
     - 
  
  
- 
  
     No 
76 (30.2%) 
24 (25.3%) 
 
100 (28.8%) 
 
 
 
Morphological Change - Atrophy 
 
 
 
     - 
  
  
0.0990 
  
     No 
36 (14.3%) 
16 (16.8%) 
 
52 (15.0%) 
     Yes 
40 (15.9%) 
8 (8.4%) 
 
48 (13.8%) 
Morphological Change - Other 
 
 
 
     - 
  
  
0.5722 
  
     No 
75 (29.8%) 
24 (25.3%) 
 
99 (28.5%) 
     Yes 
1 (0.4%) 
  
 
1 (0.3%) 
Subfoveal Fluid Center Point 
 
 
 
     - 
  
  
0.7931 
  
     Absent 
27 (10.7%) 
7 (7.4%) 
 
34 (9.8%) 
     Not Applicable 
10 (4.0%) 
2 (2.1%) 
 
12 (3.5%) 
     Present 
17 (6.7%) 
6 (6.3%) 
 
23 (6.6%) 
Subfoveal Fluid - Height at Center Point 
 
 
 
     - 
  
  
0.2698 
  
     <=200um 
14 (5.6%) 
6 (6.3%) 
 
20 (5.8%) 
     >200um 
3 (1.2%) 
 
 
3 (0.9%) 
Evidence of CNV Complex 
 
 
     - 
  
 
0.0460 
  
     Absent 
9 (3.6%) 
 
 
9 (2.6%) 
     Can't Grade 
1 (0.4%) 
 
 
1 (0.3%) 
     Definite 
232 (92.1%) 
95 (100.0%) 
 
327 (94.2%) 
     Questionable 
10 (4.0%) 
 
 
10 (2.9%) 


Novartis 
Confidential 
Page 54 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
Location of CNV Complex, by centre involvement* (derived) 
 
     - 
  
 
- 
  
CNV Leakage 
 
 
 
     - 
  
 
0.1795 
  
     Absent 
2 (0.8%) 
 
 
2 (0.6%) 
     Can't Grade 
1 (0.4%) 
1 (1.1%) 
 
2 (0.6%) 
     Definite 
230 (91.3%) 
94 (98.9%) 
 
324 (93.4%) 
     Questionable 
9 (3.6%) 
 
 
9 (2.6%) 
Area of CNV 
 
 
 
     - 
  
 
0.1179 
  
     n 
228 
92 
 
320 
     Mean 
5.589 
4.688 
 
5.330 
     Median 
4.045 
3.500 
 
3.715 
     SD 
4.899 
3.954 
 
4.659 
     Minimum 
0.30 
0.43 
 
0.30 
     Maximum 
30.09 
22.72 
 
30.09 
CNV Location 
 
 
 
     - 
  
 
0.2412 
  
     Can't Grade 
3 (1.2%) 
1 (1.1%) 
 
4 (1.2%) 
     Extrafoveal 
16 (6.3%) 
3 (3.2%) 
 
19 (5.5%) 
     Juxtafoveal 
23 (9.1%) 
9 (9.5%) 
 
32 (9.2%) 
     No CNV complex 
10 (4.0%) 
 
 
10 (2.9%) 
     Subfoveal 
200 (79.4%) 
82 (86.3%) 
 
282 (81.3%) 
CNV Location, by centre involvement* (derived) 
 
 
     - 
  
 
0.3611 
 
     Can't Grade 
3 (1.2%) 
1 (1.1%) 
 
4 (1.2%) 
     Extrafoveal 
x (x.x%) 
x (x.x%) 
 
x (x.x%) 
     Extrafoveal with centre involvement 
16 (6.3%) 
3 (3.2%) 
 
19 (5.5%) 
     Juxtafoveal 
2 (0.8%) 
2 (2.1%) 
 
4 (1.2%) 
     Juxtafoveal with centre involvement 
21 (8.3%) 
7 (7.4%) 
 
28 (8.1%) 
     No CNV complex 
2 (0.8%) 
 
 
2 (0.6%) 
     Subfoveal 
200 (79.4%) 
82 (86.3%) 
 
282 (81.3%) 


Novartis 
Confidential 
Page 55 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
Type of CNV 
 
 
 
 
     - 
  
 
0.5981 
 
     Can't Grade 
7 (2.8%) 
1 (1.1%) 
 
8 (2.3%) 
     Occult (fibrovascular PED) 
178 (70.6%) 
72 (75.8%) 
 
250 (72.0%) 
     Occult (late leakage) 
4 (1.6%) 
 
 
4 (1.2%) 
     Occult with serious PED 
10 (4.0%) 
6 (6.3%) 
 
16 (4.6%) 
     Other 
5 (2.0%) 
1 (1.1%) 
 
6 (1.7%) 
     Predominant classic 
38 (15.1%) 
15 (15.8%) 
 
53 (15.3%) 
Type of CNV (Grouping 1) 
 
 
 
 
     - 
  
 
0.6981 
 
     Can't Grade 
7 (2.8%) 
1 (1.1%) 
 
8 (2.3%) 
     Occult 
192 (76.2%) 
78 (82.1%) 
 
270 (77.8%) 
     Other 
5 (2.0%) 
1 (1.1%) 
 
6 (1.7%) 
     Predominant classic 
38 (15.1%) 
15 (15.8%) 
 
53 (15.3%) 
Type of CNV (Grouping 2) 
 
 
 
 
     - 
  
 
0.6069 
 
     Can't Grade 
7 (2.8%) 
1 (1.1%) 
 
8 (2.3%) 
     Other 
197 (78.2%) 
79 (83.2%) 
 
276 (79.5%) 
     Predominant classic 
38 (15.1%) 
15 (15.8%) 
 
53 (15.3%) 
Type of CNV (Grouping 3) 
 
 
 
 
     - 
  
 
0.5005 
 
     Can't Grade 
7 (2.8%) 
1 (1.1%) 
 
8 (2.3%) 
     Non-PED 
47 (18.7%) 
16 (16.8%) 
 
63 (18.2%) 
     PED 
188 (74.6%) 
78 (82.1%) 
 
266 (76.7%) 
CNV Center Involvement 
 
 
 
 
     - 
  
  
0.1731 
  
     Absent 
6 (2.4%) 
  
  
6 (1.7%) 
     Definite 
231 (91.7%) 
91 (95.8%) 
  
322 (92.8%) 
     Questionable 
3 (1.2%) 
  
  
3 (0.9%) 
Lesion Components - CNV 
 
 
 
 
     - 
  
  
- 
  
     CNV 
239 (94.8%) 
95 (100.0%) 
  
334 (96.3%) 
Lesion Components - Blood 
 
 
 
 
     - 
  
  
0.8264 
  
     Blood 
95 (37.7%) 
39 (41.1%) 
  
134 (38.6%) 
     No 
144 (57.1%) 
56 (58.9%) 
  
200 (57.6%) 


Novartis 
Confidential 
Page 56 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
Lesion Components - Serious PED 
 
 
 
 
     - 
  
  
0.6364 
  
     No 
227 (90.1%) 
89 (93.7%) 
  
316 (91.1%) 
     Serious PED 
12 (4.8%) 
6 (6.3%) 
  
18 (5.2%) 
Lesion Components - RPE rip/tear 
 
 
 
 
     - 
  
  
- 
  
     No 
239 (94.8%) 
95 (100.0%) 
  
334 (96.3%) 
Lesion Components - Can't Grade 
 
 
 
 
     - 
  
  
0.0240 
  
     Can't Grade 
13 (5.2%) 
  
  
13 (3.7%) 
     No 
239 (94.8%) 
95 (100.0%) 
  
334 (96.3%) 
Lesion Components - Others 
 
 
 
 
     - 
  
  
0.7288 
  
     No 
178 (70.6%) 
69 (72.6%) 
  
247 (71.2%) 
     Others 
61 (24.2%) 
26 (27.4%) 
  
87 (25.1%) 
Area of Lesion 
 
 
 
 
     - 
  
  
0.3695 
  
     n 
232 
94 
  
326 
     Mean 
6.332 
5.724 
  
6.157 
     Median 
4.400 
4.000 
  
4.335 
     SD 
5.642 
5.259 
  
5.533 
     Minimum 
0.30 
0.43 
  
0.30 
     Maximum 
35.06 
25.15 
  
35.06 
Geographic Atrophy  
 
 
 
 
     - 
  
  
0.0064 
  
     Absent 
203 (80.6%) 
88 (92.6%) 
  
291 (83.9%) 
     Definite 
49 (19.4%) 
7 (7.4%) 
  
56 (16.1%) 
Location of Geographic Atrophy - Central Subfield 
 
 
 
     - 
  
  
0.9125 
  
     No 
34 (13.5%) 
5 (5.3%) 
  
39 (11.2%) 
     Yes 
15 (6.0%) 
2 (2.1%) 
  
17 (4.9%) 
Location of Geographic Atrophy - Inner Subfield 
 
 
 
     - 
  
  
0.2850 
  
     No 
7 (2.8%) 
  
  
7 (2.0%) 
     Yes 
42 (16.7%) 
7 (7.4%) 
  
49 (14.1%) 


Novartis 
Confidential 
Page 57 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
Location of Geographic Atrophy - Other Subfield 
 
 
 
     - 
  
  
0.2795 
  
     No 
17 (6.7%) 
1 (1.1%) 
  
18 (5.2%) 
     Yes 
32 (12.7%) 
6 (6.3%) 
  
38 (11.0%) 
Location of Geographic Atrophy - Can't Grade 
 
 
 
     - 
  
  
- 
  
     No 
49 (19.4%) 
7 (7.4%) 
  
56 (16.1%) 
Geographic Atrophy - Area 
 
 
 
 
     - 
  
  
0.7834 
  
     n 
46 
7 
  
53 
     Mean 
3.207 
2.617 
  
3.129 
     Median 
1.470 
0.850 
  
1.440 
     SD 
5.397 
4.123 
  
5.216 
     Minimum 
0.06 
0.33 
  
0.06 
     Maximum 
30.69 
11.69 
  
30.69 
Retinal Abnormalities 
 
 
 
 
     - 
  
  
0.4664 
  
     Absent 
3 (1.2%) 
  
  
3 (0.9%) 
     Definite 
248 (98.4%) 
95 (100.0%) 
  
343 (98.8%) 
     Not Applicable 
1 (0.4%) 
  
  
1 (0.3%) 
Retinal Abnormalities - Drusen 
 
 
 
 
     - 
  
  
0.9035 
  
     No 
3 (1.2%) 
1 (1.1%) 
  
4 (1.2%) 
     Yes 
245 (97.2%) 
94 (98.9%) 
  
339 (97.7%) 
Retinal Abnormalities - Atrophy 
 
 
 
 
     - 
  
  
0.0076 
  
     No 
208 (82.5%) 
90 (94.7%) 
  
298 (85.9%) 
     Yes 
40 (15.9%) 
5 (5.3%) 
  
45 (13.0%) 
Retinal Abnormalities - Fibrosis 
 
 
 
 
     - 
  
  
0.9937 
  
     No 
235 (93.3%) 
90 (94.7%) 
  
325 (93.7%) 
     Yes 
13 (5.2%) 
5 (5.3%) 
  
18 (5.2%) 
Retinal Abnormalities - Hemorrhage (old format CF data) 
 
 
 
     - 
  
  
0.9897 
  
     No 
146 (57.9%) 
56 (58.9%) 
  
202 (58.2%) 
     Yes 
102 (40.5%) 
39 (41.1%) 
  
141 (40.6%) 


Novartis 
Confidential 
Page 58 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
Retinal Abnormalities - PED 
 
 
 
 
     - 
  
  
0.6179 
  
     No 
238 (94.4%) 
90 (94.7%) 
  
328 (94.5%) 
     Yes 
10 (4.0%) 
5 (5.3%) 
  
15 (4.3%) 
Retinal Abnormalities - Other 
 
 
 
 
     - 
  
  
0.5250 
  
     No 
158 (62.7%) 
57 (60.0%) 
  
215 (62.0%) 
     Yes 
90 (35.7%) 
38 (40.0%) 
  
128 (36.9%) 
Retinal Abnormalities Location Central 
 
 
 
 
     - 
  
  
0.2937 
  
     No 
2 (0.8%) 
3 (3.2%) 
  
5 (1.4%) 
     Yes 
3 (1.2%) 
1 (1.1%) 
  
1 (0.3%) 
Retinal Abnormalities Location Peripheral 
 
 
 
 
     - 
  
  
0.2937 
  
     No 
2 (0.8%) 
3 (3.2%) 
  
5 (1.4%) 
     Yes 
3 (1.2%) 
1 (1.1%) 
  
1 (0.3%) 
Hemorrhage (new format CF data) 
 
 
 
 
     - 
  
  
0.7765 
  
     Absent 
148 (58.7%) 
54 (56.8%) 
  
202 (58.2%) 
     Definite 
103 (40.9%) 
41 (43.2%) 
  
144 (41.5%) 
     Not Applicable 
1 (0.4%) 
  
  
1 (0.3%) 
Hemorrhage Location Central Subfield 
 
 
 
 
     - 
  
  
0.0730 
  
     No 
5 (2.0%) 
2 (2.1%) 
  
4 (1.2%) 
     Yes 
  
2 (2.1%) 
  
2 (0.6%) 
Hemorrhage Location Inner Subfield 
 
 
 
 
     - 
  
  
0.2937 
  
     No 
2 (0.8%) 
3 (3.2%) 
  
4 (1.2%) 
     Yes 
3 (1.2%) 
1 (1.1%) 
  
2 (0.6%) 
Hemorrhage Location Outer Subfield 
 
 
 
 
     - 
  
  
0.6353 
  
     No 
3 (1.2%) 
3 (3.2%) 
  
5 (1.4%) 
     Yes 
 
2 (0.8%) 
1 (1.1%) 
  
1 (0.3%) 


Novartis 
Confidential 
Page 59 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
CNV Location (CRF DATA) 
 
 
 
 
     - 
  
  
0.2168 
  
     Juxtafoveal 
4 (1.6%) 
  
  
4 (1.2%) 
     Subfoveal 
248 (98.4%) 
95 (100.0%) 
  
343 (98.8%) 
     Extrafoveal 
xx (x.x%) 
xx (x.x%) 
 
xx (x.x%) 
IRF (CRF DATA) 
 
 
 
 
     - 
  
  
0.4505 
  
     Absent 
60 (23.8%) 
19 (20.0%) 
  
79 (22.8%) 
     Present 
192 (76.2%) 
76 (80.0%) 
  
268 (77.2%) 
     Can’t Grade 
xx (x.x%) 
xx (x.x%) 
 
xx (x.x%) 
SRF (CRF DATA) 
 
 
 
 
     - 
  
  
0.0258 
  
     Absent 
62 (24.6%) 
13 (13.7%) 
  
75 (21.6%) 
     Can't grade 
  
1 (1.1%) 
  
1 (0.3%) 
     Present 
190 (75.4%) 
81 (85.3%) 
  
271 (78.1%) 
 
 
*: Centre involvement is concluded when 'Intraretinal Fluid - Center Involvement'='Present', 'Intraretinal Cysts - Center 
Involvement'='Definite' or 'Any Subretinal Fluid - Center Involvement'='Present'. 
 
 
 


Novartis 
Confidential 
Page 60 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.1-11 
Baseline characteristics by genotyping status 
Randomised Set 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
Age (years)* 
     - 
 
 
x.xxxx 
 
     n 
xxx 
xxx 
 
xxx 
     Mean 
xx.x 
xx.x 
 
xx.x 
     Median 
xx.x 
xx.x 
 
xx.x 
     SD 
x.x 
x.x 
 
x.x 
     Minimum 
xx 
xx 
 
xx 
     Maximum 
xx 
xx 
 
xx 
Gender 
     - 
 
 
x.xxxx 
 
     Female 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
     Male 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Race 
     - 
 
 
0.5840 
 
     AFGHAN 
1 (0.4%) 
 
 
xxx (xx.x%) 
     ……………… 
1 (0.4%) 
 
 
xxx (xx.x%) 
 
Race (Grouped) 
     - 
 
 
x.xxxx 
 
Caucasian: Afghan, Caucasian, Egypt, 
Egyptian, El Salvadore, Greek, Hispanic, 
Israeli, Italian, Maltese, Middle East, 
Middle Eastern, South American, Turkish, 
Yugoslavian 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Black African 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Asian: Asian and Indian 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Aboriginal and Torres Strait Islander 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Pacific Islander 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Not Sure 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
Ethnicity 
     - 
  
 
x.xxxx 
  
     ABORIGINAL 
xxx (xx.x%) 
 
 
xxx (xx.x%) 
     ……………… 
 
 
     WELSH 
xxx (xx.x%) 
 
 
xxx (xx.x%) 


Novartis 
Confidential 
Page 61 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
 
 
Family history of AMD 
     - 
  
 
x.xxxx 
  
     No 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
     Yes 
xxx (xx.x%) 
xxx (xx.x%) 
 
xxx (xx.x%) 
History of arterial thromboembolic events 
     - 
  
 
0.2342 
  
     No 
216 (85.7%) 
86 (90.5%) 
 
302 (87.0%) 
     Yes 
36 (14.3%) 
9 (9.5%) 
 
45 (13.0%) 
Smoking History 
 
 
     - 
  
 
0.2612 
  
     Current smoker 
24 (9.5%) 
8 (8.4%) 
 
32 (9.2%) 
     Never smoked 
108 (42.9%) 
50 (52.6%) 
 
158 (45.5%) 
     Smoked in the past 
120 (47.6%) 
37 (38.9%) 
 
157 (45.2%) 
Smoking History (Grouped) 
 
 
     - 
  
 
0.7516 
  
     Current smoker 
24 (9.5%) 
8 (8.4%) 
 
32 (9.2%) 
     Non-Smoker 
228 (90.5%) 
87 (91.6%) 
 
315 (90.8%) 
Previous exposure of non-study eye 
 
 
     - 
  
 
0.0246 
  
     No 
183 (72.6%) 
80 (84.2%) 
 
263 (75.8%) 
     Yes 
69 (27.4%) 
15 (15.8%) 
 
84 (24.2%) 
Previous exposure - treatment 
 
 
     - 
  
 
0.3904 
  
     Avastin 
10 (14.5%) 
3 (20.0%) 
 
13 (15.5%) 
     Eylea 
15 (21.7%) 
5 (33.3%) 
 
20 (23.8%) 
     Lucentis 
50 (72.5%) 
7 (46.7%) 
 
57 (67.9%) 
     Visudyne 
7 (10.1%) 
 
 
7 (8.3%) 
     Other 
2 (2.9%) 
 
 
2 (2.4%) 
Study Eye 
 
 
     - 
  
 
0.0149 
  
     Left eye 
109 (43.3%) 
55 (57.9%) 
 
164 (47.3%) 
     Right eye 
143 (56.7%) 
40 (42.1%) 
 
183 (52.7%) 


Novartis 
Confidential 
Page 62 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
Best Corrective Visual Acuity 
 
 
     - 
  
 
0.2503 
  
     n 
252 
95 
 
347 
     Mean 
63.8 
61.8 
 
63.2 
     Median 
67.0 
63.0 
 
66.0 
     SD 
13.7 
14.7 
 
14.0 
     Minimum 
23 
23 
 
23 
     Maximum 
90 
85 
 
90 
BCVA (Categorical) 
     - 
  
 
0.1910 
  
     <70 
145 (57.5%) 
62 (65.3%) 
  
207 (59.7%) 
     >=70 
107 (42.5%) 
33 (34.7%) 
  
140 (40.3%) 
Central Subfield Foveal Thickness 
 
 
     - 
  
 
0.4227 
  
     n 
252 
95 
  
347 
     Mean 
445.0 
461.6 
  
449.5 
     Median 
405.0 
409.0 
  
406.0 
     SD 
175.6 
162.6 
 
172.1 
     Minimum 
169 
256 
  
169 
     Maximum 
1309 
1123 
 
1309 
Central Subfield Foveal Volume 
 
 
 
     - 
  
 
0.3304 
  
     n 
252 
95 
  
347 
     Mean 
0.4 
0.4 
 
0.4 
     Median 
0.3 
0.3 
 
0.3 
     SD 
0.2 
0.3 
 
0.2 
     Minimum 
0 
0 
  
0 
     Maximum 
3 
3 
 
3 
Intraretinal Fluid 
 
 
 
     - 
  
  
0.7260 
  
     Absent 
159 (63.1%) 
58 (61.1%) 
 
217 (62.5%) 
     Present 
93 (36.9%) 
37 (38.9%) 
 
130 (37.5%) 
Intraretinal Fluid - Center Involvement 
 
 
     - 
  
 
0.6946 
  
     Absent 
8 (3.2%) 
4 (4.2%) 
 
12 (3.5%) 
     Present 
85 (33.7%) 
33 (34.7%) 
 
118 (34.0%) 


Novartis 
Confidential 
Page 63 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
Intraretinal Cysts 
     - 
  
 
0.8995 
  
     Absent 
108 (42.9%) 
40 (42.1%) 
  
148 (42.7%) 
     Definite 
144 (57.1%) 
55 (57.9%) 
  
199 (57.3%) 
Intraretinal Cysts - Center Involvement 
 
 
     - 
  
 
0.3667 
  
     Absent 
8 (3.2%) 
5 (5.3%) 
  
13 (3.7%) 
     Definite 
136 (54.0%) 
50 (52.6%) 
  
186 (53.6%) 
Any Subretinal Fluid 
 
 
 
 
     - 
  
 
0.0341 
  
     Absent 
51 (20.2%) 
10 (10.5%) 
 
61 (17.6%) 
     Present 
201 (79.8%) 
85 (89.5%) 
 
286 (82.4%) 
Any Subretinal Fluid - Center Involvement 
 
 
 
 
     - 
  
 
0.1079 
  
     Absent 
18 (7.1%) 
3 (3.2%) 
 
21 (6.1%) 
     Present 
183 (72.6%) 
82 (86.3%) 
 
265 (76.4%) 
Morphological Changes 
 
 
 
 
     - 
  
 
0.3693 
  
     Absent 
176 (69.8%) 
71 (74.7%) 
  
247 (71.2%) 
     Definite 
76 (30.2%) 
24 (25.3%) 
 
100 (28.8%) 
Morphological Change - Epiretinal Membrane 
     - 
  
  
0.4748 
  
     No 
48 (19.0%) 
13 (13.7%) 
 
61 (17.6%) 
     Yes 
29 (11.5%) 
11 (11.6%) 
 
40 (11.5%) 
No Intraretinal Fluid or Cysts (derived) 
 
 
     - 
  
 
0.7266 
  
     IRF or IR Cyst or both (IRF and Cyst) 
154 (61.1%) 
60 (63.2%) 
 
214 (61.7%) 
     No IRF nor IR Cyst 
98 (38.9%) 
35 (36.8%) 
 
133 (38.3%) 
 
 
 


Novartis 
Confidential 
Page 64 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
Morphological Change - Vitreo-Retinal Traction 
 
     - 
  
  
0.7219 
  
     No 
38 (15.1%) 
13 (13.7%) 
 
51 (14.7%) 
     Yes 
38 (15.1%) 
11 (11.6%) 
 
49 (14.1%) 
Morphological Change - Macular Hole 
 
 
 
     - 
  
  
- 
  
     No 
76 (30.2%) 
24 (25.3%) 
 
100 (28.8%) 
Morphological Change - Atrophy 
 
 
 
     - 
  
  
0.0990 
  
     No 
36 (14.3%) 
16 (16.8%) 
 
52 (15.0%) 
     Yes 
40 (15.9%) 
8 (8.4%) 
 
48 (13.8%) 
Morphological Change - Other 
 
 
 
     - 
  
  
0.5722 
  
     No 
75 (29.8%) 
24 (25.3%) 
 
99 (28.5%) 
     Yes 
1 (0.4%) 
  
 
1 (0.3%) 
Subfoveal Fluid Center Point 
 
 
 
     - 
  
  
0.7931 
  
     Absent 
27 (10.7%) 
7 (7.4%) 
 
34 (9.8%) 
     Not Applicable 
10 (4.0%) 
2 (2.1%) 
 
12 (3.5%) 
     Present 
17 (6.7%) 
6 (6.3%) 
 
23 (6.6%) 
Subfoveal Fluid - Height at Center Point 
 
 
 
     - 
  
  
0.2698 
  
     <=200um 
14 (5.6%) 
6 (6.3%) 
 
20 (5.8%) 
     >200um 
3 (1.2%) 
 
 
3 (0.9%) 
Evidence of CNV Complex 
 
 
     - 
  
 
0.0460 
  
     Absent 
9 (3.6%) 
 
 
9 (2.6%) 
     Can't Grade 
1 (0.4%) 
 
 
1 (0.3%) 
     Definite 
232 (92.1%) 
95 (100.0%) 
 
327 (94.2%) 
     Questionable 
10 (4.0%) 
 
 
10 (2.9%) 
Location of CNV Complex, by centre involvement* (derived) 
 
     - 
  
 
- 
  


Novartis 
Confidential 
Page 65 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
CNV Leakage 
 
 
 
     - 
  
 
0.1795 
  
     Absent 
2 (0.8%) 
 
 
2 (0.6%) 
     Can't Grade 
1 (0.4%) 
1 (1.1%) 
 
2 (0.6%) 
     Definite 
230 (91.3%) 
94 (98.9%) 
 
324 (93.4%) 
     Questionable 
9 (3.6%) 
 
 
9 (2.6%) 
Area of CNV 
 
 
 
     - 
  
 
0.1179 
  
     n 
228 
92 
 
320 
     Mean 
5.589 
4.688 
 
5.330 
     Median 
4.045 
3.500 
 
3.715 
     SD 
4.899 
3.954 
 
4.659 
     Minimum 
0.30 
0.43 
 
0.30 
     Maximum 
30.09 
22.72 
 
30.09 
CNV Location 
 
 
 
     - 
  
 
0.2412 
  
     Can't Grade 
3 (1.2%) 
1 (1.1%) 
 
4 (1.2%) 
     Extrafoveal 
16 (6.3%) 
3 (3.2%) 
 
19 (5.5%) 
     Juxtafoveal 
23 (9.1%) 
9 (9.5%) 
 
32 (9.2%) 
     No CNV complex 
10 (4.0%) 
 
 
10 (2.9%) 
     Subfoveal 
200 (79.4%) 
82 (86.3%) 
 
282 (81.3%) 
CNV Location, by centre involvement* (derived) 
 
 
     - 
  
 
0.3611 
 
     Can't Grade 
3 (1.2%) 
1 (1.1%) 
 
4 (1.2%) 
     Extrafoveal 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
     Extrafoveal with centre involvement 
16 (6.3%) 
3 (3.2%) 
 
19 (5.5%) 
     Juxtafoveal 
2 (0.8%) 
2 (2.1%) 
 
4 (1.2%) 
     Juxtafoveal with centre involvement 
21 (8.3%) 
7 (7.4%) 
 
28 (8.1%) 
     No CNV complex 
2 (0.8%) 
 
 
2 (0.6%) 
     Subfoveal 
200 (79.4%) 
82 (86.3%) 
 
282 (81.3%) 
Type of CNV 
 
 
 
 
     - 
  
 
0.5981 
 
     Can't Grade 
7 (2.8%) 
1 (1.1%) 
 
8 (2.3%) 
     Occult (fibrovascular PED) 
178 (70.6%) 
72 (75.8%) 
 
250 (72.0%) 
     Occult (late leakage) 
4 (1.6%) 
 
 
4 (1.2%) 
     Occult with serious PED 
10 (4.0%) 
6 (6.3%) 
 
16 (4.6%) 
     Other 
5 (2.0%) 
1 (1.1%) 
 
6 (1.7%) 
     Predominant classic 
38 (15.1%) 
15 (15.8%) 
 
53 (15.3%) 


Novartis 
Confidential 
Page 66 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
Type of CNV (Grouping 1) 
 
 
 
 
     - 
  
 
0.6981 
 
     Can't Grade 
7 (2.8%) 
1 (1.1%) 
 
8 (2.3%) 
     Occult 
192 (76.2%) 
78 (82.1%) 
 
270 (77.8%) 
     Other 
5 (2.0%) 
1 (1.1%) 
 
6 (1.7%) 
     Predominant classic 
38 (15.1%) 
15 (15.8%) 
 
53 (15.3%) 
Type of CNV (Grouping 2) 
 
 
 
 
     - 
  
 
0.6069 
 
     Can't Grade 
7 (2.8%) 
1 (1.1%) 
 
8 (2.3%) 
     Other 
197 (78.2%) 
79 (83.2%) 
 
276 (79.5%) 
     Predominant classic 
38 (15.1%) 
15 (15.8%) 
 
53 (15.3%) 
Type of CNV (Grouping 3) 
 
 
 
 
     - 
  
 
0.5005 
 
     Can't Grade 
7 (2.8%) 
1 (1.1%) 
 
8 (2.3%) 
     Non-PED 
47 (18.7%) 
16 (16.8%) 
 
63 (18.2%) 
     PED 
188 (74.6%) 
78 (82.1%) 
 
266 (76.7%) 
CNV Center Involvement 
 
 
 
 
     - 
  
  
0.1731 
  
     Absent 
6 (2.4%) 
  
  
6 (1.7%) 
     Definite 
231 (91.7%) 
91 (95.8%) 
  
322 (92.8%) 
     Questionable 
3 (1.2%) 
  
  
3 (0.9%) 
Lesion Components - CNV 
 
 
 
 
     - 
  
  
- 
  
     CNV 
239 (94.8%) 
95 (100.0%) 
  
334 (96.3%) 
Lesion Components - Blood 
 
 
 
 
     - 
  
  
0.8264 
  
     Blood 
95 (37.7%) 
39 (41.1%) 
  
134 (38.6%) 
     No 
144 (57.1%) 
56 (58.9%) 
  
200 (57.6%) 
Lesion Components - Serious PED 
 
 
 
 
     - 
  
  
0.6364 
  
     No 
227 (90.1%) 
89 (93.7%) 
  
316 (91.1%) 
     Serious PED 
12 (4.8%) 
6 (6.3%) 
  
18 (5.2%) 
Lesion Components - RPE rip/tear 
 
 
 
 
     - 
  
  
- 
  
     No 
239 (94.8%) 
95 (100.0%) 
  
334 (96.3%) 


Novartis 
Confidential 
Page 67 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
Lesion Components - Can't Grade 
 
 
 
 
     - 
  
  
0.0240 
  
     Can't Grade 
13 (5.2%) 
  
  
13 (3.7%) 
     No 
239 (94.8%) 
95 (100.0%) 
  
334 (96.3%) 
 
 
 
 
Lesion Components - Others 
 
 
 
 
     - 
  
  
0.7288 
  
     No 
178 (70.6%) 
69 (72.6%) 
  
247 (71.2%) 
     Others 
61 (24.2%) 
26 (27.4%) 
  
87 (25.1%) 
Area of Lesion 
 
 
 
 
     - 
  
  
0.3695 
  
     n 
232 
94 
  
326 
     Mean 
6.332 
5.724 
  
6.157 
     Median 
4.400 
4.000 
  
4.335 
     SD 
5.642 
5.259 
  
5.533 
     Minimum 
0.30 
0.43 
  
0.30 
     Maximum 
35.06 
25.15 
  
35.06 
Geographic Atrophy 
 
 
 
 
     - 
  
  
0.0064 
  
     Absent 
203 (80.6%) 
88 (92.6%) 
  
291 (83.9%) 
     Definite 
49 (19.4%) 
7 (7.4%) 
  
56 (16.1%) 
Location of Geographic Atrophy - Central Subfield 
 
 
 
     - 
  
  
0.9125 
  
     No 
34 (13.5%) 
5 (5.3%) 
  
39 (11.2%) 
     Yes 
15 (6.0%) 
2 (2.1%) 
  
17 (4.9%) 
Location of Geographic Atrophy - Inner Subfield 
 
 
 
     - 
  
  
0.2850 
  
     No 
7 (2.8%) 
  
  
7 (2.0%) 
     Yes 
42 (16.7%) 
7 (7.4%) 
  
49 (14.1%) 
Location of Geographic Atrophy - Other Subfield 
 
 
 
     - 
  
  
0.2795 
  
     No 
17 (6.7%) 
1 (1.1%) 
  
18 (5.2%) 
     Yes 
32 (12.7%) 
6 (6.3%) 
  
38 (11.0%) 
Location of Geographic Atrophy - Can't Grade 
 
 
 
     - 
  
  
- 
  
     No 
49 (19.4%) 
7 (7.4%) 
  
56 (16.1%) 


Novartis 
Confidential 
Page 68 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
Geographic Atrophy - Area 
 
 
 
 
     - 
  
  
0.7834 
  
     n 
46 
7 
  
53 
     Mean 
3.207 
2.617 
  
3.129 
     Median 
1.470 
0.850 
  
1.440 
     SD 
5.397 
4.123 
  
5.216 
     Minimum 
0.06 
0.33 
  
0.06 
     Maximum 
30.69 
11.69 
  
30.69 
Retinal Abnormalities 
 
 
 
 
     - 
  
  
0.4664 
  
     Absent 
3 (1.2%) 
  
  
3 (0.9%) 
     Definite 
248 (98.4%) 
95 (100.0%) 
  
343 (98.8%) 
     Not Applicable 
1 (0.4%) 
  
  
1 (0.3%) 
Retinal Abnormalities - Drusen 
 
 
 
 
     - 
  
  
0.9035 
  
     No 
3 (1.2%) 
1 (1.1%) 
  
4 (1.2%) 
     Yes 
245 (97.2%) 
94 (98.9%) 
  
339 (97.7%) 
Retinal Abnormalities - Atrophy 
 
 
 
 
     - 
  
  
0.0076 
  
     No 
208 (82.5%) 
90 (94.7%) 
  
298 (85.9%) 
     Yes 
40 (15.9%) 
5 (5.3%) 
  
45 (13.0%) 
Retinal Abnormalities - Fibrosis 
 
 
 
 
     - 
  
  
0.9937 
  
     No 
235 (93.3%) 
90 (94.7%) 
  
325 (93.7%) 
     Yes 
13 (5.2%) 
5 (5.3%) 
  
18 (5.2%) 
Retinal Abnormalities - Hemorrhage (old format CF data) 
 
 
 
     - 
  
  
0.9897 
  
     No 
146 (57.9%) 
56 (58.9%) 
  
202 (58.2%) 
     Yes 
102 (40.5%) 
39 (41.1%) 
  
141 (40.6%) 
Retinal Abnormalities - PED 
 
 
 
 
     - 
  
  
0.6179 
  
     No 
238 (94.4%) 
90 (94.7%) 
  
328 (94.5%) 
     Yes 
10 (4.0%) 
5 (5.3%) 
  
15 (4.3%) 
 
 
 
 


Novartis 
Confidential 
Page 69 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
Retinal Abnormalities - Other 
 
 
 
 
     - 
  
  
0.5250 
  
     No 
158 (62.7%) 
57 (60.0%) 
  
215 (62.0%) 
     Yes 
90 (35.7%) 
38 (40.0%) 
  
128 (36.9%) 
Retinal Abnormalities Location Central 
 
 
 
 
     - 
  
  
0.2937 
  
     No 
2 (0.8%) 
3 (3.2%) 
  
5 (1.4%) 
     Yes 
3 (1.2%) 
1 (1.1%) 
  
1 (0.3%) 
Retinal Abnormalities Location Peripheral 
 
 
 
 
     - 
  
  
0.2937 
  
     No 
2 (0.8%) 
3 (3.2%) 
  
5 (1.4%) 
     Yes 
3 (1.2%) 
1 (1.1%) 
  
1 (0.3%) 
Hemorrhage (new format CF data) 
 
 
 
 
     - 
  
  
0.7765 
  
     Absent 
148 (58.7%) 
54 (56.8%) 
  
202 (58.2%) 
     Definite 
103 (40.9%) 
41 (43.2%) 
  
144 (41.5%) 
     Not Applicable 
1 (0.4%) 
  
  
1 (0.3%) 
Hemorrhage Location Central Subfield 
 
 
 
 
     - 
  
  
0.0730 
  
     No 
5 (2.0%) 
2 (2.1%) 
  
4 (1.2%) 
     Yes 
  
2 (2.1%) 
  
2 (0.6%) 
Hemorrhage Location Inner Subfield 
 
 
 
 
     - 
  
  
0.2937 
  
     No 
2 (0.8%) 
3 (3.2%) 
  
4 (1.2%) 
     Yes 
3 (1.2%) 
1 (1.1%) 
  
2 (0.6%) 
Hemorrhage Location Outer Subfield 
 
 
 
 
     - 
  
  
0.6353 
  
     No 
3 (1.2%) 
3 (3.2%) 
  
5 (1.4%) 
     Yes 
2 (0.8%) 
1 (1.1%) 
  
1 (0.3%) 
CNV Location (CRF DATA) 
 
 
 
 
     - 
  
  
0.2168 
  
     Juxtafoveal 
4 (1.6%) 
  
  
4 (1.2%) 
     Subfoveal 
248 (98.4%) 
95 (100.0%) 
  
343 (98.8%) 
     Extrafoveal 
xx (x.x%) 
xx (x.x%) 
 
xx (x.x%) 
 
 
 
 


Novartis 
Confidential 
Page 70 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
 
Genotype Sample 
(N=X) 
NO Genotype Sample 
(N=X) 
P Value 
Total 
(N=X) 
IRF (CRF DATA) 
 
 
 
 
     - 
  
  
0.4505 
  
     Absent 
60 (23.8%) 
19 (20.0%) 
  
79 (22.8%) 
     Present 
192 (76.2%) 
76 (80.0%) 
  
268 (77.2%) 
     Can’t Grade 
xx (x.x%) 
xx (x.x%) 
 
xx (x.x%) 
SRF (CRF DATA) 
 
 
 
 
     - 
  
  
0.0258 
  
     Absent 
62 (24.6%) 
13 (13.7%) 
  
75 (21.6%) 
     Can't grade 
  
1 (1.1%) 
  
1 (0.3%) 
     Present 
190 (75.4%) 
81 (85.3%) 
  
271 (78.1%) 
 
 
*: Centre involvement is concluded when 'Intraretinal Fluid - Center Involvement'='Present', 'Intraretinal Cysts - Center 
Involvement'='Definite' or 'Any Subretinal Fluid - Center Involvement'='Present'. 
 
 
 


Novartis 
Confidential 
Page 71 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.1-12 
Baseline Medical History Questions by treatment group  
Randomised Set 
 
 
 
Intensive  
(N=X) 
n (%) 
 Relaxed  
(N=X) 
n (%) 
Total 
(N=X) 
n (%) 
 
 
 
 
 
Are there any relevant Medical history/Current medical conditions to be reported?* 
 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 72 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.1-13 
Medical History, by primary system organ class, preferred terms and treatment 
Randomised Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
System Organ Class (SOC) 
           Preferred Term (PT) 
Nr (%) of  
Subjects 
Nr (%) of  
Subjects 
Nr (%) of  
Subjects 
 
 
 
 
 
All Body Systems 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
SOC1 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT1 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT2 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
SOC2 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT1 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT2 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x) 
x (xx.x) 
x (xx.x) 
……….. 
 
 
 
 


Novartis 
Confidential 
Page 73 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.1-14 
Ocular Medical History, by primary system organ class, preferred terms 
Randomised Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
System Organ Class (SOC) 
           Preferred Term (PT) 
Nr (%) of  
Subjects 
Nr (%) of  
Subjects 
Nr (%) of  
Subjects 
 
 
 
 
 
Eye disorders 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT1 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT2 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 


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Table 14.1-15 Medical History - Arterial Thomboembolic Events 
Randomised Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
Arterial Thomboembolic Events (ATEs)* 
xx.x 
x 
xx.x 
x 
xx.x 
x 
Nonfatal myocardial infarction 
xx.x 
x 
xx.x 
x 
xx.x 
x 
Nonfatal stroke 
xx.x 
x 
xx.x 
x 
xx.x 
x 
 
 
 
 
 
 
 
* ATEs defined as nonfatal myocardial infarction, nonfatal stroke, vascular death and death of unknown cause 
AE: Adverse Event 
Note: Some patients may have experienced multiple events 
 


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Table 14.1-16  
Baseline AMD characteristics (STUDY EYE) by treatment group 
Randomised Set 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Was any treatment ever given to the fellow eye prior to Screening? 
 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Lucentis 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Eylea 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Visudyne 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Avastin 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Steroids 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Total BCVA Score (ETDRS letters) 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Visual Acuity - Categorical (20/40) 
 
 
 
 
>=70 letters 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
<70 letters 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
 
 
 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
Central Subfield Foveal  Thickness (µm)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Central Subfield Volume (mm3)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Area of Lesion (mm2)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Intra-Retinal Fluid Status 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
Intra-Retinal Fluid Status* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Intra-Retinal Fluid Centre Involvement* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Intra-Retinal Cysts* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Intra-Retinal Cysts Centre Involvement* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Sub-Retinal Fluid Status 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Sub-Retinal Fluid Status* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
Sub-Retinal Fluid Centre Involvement* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Sub-Retinal Fluid at Centrepoint* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Sub-Retinal Fluid Height at Centrepoint 
 
 
 
 
<=200μm 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
>200 μm 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Applicable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Sub-Retinal Fluid Height at Centrepoint* 
 
 
 
 
<=200μm 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
>200 μm 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Applicable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Morphologic Changes* 
 
 
 
 
Epiretinal Membrane 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Vitreoretinal Traction 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Macular Hole 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Atrophy 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
 
 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
Area of CNV (mm2)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
CNV Complex (lesion) 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Definite 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Questionable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…… 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
CNV Complex (lesion)* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Definite 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Questionable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…… 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
CNV Complex (lesion) Location 
 
 
 
 
Subfoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal with centre 
involvement 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal with centre 
involvement 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
CNV Location 
 
 
 
 
Subfoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
CNV Location* 
 
 
 
 
Subfoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Juxtafoveal with centre 
involvement 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Extrafoveal with centre 
involvement 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
CNV Secondary to …..* 
 
 
 
 
AMD 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Angioid Streaks 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Idiopathic 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Pathologic Myopia 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Macular telangiectasis 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Type of CNV* 
 
 
 
 
Predominantly classic 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Occult 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Fibrovascular PED 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Serous PED 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
CNV Leakage* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Present 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Lesion Components* 
 
 
 
 
Blood 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
CNV 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Serous PED 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
RPE Tear 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Geographic Atrophy (Status)* 
 
 
 
 
Absent 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Definite 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Can’t Grade 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Not Applicable 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Geographic Atrophy Location* 
 
 
 
 
Central Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Inner Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Outer Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Geographic Atrophy Area (mm2)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 


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Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Haemorrhage* 
 
 
 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Haemorrhage Location* 
 
 
 
 
Central Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Inner Subfield  
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Outer Subfield 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Retinal Abnormality* 
 
 
 
 
Drusen 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Atrophy 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Fibrosis 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PED 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Retinal Abnormality Location* 
 
 
 
 
Central 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Periphery 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
* Source: 
 
Note: Geographic Atrophy not assessed by all sites. 


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Table 14.1-17 
Baseline AMD characteristics (FELLOW EYE) by treatment group 
Randomised Set 
 
 
 
Intensive  
(N=X) 
n (%) 
 Relaxed  
(N=X) 
n (%) 
Total 
(N=X) 
n (%) 
 
 
 
 
 
Fellow Eye 
 
 
Left 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Right 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Was any treatment ever given to the fellow eye prior to Screening? 
 
 
No 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Yes 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Lucentis 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Eylea 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Visudyne 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Avastin 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Steroids 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Other 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
 


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Section 14.2 – Efficacy and other non-safety data (e.g. PK, PK/PD, health economics, QoL) 
Figures (Section 14.2) 


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Figure 14.2-1 
Absolute BCVA over time by treatment  
Full Analysis Set 
 
 
 
Note: Locally weighted scatterplot smooth (loess) curves 


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Figure 14.2-2 
Absolute change in BCVA over time by treatment  
Per Protocol Set 
 
 
 
 
 


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Figure 14.2-3 
Visual Acuity over time, stratified by baseline acuity 
Full Analysis Set 
 
Example:  
 
 
 
 


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Figure 14.2-4 
Visual Acuity over time, stratified by baseline acuity 
Per Protocol Set 
 
Example:  
 
 
 
 


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Figure 14.2-5 
Change in BCVA from baseline stratified by visual acuity  
Full Analysis Set 
 
 
Example:  
 
 
 
 
 


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Figure 14.2-6 
Change in BCVA from baseline stratified by visual acuity  
Per Protocol Set 
 
 
Example:  
 
 
 
 
 


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Figure 14.2-7 
Proportion of Patients with >= 15 letter increase in BCVA from baseline, over time by treatment  
Full Analysis Set 
 
 
 
 


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Figure 14.2-8 
Proportion of Patients with >= 15 letter increase in BCVA from baseline at Month 12 and 24 
Full Analysis Set 
 
Bar graph with p-values 
 
 
 
p = x.xxxx 
p = x.xxxx 


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Figure 14.2-9 
Proportion of patients achieving >=6/12 vision, over time by treatment  
Full Analysis Set 
 
 
 
Time series graph as per Figure 14.2-7. 
 
 


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Figure 14.2-10 Proportion of of patients achieving >=6/12 vision at Month 12 and 24 
Full Analysis Set 
 
 
Column graph as per Figure 14.2-8. 
 
 


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Figure 14.2-11 Proportion of patients showing worse than 6/60 vision, over time by treatment  
Full Analysis Set 
 
Time series graph as per Figure 14.2-7. 
 
 
 


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Figure 14.2-12 Proportion of of patients showing worse than 6/60 vision at Month 12 and 24 
Full Analysis Set 
 
 
Column graph as per Figure 14.2-8. 
 
 


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Figure 14.2-13 Proportion of patients with IRF and BCVA, over time by treatment  
Full Analysis Set 
 
 
 
 
 
 
Note to Programmer: “IRF” refers to IRF and IRC (cysts) grouped together 


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Figure 14.2-14 Proportion of patients with SRF and BCVA, over time by treatment 
Full Analysis Set 
 
As per Figure 14.2-13. 
 
 


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Figure 14.2-15 Proportion of patients with IRF and SRF, and BCVA, over time by treatment 
 
Full Analysis Set 
 
As per Figure 14.2-13. 
 
 
 
Note to Programmer: “IRF” refers to IRF and IRC (cysts) grouped together 


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Figure 14.2-16 Proportion of patients with neither IRF or SRF, and BCVA, over time by treatment 
 
Full Analysis Set 
 
 
 
 
Note to Programmer: “IRF” refers to IRF and IRC (cysts) grouped together 


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Figure 14.2-17 Proportion of patients with Geographic Atrophy and BCVA, over time by treatment 
 
Full Analysis Set 
 
As per Figure 14.2-13. 
 


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Figure 14.2-18 Proportion of Patients with IRF over time by treatment  
Full Analysis Set 
 
Time series graph as per Figure 14.2-7. 
 
 
 
Note to Programmer: “IRF” refers to IRF and IRC (cysts) grouped together 


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Figure 14.2-19 Proportion of Patients with SRF over time by treatment  
Full Analysis Set 
 
Time series graph as per Figure 14.2-7. 
 
 
 


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Figure 14.2-20 Proportion of Patients with IRF and SRF over time by treatment  
Full Analysis Set 
 
Time series graph as per Figure 14.2-7. 
 
 
 
Note to Programmer: “IRF” refers to IRF and IRC (cysts) grouped together 


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Figure 14.2-21 Proportion of Patients with neither IRF or SRF over time by treatment  
Full Analysis Set 
 
Time series graph as per Figure 14.2-7. 
 
 
 
Note to Programmer: “IRF” refers to IRF and IRC (cysts) grouped together 


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Figure 14.2-22 Proportion of Patients with Geographic Atrophy over time by treatment  
Full Analysis Set 
 
Time series graph as per Figure 14.2-7. 
 


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Figure 14.2-23 Change in geographic atrophy area from baseline over time by treatment  
Full Analysis Set 
 
 
Time series graph as per Figure 14.2-5. 
 


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Figure 14.2-24 Change in Central Subfield Foveal Thickness from baseline, over time by treatment  
Full Analysis Set 
 
Time series graph as per Figure 14.2-5. 
 


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Figure 14.2-25 Number of injections by treatment at 12 and 24 months 
Full Analysis Set 
 
 
 
 
 
 
 
Baseline to <Month 12 
Month 12 to Month 24 
Baseline to Month 24 


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Tables (Section 14.2) 
Table 14.2-1 
Visual Acuity – Summary and Change from Baseline 
Full Analysis Set and Per-Protocol Set 
 
Visit 
Statistic 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Actual Value 
Absolute 
Change from 
Baseline* 
Actual Value 
Absolute 
Change from 
Baseline 
Actual Value 
Absolute 
Change from 
Baseline 
 
 
 
 
 
 
 
 
Screening 
n 
x 
- 
x 
- 
x 
- 
 
Mean 
x.x 
 
 - 
x.x 
- 
x.x 
- 
 
Median 
x.x 
- 
x.x 
- 
x.x 
- 
 
SD 
x.x 
- 
x.x 
- 
x.x 
- 
 
Minimum 
x 
- 
x 
- 
x 
- 
 
Maximum 
x 
- 
x 
- 
x 
- 
 
 
 
 
 
 
 
 
Baseline* 
n 
x 
- 
x 
- 
x 
- 
 
Mean 
x.x 
- 
x.x 
- 
x.x 
- 
 
Median 
x.x 
- 
x.x 
- 
x.x 
- 
 
SD 
x.x 
- 
x.x 
- 
x.x 
- 
 
Minimum 
x 
- 
x 
- 
x 
- 
 
Maximum 
x 
- 
x 
- 
x 
- 
 
 
 
 
 
 
 
 
Week n 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continued through to Month 24 
 
*Baseline: The last available non-missing value collected just prior to the start of treatment in the study eye 
SD: Standard Deviation 
 
 


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Table 14.2-2 
Visual Acuity – Mixed Model Analysis 
Full Analysis Set 
 
Random Effects Mixed Model* 
Treatment Effects 
Num d.f. Den d.f. 
F-stat 
p-value 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Baseline Effect 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Treatment  
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Visit 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 Treatment*Visit 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
Least Squares Means 
 Month 2 (95% CI) 
 
 
 
 
 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
 Month 12 (95% CI) 
 
 
 
 
 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
 Month 24 (95% CI) 
 
 
 
 
 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
Treatment Effect 
 Month 2, Treatment Effect (95%CI) 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 2, p-value 
 
 
 
 
 
x.xxxx 
 Month 12, Treatment Effect (95%CI) 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 12, p-value 
 
 
 
 
 
x.xxxx 
 Month 24, Treatment Effect (95%CI) 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 24, p-value 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
*Mixed Model: Change from Baseline (BCVA) = Baseline (BCVA) + Treatment + Visit (weeks) + Treatment * Visit + Subject (random effect) 
CI: Confidence Interval;  
 
Note to Programmer: The above table is an example only. Output to be updated to reflect aspects of the final 
model as appropriate. 


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Table 14.2-3 Visual Acuity – Mixed Model Analysis 
Per Protocol Set 
 
Mixed Model* 
Treatment Effects 
Num d.f. Den d.f. 
F-stat 
p-value 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Treatment Main Effects 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Visits 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Baseline Effect 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Class variable 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Treatment * Visit 
x 
xx 
x.xx 
x.xxxx 
 
 
 
Least Squares Means 
 Month 2 (95% CI) 
 
 
 
 
 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
 Month 12 (95% CI) 
 
 
 
 
 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
 Month 24 (95% CI) 
 
 
 
 
 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
Treatment Effect 
 Month 2, Treatment Effect (95%CI) 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 2, p-value 
 
 
 
 
 
x.xxxx 
 Month 12, Treatment Effect (95%CI) 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 12, p-value 
 
 
 
 
 
x.xxxx 
 Month 24, Treatment Effect (95%CI) 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 24, p-value 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
*Mixed Model: Change from Baseline (BCVA) = Baseline (BCVA) + Treatment + Visit (weeks) + Treatment * Visit + Subject (random effect) 
CI: Confidence Interval 
Note to Programmer: The above table is an example only. Output to be updated to reflect aspects of the final 
model as appropriate. 


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Table 14.2-4 Proportion of Patients with >=15 letters change from baseline – Logistic Regression 
Full Analysis Set 
 
Intensive  
(N=X) 
 
Relaxed  
(N=X) 
 
 
 
Letters change from baseline to Month 12 
 
 
 
>= 15 letters                  YES 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
NO 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratio* 
 
 
 
 Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 p-value 
 
x.xxxx 
 
 
 
 
Letters change from baseline to Month 24 
 
 
 
>= 15 letters                  YES 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
NO 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratio* 
 
 
 
 Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 p-value 
 
x.xxxx 
 
 
 
 
*Logistic regression model includes treatment as factor and baseline BCVA as covariate 
 
 


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Table 14.2-4 Proportion of Patients with less than 15 letters lost change from baseline – Logistic Regression 
Full Analysis Set 
 
Intensive  
(N=X) 
 
Relaxed  
(N=X) 
 
 
 
Letters change from baseline to Month 12 
 
 
 
<15 letters lost               YES 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
NO 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratio* 
 
 
 
 Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 p-value 
 
x.xxxx 
 
 
 
 
Letters change from baseline to Month 24 
 
 
 
<15 letters lost               YES 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
NO 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratio* 
 
 
 
 Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 p-value 
 
x.xxxx 
 
 
 
 
*Logistic regression model includes treatment as factor and baseline BCVA as covariate 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-5 Proportion of Patients who achieve >=6/12 visual acuity – Logistic Regression 
Full Analysis Set 
 
Intensive  
(N=X) 
 
Relaxed  
(N=X) 
 
 
 
Baseline 
 
 
 
>= 6/12 visual acuity 
xx (xx.x%) 
 
xx (xx.x%) 
<6/12 visual acuity  
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Month 12 
 
 
 
>= 6/12 visual acuity 
xx (xx.x%) 
 
xx (xx.x%) 
<6/12 visual acuity  
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratio* 
 
 
 
 Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 p-value 
 
x.xxxx 
 
 
 
 
Month 24 
 
 
 
>= 6/12 visual acuity 
xx (xx.x%) 
 
xx (xx.x%) 
<6/12 visual acuity  
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratio* 
 
 
 
 Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 p-value 
 
x.xxxx 
 
 
 
 
*Logistic regression model includes treatment as factor and baseline BCVA as covariate 
 
 


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Table 14.2-6 Proportion of Patients who achieve <=6/60 visual acuity – Logistic Regression 
Full Analysis Set 
 
Intensive  
(N=X) 
 
Relaxed  
(N=X) 
 
 
 
Baseline 
 
 
 
<= 6/60 visual acuity 
xx (xx.x%) 
 
xx (xx.x%) 
>6/60 visual acuity  
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Month 2 
 
 
 
<= 6/60 visual acuity 
xx (xx.x%) 
 
xx (xx.x%) 
>6/60 visual acuity  
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratio* 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
p-value 
 
x.xxxx 
 
 
 
 
Month 12 
 
 
 
<= 6/60 visual acuity 
xx (xx.x%) 
 
xx (xx.x%) 
>6/60 visual acuity  
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratio* 
 
 
 
 Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 p-value 
 
x.xxxx 
 
 
 
 
Month 24 
 
 
 
<= 6/60 visual acuity 
xx (xx.x%) 
 
xx (xx.x%) 
>6/60 visual acuity  
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratio* 
 
 
 
 Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 p-value 
 
x.xxxx 
 
 
 
 
*Logistic regression model includes treatment as factor and baseline BCVA as covariate 
 
 


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Table 14.2-7 
Interval Decision Summary Table 
Full Analysis Set 
 
Visit 
Interval Decision* 
Intensive 
(N=X) 
Relaxed 
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Week 8 
 
 
 
 
 
Loss in VA 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Haemorrhage 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
IRF/SRF 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Loss in VA AND Haemorrhage 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Loss in VA AND IRF/SRF 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Loss in VA AND Haemorrhage AND IRF/SRF 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
Haemorrhage AND IRF/SRF 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
Week n 
……………. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Interval Decisions: 
Loss in VA:  
A loss of VA of >=5 letters or more than the best VA recorded since treatment started (Where VA loss is considered, by the 
investigator, to be due to disease activity); 
Haemorrhage: 
New retinal haemorrhage; 
IRF/SRF: 
Intensive Arm: The presence of any intra-retinal fluid or sub-retinal fluid on OCT 
   Relaxed Arm: The presence of any intra-retinal fluid or sub-retinal fluid >200 μm in height at foveal centre? 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-8 
Number of Injections  
 
Visit 
 
Intensive 
(N=X)  
 Relaxed 
(N=X)  
Total 
(N=X) 
 
 
 
 
 
Number of Injections 
n 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
 
 
 
 
 
Exposure (year) 
n 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
 
 
 
 
 
Injections per year* 
 
xx 
xx 
xx 
 
 
 
 
 
* Injections per year = Total number of injections / total exposure to treatment (years) 
 
Visit 
 
Intensive 
(N=X)  
 Relaxed 
(N=X)  
Total 
(N=X) 
 
 
 
 
 
Number of Injections 
n 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
 
 
 
 
 
Exposure (year) 
n 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Min; Max 
x;x 
x;x 
x;x 
 
 
 
 
 
Injections per year* 
 
xx 
xx 
xx 
 
 
 
 
 
* Injections per year = Total number of injections / total exposure to treatment (years) 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-9 
Number of Injections from Baseline to Months 12 and 24 – Negative Binomial Regression  
Full Analysis Set 
 
 
Negative Binomial Regression* 
 
Treatment Effects 
 
Estimate 
Standard 
Error 
Chi-square 
p-value 
 
Intensive  
(N=X) 
 
 Relaxed  
(N=X) 
Parameter Estimates 
 
 
 
 
 
 
 
 
Intercept 
x.xx 
x.xxxx 
x.xx 
x.xxxx 
 
 
 
 
Treatment 
x.xx 
x.xxxx 
x.xx 
x.xxxx 
 
 
 
 
Disperson 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Least Squares Means 
 
 
 
 
 
 
 
 
Least Squares Means (95% CI) 
 
 
 
 
 
x.xx (x.xx, x.xx) 
 
x.xx (x.xx, x.xx) 
Treatment Effect 
 
 
 
 
 
 
 
 
Treatment Effect (95% CI) 
 
 
 
 
 
 
x.xx (x.xx, x.xx) 
p-value 
 
 
 
 
 
 
x.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* number of injections will be the outcome variable, and treatment and BL BCVA as a predictor. The logarithm of length of time (year) each subject is in 
the study up to their 24 month visit will be used as an offset variable.   
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-10 
Treatment Interval Summary (Based on Interval Decision) 
Full Analysis Set and Per-Protocol Set 
 
Statistic 
Intensive 
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
n 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
Median 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
Minimum 
x 
x 
x 
Maximum 
x 
x 
x 
 
 
 
 
SD: Standard Deviation 
 
 
 
  
 
 
Average treatment interval for each group - need to average it out for patient then average out for the treatment arm 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-11 
Treatment Interval Summary (Based on Actual Intervals between Visits) 
Full Analysis Set and Per-Protocol Set 
 
Statistic 
Intensive 
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
n 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
Median 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
Minimum 
x 
x 
x 
Maximum 
x 
x 
x 
 
 
 
 
SD: Standard Deviation 
 
 
 
  
 
 
Average treatment interval for each group - need to average it out for patient then average out for the treatment arm 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-12 
Treatment Interval Visit Summary (Based on Interval Decision) 
Full Analysis Set 
 
Visit 
Interval 
Intensive  
(N=x) 
 Relaxed  
(N=x) 
Total 
(N=x) 
 
 
 
 
 
Week 4 
4 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Week 8 
4 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Week 12  
4 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
6 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
8 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
10 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
12 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Week n  
4 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
6 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
8 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
10 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
12 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-13 
Treatment Interval Visit Summary (Based on Actual Intervals between Visits) 
Full Analysis Set 
 
Visit 
Interval 
Intensive  
(N=x) 
 Relaxed  
(N=x) 
Total 
(N=x) 
 
 
 
 
 
Week 4 
4 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Week 8 
4 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Week 12  
4 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
6 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
8 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
10 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
12 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Week n  
4 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
6 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
8 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
10 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
12 Weeks 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-14 Breakpoint Set Interval - Summary  
Full Analysis Set 
 
Visit 
Interval 
Intensive  
(N=x) 
 Relaxed  
(N=x) 
Total 
(N=x) 
 
 
 
 
 
Week 52  
4 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
6 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
8 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
10 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
12 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
Has not reached 
breakpoint 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
 
 
 
 
Week 104  
4 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
6 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
8 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
10 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
12 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
Has not reached 
breakpoint 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
 
 
 
 
 
 
 
Note to Programmer: Use assigned interval (Interval Decision)  


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Table 14.2-15 Post-Breakpoint Maximum Inteval - Summary  
Full Analysis Set 
 
Visit 
Interval 
Intensive  
(N=x) 
 Relaxed  
(N=x) 
Total 
(N=x) 
 
 
 
 
 
Week 52  
4 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
6 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
8 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
10 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
Has not reached 
breakpoint 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
 
 
 
 
Week 104  
4 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
6 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
8 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
10 Weeks 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
Has not reached 
breakpoint 
x (x.xx%) 
x (x.xx%) 
x (x.xx%) 
 
 
 
 
 
 
 
 
Note to Programmer: Use assigned interval (Interval Decision)  


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-16 
Time to Breakpoint - Summary  
Full Analysis Set 
 
 
Intensive  
(N=x) 
 Relaxed  
(N=x) 
Total 
(N=x) 
 
 
 
 
Time to Meet Breakpoint Criteria (weeks) 
n 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
Median 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
Minimum 
x 
x 
x 
Maximum 
x 
x 
x 
 
 
 
 
SD: Standard Deviation 
 


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Table 14.2-17 
Time to Breakpoint – Survival Analysis 
Full Analysis Set 
 
 
 
Intensive  
(N=x) 
 Relaxed  
(N=x) 
Total 
(N=x) 
 
 
 
 
 
Total Subjects 
x 
x 
X 
 
Event n(%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
Censored n(%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Time to Events (Weeks) 
 
 
 
 
25 Percentile (95% CI) 
x (xx,xx) 
x (xx,xx) 
x (xx,xx) 
 
Median (95% CI) 
x (xx,xx) 
x (xx,xx) 
x (xx,xx) 
 
75 Percentile (95% CI) 
x (xx,xx) 
x (xx,xx) 
x (xx,xx) 
 
Range 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-18 
Geographic Atrophy Area – Summary and Change from Baseline (Central Reading Center Data) 
Full Analysis Set 
 
Visit 
Statistic 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Actual Value 
Absolute 
Change from 
Baseline* 
Actual Value 
Absolute 
Change from 
Baseline 
Actual Value 
Absolute 
Change from 
Baseline 
 
 
 
 
 
 
 
 
Screening 
n 
x 
- 
x 
- 
x 
- 
 
Mean 
x.x 
- 
x.x 
- 
x.x 
- 
 
Median 
x.x 
- 
x.x 
- 
x.x 
- 
 
SD 
x.x 
- 
x.x 
- 
x.x 
- 
 
Minimum 
x 
- 
x 
- 
x 
- 
 
Maximum 
x 
- 
x 
- 
x 
- 
 
 
 
 
 
 
 
 
Baseline* 
n 
x 
- 
x 
- 
x 
- 
 
Mean 
x.x 
- 
x.x 
- 
x.x 
- 
 
Median 
x.x 
- 
x.x 
- 
x.x 
- 
 
SD 
x.x 
- 
x.x 
- 
x.x 
- 
 
Minimum 
x 
- 
x 
- 
x 
- 
 
Maximum 
x 
- 
x 
- 
x 
- 
 
 
 
 
 
 
 
 
Week n 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continued through to Month 24 
 
*Baseline: The last available non-missing value collected just prior to the start of treatment in the study eye 
SD: Standard Deviation 


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Table 14.2-19 
Geographic Atrophy – Categorical Summary 
Full Analysis Set 
 
Visit 
 
Intensive  
 Relaxed  
Total 
 
 
 
 
 
Baseline* 
Present 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
Absent 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Week 4 
Present 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
Absent 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Week 8 
Present 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
Absent 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Week n 
Present 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
Absent 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
*Baseline: The last available non-missing value collected just prior to the start of treatment in the study eye 
SD: Standard Deviation 
 
 


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Table 14.2-20 
Geographic Atrophy – Survival Analysis 
Full Analysis Set 
 
 
 
Intensive  
(N=x) 
 Relaxed  
(N=x) 
Total 
(N=x) 
 
 
 
 
 
Total Subjects 
x 
x 
X 
 
Event n(%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
Censored n(%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Time to Events (Weeks) 
 
 
 
 
25 Percentile (95% CI) 
x (xx,xx) 
x (xx,xx) 
x (xx,xx) 
 
Median (95% CI) 
x (xx,xx) 
x (xx,xx) 
x (xx,xx) 
 
75 Percentile (95% CI) 
x (xx,xx) 
x (xx,xx) 
x (xx,xx) 
 
Range 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 
Intensive  
(N=x) 
 Relaxed  
(N=x) 
Total 
(N=x) 
 
 
 
 
 
Total Subjects 
x 
x 
X 
 
Event n(%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
Censored n(%) 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
Time to Events (Weeks) 
 
 
 
 
25 Percentile (95% CI) 
x (xx,xx) 
x (xx,xx) 
x (xx,xx) 
 
Median (95% CI) 
x (xx,xx) 
x (xx,xx) 
x (xx,xx) 
 
75 Percentile (95% CI) 
x (xx,xx) 
x (xx,xx) 
x (xx,xx) 
 
Range 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 
 


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Table 14.2-21 
Geographic Atrophy – Mixed Model Analysis 
Full Analysis Set 
 
Mixed Model* 
Treatment Effects 
Num d.f. Den d.f. 
F-stat 
p-value 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Treatment Main Effects 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Visits 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Baseline Effect 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Class variable 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Class variable 
x 
xx 
x.xx 
x.xxxx 
 
 
 
Least Squares Means 
 Month 2 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
 Month 12 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
 Month 24 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
Treatment Effect 
 Month 2, Treatment Effect (95%CI) 
 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 2, p-value 
 
 
 
 
 
 
x.xxxx 
 Month 12, Treatment Effect (95%CI) 
 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 12, p-value 
 
 
 
 
 
 
x.xxxx 
 Month 24, Treatment Effect (95%CI) 
 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 24, p-value 
 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
*Mixed Model: Change from Baseline (Geographic Atrophy Area) = Baseline (Geographic Atrophy Area) + Treatment + Visit (weeks)  
CI: Confidence Interval; SE: Standard Error 
 
 
 
Note to Programmer: The above table is an example only. Output to be updated to reflect aspects of the final 
model as appropriate. 


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Table 14.2-22 
Geographic Atrophy – Mixed Model Analysis 
Per Protocol Set 
 
Mixed Model* 
Treatment Effects 
Num d.f. Den d.f. 
F-stat 
p-value 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Treatment Main Effects 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Visits 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Baseline Effect 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Class variable 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Class variable 
x 
xx 
x.xx 
x.xxxx 
 
 
 
Least Squares Means 
 Month 2 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
 Month 12 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
 Month 24 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
Treatment Effect 
 Month 2, Treatment Effect (95%CI) 
 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 2, p-value 
 
 
 
 
 
 
x.xxxx 
 Month 12, Treatment Effect (95%CI) 
 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 12, p-value 
 
 
 
 
 
 
x.xxxx 
 Month 24, Treatment Effect (95%CI) 
 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 24, p-value 
 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
*Mixed Model: Change from Baseline (Geographic Atrophy Area) = Baseline (Geographic Atrophy Area) + Treatment + Visit (weeks)  
CI: Confidence Interval; SE: Standard Error 
 
 
 
Note to Programmer: The above table is an example only. Output to be updated to reflect aspects of the final 
model as appropriate. 


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Table 14.2-23 
Proportion of Patients with Geographic Atrophy from Baseline to Month 24 – Logistic Regression 
Full Analysis Set 
 
Intensive  
(N=X) 
 
Relaxed  
(N=X) 
 
 
 
Status of Geographic Atrophy 
 
 
 
Baseline 
 
 
 
 
Absent 
xx (xx.x%) 
 
xx (xx.x%) 
 
Present 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Month 24 
 
 
 
 
 
Absent 
xx (xx.x%) 
 
xx (xx.x%) 
 
Present 
xx (xx.x%) 
 
xx (xx.x%) 
                                     Newly developed geographic atrophy only 
xx (xx.x%) 
 
xx (xx.x%) 
 
 
 
Odds Ratios* 
 
 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
*Logistic regression model (proportion of newly developed geographic atrophy at Month 24) includes treatment as factor 
  


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Table 14.2-24 
Proportion of Patients showing intra-retinal /  sub-retinal fluid, by visit 
Full Analysis Set 
 
 
 
 
 
Intensive  
(N=X) 
n (%) 
 Relaxed  
(N=X) 
n (%) 
p-value 
(Logistic Regression) 
Total 
(N=X) 
n (%) 
 
 
 
 
 
 
Screening 
Intra-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
No Intra-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
Intra-retinal Fluid – Center Involvement  
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
No Intra-retinal Fluid – Center Involvement 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
No Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
No Intra-retinal Fluid or Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
Intra-retinal Fluid OR Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
Intra-retinal Fluid AND Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
 
 
 
 
 
Baseline 
Intra-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
No Intra-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
Intra-retinal Fluid – Center Involvement  
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
No Intra-retinal Fluid – Center Involvement 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
No Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
No Intra-retinal Fluid or Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
Intra-retinal Fluid OR Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
Intra-retinal Fluid AND Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
 
 
 
 
 
Week n 
Intra-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
No Intra-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
Sub-retinal Fluid 
x (xx.x) 
x (xx.x) 
x.xxx 
x (xx.x) 
 
………… 
 
 
 
 


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Table 14.2-25 Proportion of patients with SRF at baseline who never resolve their SRF (irrespective of their IRF) – Logistic 
Regression 
Full Analysis Set 
 
Intensive  
(N=X) 
 
Relaxed  
(N=X) 
 
 
 
Month 2 
xx (xx.x%) 
 
xx (xx.x%) 
 
Odds Ratio* 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
Month 12 
xx (xx.x%) 
 
xx (xx.x%) 
 
Odds Ratio* 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
Month 24 
xx (xx.x%) 
 
xx (xx.x%) 
 
Odds Ratio* 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
 
 
 
 
*Logistic regression model includes treatment as factor and baseline BCVA as covariate 
 
 


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Table 14.2-26 Proportion of patients with IRF at baseline who never resolve their IRF (irrespective of their SRF) – Logistic 
Regression 
Full Analysis Set 
 
Intensive  
(N=X) 
 
Relaxed  
(N=X) 
 
 
 
Month 2 
xx (xx.x%) 
 
xx (xx.x%) 
 
Odds Ratio* 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
Month 12 
xx (xx.x%) 
 
xx (xx.x%) 
 
Odds Ratio* 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
Month 24 
xx (xx.x%) 
 
xx (xx.x%) 
 
Odds Ratio* 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
 
 
 
 
*Logistic regression model includes treatment as factor and baseline BCVA as covariate 
 
 


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Table 14.2-27 Proportion of patients with IRF and SRF at baseline who never resolve either their IRF or SRF – Logistic Regression 
Full Analysis Set 
 
Intensive  
(N=X) 
 
Relaxed  
(N=X) 
 
 
 
Month 2 
xx (xx.x%) 
 
xx (xx.x%) 
 
Odds Ratio* 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
Month 12 
xx (xx.x%) 
 
xx (xx.x%) 
 
Odds Ratio* 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
Month 24 
xx (xx.x%) 
 
xx (xx.x%) 
 
Odds Ratio* 
 
 
 
 
 
Odds Ratio (95% CI) 
 
x.xx (x.xx,x.xx) 
 
 
 
p-value 
 
x.xxxx 
 
 
 
 
 
 
 
 
*Logistic regression model includes treatment as factor and baseline BCVA as covariate 
 
 


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Table 14.2-28 
Intra-Retinal and Sub-Retinal Fluid – Generalized Estimating Equation  
Full Analysis Set 
 
Generalised Estimating Equation* 
 
Treatment Effects 
Odds 
Ratio 
95% CI 
Lower 
95% CI 
Upper 
p-value 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Intra-Retinal Fluid 
 
 
 
 
 
 
 
Parameter Estimates 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit  
x.xx 
x.xx 
x.xx 
x.xxxx 
 
 
 
Least Squares Means 
  
Month n 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
  
Month n 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
 
 
 
 
 
 
 
Sub-Retinal Fluid 
 
 
 
 
 
 
 
Parameter Estimates 
 
 
 
 
 
 
 
Intercept 
x.xx 
x.xx 
x.xx 
x.xxxx 
 
 
 
Treatment 
x.xx 
x.xx 
x.xx 
x.xxxx 
 
 
 
Month  
x.xx 
x.xx 
x.xx 
x.xxxx 
 
 
 
Least Squares Means 
 
 
 
 
 
 
 
  
Month n 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
  
Month n 
 
 
 
 
 
x.xx (x.xx) 
x.xx (x.xx) 
 
 
 
 
 
 
*Generalised Estimating Equation (GEE) 
 


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Table 14.2-29 Central Retinal Thickness – Summary and Change from Baseline, by treatment 
Full Analysis Set 
 
Visit 
Statistic 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Actual Value 
Absolute 
Change from 
Baseline* 
Actual Value 
Absolute 
Change from 
Baseline 
Actual Value 
Absolute 
Change from 
Baseline 
 
 
 
 
 
 
 
 
Screening 
n 
x 
- 
x 
- 
x 
- 
 
Mean 
x.x 
- 
x.x 
- 
x.x 
- 
 
Median 
x.x 
- 
x.x 
- 
x.x 
- 
 
SD 
x.x 
- 
x.x 
- 
x.x 
- 
 
Minimum 
x 
- 
x 
- 
x 
- 
 
Maximum 
x 
- 
x 
- 
x 
- 
 
 
 
 
 
 
 
 
Baseline 
n 
x 
- 
x 
- 
x 
- 
 
Mean 
x.x 
- 
x.x 
- 
x.x 
- 
 
Median 
x.x 
- 
x.x 
- 
x.x 
- 
 
SD 
x.x 
- 
x.x 
- 
x.x 
- 
 
Minimum 
x 
- 
x 
- 
x 
- 
 
Maximum 
x 
- 
x 
- 
x 
- 
 
 
 
 
 
 
 
 
Week n 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continued through to Month 24 
 
 
 
 
 
 
*Baseline: The last available non-missing value collected just prior to the start of treatment in the study eye 
SD: Standard Deviation 
 
 


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Table 14.2-30 
Central Retinal Thickness – Mixed Model Analysis 
Full Analysis Set 
 
 
Random effect Mixed Model * 
 
Treatment Effects 
Num 
d.f. 
Den d.f. 
F-stat 
p-value 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
 Treatment Main Effects 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Visits 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Baseline Effect 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Class variable 
x 
xx 
x.xx 
x.xxxx 
 
 
 
 Class variable 
x 
xx 
x.xx 
x.xxxx 
 
 
 
Least Squares Means 
 Month 2 (95%CI) 
 
 
 
 
 
x.xx (x.xx,x.xx) 
x.xx (x.xx,x.xx) 
 Month 12 (95%CI) 
 
 
 
 
 
x.xx (x.xx,x.xx) 
x.xx (x.xx,x.xx) 
 Month 24 (95%CI) 
 
 
 
 
 
 
 
Treatment Effect 
 Month 2, Treatment Effect (95%CI) 
 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 2, p-value 
 
 
 
 
 
 
x.xxxx 
 Month 12, Treatment Effect (95%CI) 
 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 12, p-value 
 
 
 
 
 
 
x.xxxx 
 Month 24, Treatment Effect (95%CI) 
 
 
 
 
 
 
x.xx (x.xx,x.xx) 
 Month 24, p-value 
 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
*Mixed Model: Change from Baseline (CRT) = Baseline (CRT) + Treatment + Visit (weeks) + Treatment * Visit + Subject (random effect) 
CI: Confidence Interval; CRT: Central Retinal Thickness; SE: Standard Error 
 
 


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Table 14.2-31 
Genotyping by Treatment 
Full Analysis Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
P Value 
Total 
(N=X) 
rsXXXXXXXX 
     - 
x.xxxx 
     GG 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     GT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     TT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
rsXXXXXXXX 
     - 
x.xxxx 
     CC 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     CT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     TT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
rsXXXXXXXX 
     - 
x.xxxx 
     CC 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     CT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
…….. 
 
 
 
 
 
 
 
 
 
 
* Fisher Analysis 
 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Table 14.2-32 
Genotyping by Race 
Full Analysis Set 
 
 
Asian 
(N=X) 
 Caucasian  
(N=X) 
P Value* 
Total 
(N=X) 
rsXXXXXXXX 
     - 
x.xxxx 
     GG 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     GT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     TT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
rsXXXXXXXX 
     - 
x.xxxx 
     CC 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     CT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     TT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
rsXXXXXXXX 
     - 
x.xxxx 
     CC 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     CT 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
…….. 
 
 
 
 
 
 
 
 
 
 
* Fisher Analysis 
 
 


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Listings (Section 14.2) 
Not applicable. 


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Section 14.3 – Safety data 
Tables (Section 14.3) 
Table 14.3-1 
Number (%) of patients receiving each dose and regimen of study medication by treatment and visit 
Safety Set 
 
Visit 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
Baseline 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week 4 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week 8 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Week n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Month n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Month n 
x (xx.x) 
x (xx.x) 
x (xx.x) 
Month 24 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 


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Table 14.3-2 
Duration of exposure to study drug, by treatment 
Safety Set 
 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Duration of Exposure (days)* 
 
 
 
 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
SD: Standard Deviation 
*Duration of Exposure = Date of first treatment to date of End of Treatment 
 
 


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Table 14.3-3 
Medications and significant non-drug therapies taken prior to the start of study drug by ATC class, preferred 
term and treatment 
Safety Set 
 
Anatomic Therapeutic Classification (ATC) 
              Preferred Term (PT) 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Any ATC Class with medication/surgery 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
Nr of concomitant medications reported 
 
x 
x 
x 
 
 
 
 
 
 
ATC1 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT1 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT2 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…. 
 
…. 
…. 
…. 
 
PTx 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
ATC1 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT1 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT2 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…. 
 
…. 
…. 
…. 
 
PTx 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
……….. 
 
 
 
 
Note: Patients who take the same medication (in terms of the preferred term) more than once will be counted only once for that medication. 
 


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Table 14.3-4 
Forbidden concomitant medications and significant non-drug therapies after start of study drug by ATC class, 
preferred term and treatment 
Safety Set 
 
Anatomic Therapeutic Classification (ATC) 
              Preferred Term (PT) 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
 
 
 
 
 
Any ATC Class with medication/surgery 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
Nr of concomitant medications reported 
 
x 
x 
x 
 
 
 
 
 
 
ATC1 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT1 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT2 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…. 
 
…. 
…. 
…. 
 
PTx 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
 
 
 
 
 
ATC1 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT1 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
PT2 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
 
…. 
 
…. 
…. 
…. 
 
PTx 
 
x (xx.x) 
x (xx.x) 
x (xx.x) 
……….. 
 
 
 
 
Note: Patients who take the same medication (in terms of the preferred term) more than once will be counted only once for that medication. 
 
 


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Table 14.3-5 
Vital signs by visit and treatment 
Safety Set 
 
Visit 
Statistic 
Intensive 
(N=X) 
 Relaxed 
(N=X)  
Total 
(N=X) 
 
 
 
 
 
Systolic Blood Pressure  (SBP) (mmHg) 
 
 
Screening 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Baseline 
n 
x 
x 
x 
 
Mean 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
SD 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 
 
 
 
 
Diastolic Blood Pressure  (DBP) (mmHg) 
 
 
………… 
 
 
 
 
*Baseline: The last available non-missing value collected just prior to the start of treatment in the study eye 
SD: Standard Deviation 


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Table 14.3-6 
Ophthalmic Examination – Intraocular Pressure (IOP) by treatment 
Safety Set 
 
Visit 
Statistic 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Actual Value 
Absolute 
Change from 
Baseline* 
Actual Value 
Absolute 
Change from 
Baseline 
Actual Value 
Absolute 
Change from 
Baseline 
 
 
 
 
 
 
 
 
Screening 
n 
x 
- 
x 
- 
x 
- 
 
Mean 
x.x 
- 
x.x 
- 
x.x 
- 
 
Median 
x.x 
- 
x.x 
- 
x.x 
- 
 
SD 
x.x 
- 
x.x 
- 
x.x 
- 
 
Minimum 
x 
- 
x 
- 
x 
- 
 
Maximum 
x 
- 
x 
- 
x 
- 
 
 
 
 
 
 
 
 
Baseline 
n 
x 
- 
x 
- 
x 
- 
 
Mean 
x.x 
- 
x.x 
- 
x.x 
- 
 
Median 
x.x 
- 
x.x 
- 
x.x 
- 
 
SD 
x.x 
- 
x.x 
- 
x.x 
- 
 
Minimum 
x 
- 
x 
- 
x 
- 
 
Maximum 
x 
- 
x 
- 
x 
- 
 
 
 
 
 
 
 
 
Week n 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continued through to Month 24 
 
 
 
 
 
 
*Baseline: The last available non-missing value collected just prior to the start of treatment in the study eye 
SD: Standard Deviation 


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Listings (Section 14.3) 
Listing 14.3-1 
Patients with notably abnormal vital signs 
Safety Set 
 
Subject 
Number 
Visit 
Were Vital Signs 
Performed? 
Date of Vital Signs 
Assessment 
(YYYY-MM-DD) 
Systolic Blood 
Pressure 
 (mmHg)* 
Diastolic Blood 
Pressure 
 (mmHg)* 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXH 
XXXH 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXH 
XXXH 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXL 
XXXL 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXL 
XXXL 
………….. 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXH 
XXXH 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXH 
XXXH 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXL 
XXXL 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXL 
XXXL 
………….. 
 
 
 
 
 
*Flags: H=High (Systolic - >180 and increase from baseline of >20, Diastolic - >105 and increase from baseline of >15) 
L=Low (Systolic - <90 and decrease from baseline of >20, Diastolic - <50 and decrease from baseline of >15)  


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Section 14.3.1 – Displays of adverse events 
Figures (Section 14.3.1) 
No Output 


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Tables (Section 14.3.1) 
Table 14.3.1-1 
Incidence of adverse events, regardless of study drug relationship, by primary system organ class, 
preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 


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Table 14.3.1-2 
Incidence of ocular adverse events, regardless of study drug relationship, by primary system organ class, 
preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Ocular 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 


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Table 14.3.1-3 
Incidence of adverse events, regardless of study drug relationship by primary system organ class, preferred 
term, maximum severity and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive 
(N=X) 
 
Relaxed 
(N=X) 
 
Total 
(N=X) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
 
 
 
 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PT1 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PT2 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           …. 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PTx 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PT1 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PT2 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           …. 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PTx 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Subjects are counted once at maximum severity within each sub grouping.                                                              


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Table 14.3.1-4 
Incidence of ocular adverse events, regardless of study drug relationship by primary system organ class, 
preferred term, maximum severity and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive 
(N=X) 
 
Relaxed 
(N=X) 
 
Total 
(N=X) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
 
 
 
 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PT1 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PT2 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           …. 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PTx 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PT1 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PT2 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           …. 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
           PTx 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Subjects are counted once at maximum severity within each sub grouping.                                                              


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Table 14.3.1-5 
Incidence of adverse events, by primary system organ class, preferred term, maximum relationship to study drug 
and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 
Relaxed  
(N=X) 
 
Total 
(N=X) 
Not Suspected 
Suspected 
 
Not Suspected 
Suspected 
 
Not Related 
Related* 
 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
           PT1 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
           PT2 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
           …. 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
           PTx 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
           PT1 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
           PT2 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
           …. 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
           PTx 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
 
 
 
 
 
 
 
 
*Related: includes possibly, probably and definitely related 
Note: Percentages are based on the number of subjects in each group. 


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Table 14.3.1-6 
Incidence of adverse events suspected to be related to study drug, by primary system organ class, preferred 
term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 
 
 


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Table 14.3.1-7 
Incidence of ocular adverse events suspected to be related to study drug, by primary system organ class, 
preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 


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Table 14.3.1-8 
Incidence of serious adverse events, regardless of study drug relationship, by primary system organ class, 
preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 


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Table 14.3.1-9 
Incidence of ocular serious adverse events, regardless of study drug relationship, by primary system organ 
class, preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 
 
 


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Table 14.3.1-10 
Incidence of adverse events leading to treatment withdrawal, regardless of study drug relationship, by 
primary system organ class, preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 


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Table 14.3.1-11 
Incidence of ocular adverse events leading to treatment withdrawal, regardless of study drug relationship, 
by primary system organ class, preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 


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Table 14.3.1-12 Incidence of adverse events leading to study drug interruption, regardless of study drug relationship, by primary 
system organ class, preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 


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Table 14.3.1-13 Incidence of ocular adverse events leading to study drug interruption, regardless of study drug relationship, by 
primary system organ class, preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 
 


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Table 14.3.1-14 Incidence of adverse events requiring significant additional therapy, regardless of study drug relationship, by 
primary system organ class, preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 


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Table 14.3.1-15 Incidence of ocular adverse events requiring significant additional therapy, regardless of study drug 
relationship, by primary system organ class, preferred term and treatment 
Safety Set 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 
 


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Table 14.3.1-16 
Deaths, by primary system organ class, preferred term and treatment 
Safety Set 
 
Principal Cause of Death 
 
System Organ Class (SOC) 
           Preferred Term (PT) 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
All Body Systems 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
 
 
 
 
 
 
 
SOC2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT1 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
PT2 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
 
…. 
…. 
…. 
…. 
…. 
…. 
…. 
 
PTx 
x (xx.x%) 
x 
x (xx.x%) 
x 
x (xx.x%) 
x 
……….. 
 
 
 
 
 
 
AE: Adverse Event 
Note: Multiple records from the same subject are only counted once within the same category 


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Table 14.3.1-17 
Arterial Thomboembolic Events 
Safety Set 
 
 
Intensive  
(N=X) 
 Relaxed  
(N=X) 
Total 
(N=X) 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
Nr (%) of 
Subjects 
Nr of  
AEs 
 
 
 
 
 
 
 
 
Arterial Thomboembolic Events (ATEs)* 
xx.x 
x 
xx.x 
x 
xx.x 
x 
Nonfatal myocardial infarction 
xx.x 
x 
xx.x 
x 
xx.x 
x 
Nonfatal stroke 
xx.x 
x 
xx.x 
x 
xx.x 
x 
Vascular death and death of unknown 
cause 
xx.x 
x 
xx.x 
x 
xx.x 
x 
 
 
 
 
 
 
 
* ATEs defined as nonfatal myocardial infarction, nonfatal stroke, vascular death and death of unknown cause 
AE: Adverse Event 
Note: Some patients may have experienced multiple events 


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Section 14.3.2 – Listings of deaths, other serious and significant adverse events 
Listings (Section 14.3.2) 
Listing 14.3.2-1 Deaths, by treatment 
Safety Set 
 
Site / Subject 
Number 
Age 
Sex 
Race 
Date of Last Dose 
(YYYY-MM-DD) 
Date of Death 
(YYYY-MM-DD) 
Study 
Day* 
Principal cause reported 
 
 
 
 
 
 
 
 
XXX / XXX-XX 
XX 
Male 
Caucasian 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
ABCD 
XXX / XXX-XX 
XX 
Female 
Asian 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
ABCD 
XXX / XXX-XX 
XX 
XX 
XX 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
ABCD 
XXX / XXX-XX 
XX 
XX 
XX 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
ABCD 
XXX / XXX-XX 
XX 
XX 
XX 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
ABCD 
XXX / XXX-XX 
XX 
XX 
XX 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
ABCD 
XXX / XXX-XX 
XX 
XX 
XX 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
ABCD 
XXX / XXX-XX 
XX 
XX 
XX 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
ABCD 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Relative to the first day of treatment (Baseline) 


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Listing 14.3.2-2 Serious adverse events, by treatment 
Safety Set 
 
Site / Subject 
Number 
Age /  
Sex /  
Race 
Adverse Event (REPORTED/  
Preferred /  
System Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study day 
End Date 
(YYYY-MM-DD) / 
Study day 
Duration 
(Days) 
Severity 
Relationship 
to Study 
Medication 
Action 
Taken 
 
 
 
 
 
 
 
 
 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mild 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mod 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Sev 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mild 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mod 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Sev 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mild 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mod 
susp 
X 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Relationship to study drug: Not susp=Not suspected, Susp=Suspected 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Study day is relative to the first day of treatment (Baseline) 


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Listing 14.3.2-3 Adverse events causing study drug discontinuation by treatment 
Safety Set 
 
Site / Subject 
Number 
Age /  
Sex /  
Race 
Adverse Event (REPORTED/  
Preferred /  
System Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study day 
End Date 
(YYYY-MM-DD) / 
Study day 
Duration 
(Days) 
Severity 
Relationship 
to Study 
Medication 
Action 
Taken 
 
 
 
 
 
 
 
 
 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mild 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mod 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Sev 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mild 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mod 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Sev 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mild 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mod 
susp 
X 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Relationship to study drug: Not susp=Not suspected, Susp=Suspected 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Study day is relative to the first day of treatment (Baseline) 


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Listing 14.3.2-4 Adverse events requiring interruption by treatment 
Safety Set 
 
Site / Subject 
Number 
Age /  
Sex /  
Race 
Adverse Event (REPORTED/  
Preferred /  
System Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study day 
End Date 
(YYYY-MM-DD) / 
Study day 
Duration 
(Days) 
Severity 
Relationship 
to Study 
Medication 
Action 
Taken 
 
 
 
 
 
 
 
 
 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mild 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mod 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Sev 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mild 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mod 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Sev 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mild 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD 
YYYY-MM-DD 
XX 
Mod 
susp 
X 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Relationship to study drug: Not susp=Not suspected, Susp=Suspected 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Study day is relative to the first day of treatment (Baseline) 
 


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Listing 14.3.2-5 Adverse events requiring significant additional therapy 
Safety Set 
 
Site / Subject 
Number 
Age /  
Sex /  
Race 
Adverse Event (REPORTED/  
Preferred /  
System Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study day 
End Date 
(YYYY-MM-DD) / 
Study day 
Duration 
(Days) 
Severity 
Relationship 
to Study 
Medication 
Action 
Taken 
 
 
 
 
 
 
 
 
 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD / 
X 
YYYY-MM-DD / 
X 
XX 
Mild 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD / 
X 
YYYY-MM-DD / 
X 
XX 
Mod 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD / 
X 
YYYY-MM-DD / 
X 
XX 
Sev 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD / 
X 
YYYY-MM-DD / 
X 
XX 
Mild 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD / 
X 
YYYY-MM-DD / 
X 
XX 
Mod 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD / 
X 
YYYY-MM-DD / 
X 
XX 
Sev 
susp 
X 
XXX / XXX-XX 
55/M/Ca 
ABCD / abcd / abcd 
YYYY-MM-DD / 
X 
YYYY-MM-DD / 
X 
XX 
Mild 
Not susp 
X 
XXX / XXX-XX 
76/F/As 
ABCD / abcd / abcd 
YYYY-MM-DD / 
X 
YYYY-MM-DD / 
X 
XX 
Mod 
susp 
X 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Relationship to study drug: Not susp=Not suspected, Susp=Suspected 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Study day is relative to the first day of treatment (Baseline) 
 


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Section 14.3.3 – Narratives of deaths, other serious and significant adverse events (non Biometric deliverables) 
No output 
Section 14.3.4 – Abnormal laboratory value listings 
Listings (Section 14.3.4) 
No output 


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Listings (Section 16.1.7) 
Listing 16.1.7-1 Randomized allocation to treatment 
All Enrolled 
 
Site 
Subject 
Number 
Age /  
Sex /  
Race 
Randomisation 
Number 
Treatment 
Randomisation Date  
(YYYY-MM-DD) /  
Study Day 
 
 
 
 
 
 
XXX 
XXX-XX 
55/M/Ca 
XXXX 
Intensive 
YYYY-MM-DD / X 
XXX 
XXX-XX 
76/F/As 
XXXX 
Relaxed 
YYYY-MM-DD / X 
XXX 
XXX-XX 
55/M/Ca 
XXXX 
Relaxed 
YYYY-MM-DD / X 
XXX 
XXX-XX 
76/F/As 
XXXX 
Intensive 
YYYY-MM-DD / X 
XXX 
XXX-XX 
55/M/Ca 
XXXX 
Intensive 
YYYY-MM-DD / X 
XXX 
XXX-XX 
76/F/As 
XXXX 
Intensive 
YYYY-MM-DD / X 
XXX 
XXX-XX 
55/M/Ca 
XXXX 
Relaxed 
YYYY-MM-DD / X 
XXX 
XXX-XX 
76/F/As 
XXXX 
Relaxed 
YYYY-MM-DD / X 
……. 
 
 
 
 
 
 
 
 
 
 
 
Note: Study day is relative to the first day of treatment (Baseline) 
 


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Section 16.1.9 – Documentation of statistical methods 
Tables (Section 16.1.9) 
No output 


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Section 16.2 – Patient data listings 
Section 16.2.1 – Discontinued patients 
Listing 16.2.1-1 Study phase completion by treatment 
Full Analysis Set 
 
Site / Subject 
Number 
Age / 
Sex / 
Race 
Study phase 
Last known date on study 
drug 
(YYYY-MM-DD) /  
Study Day 
Completed 
Primary 
reason  
Was 
treatment 
code 
revealed 
Date 
Revealed 
 
 
 
 
 
 
 
 
XXX / XXX-XX 
55/M/Ca 
Comparative 
YYYY-MM-DD / X 
Yes 
- 
No 
- 
XXX / XXX-XX 
76/F/As 
Comparative 
YYYY-MM-DD / X 
Yes 
- 
No 
- 
XXX / XXX-XX 
55/M/Ca 
Comparative 
YYYY-MM-DD / X 
No 
Abcd 
No 
- 
XXX / XXX-XX 
76/F/As 
Comparative 
YYYY-MM-DD / X 
Yes 
- 
No 
- 
XXX / XXX-XX 
55/M/Ca 
Comparative 
YYYY-MM-DD / X 
Yes 
- 
No 
- 
XXX / XXX-XX 
76/F/As 
Comparative 
YYYY-MM-DD / X 
Yes 
- 
No 
- 
XXX / XXX-XX 
55/M/Ca 
Comparative 
YYYY-MM-DD / X 
Yes 
- 
No 
- 
XXX / XXX-XX 
76/F/As 
Comparative 
YYYY-MM-DD / X 
Yes 
- 
No 
- 
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Study day is relative to the first day of treatment (Baseline) 


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Listing 16.2.1-2 Screened subjects discontinued from study prior to randomization 
All subjects 
 
Site / Subject 
Number 
Age / 
Sex / 
Race 
Date of Discontinuation 
(YYYY-MM-DD) 
Primary reason for 
discontinuation 
 
 
 
 
XXX / XXX-XX 
55/M/Ca 
YYYY-MM-DD 
Adverse Event 
XXX / XXX-XX 
76/F/As 
YYYY-MM-DD 
Lost to follow-up 
XXX / XXX-XX 
55/M/Ca 
YYYY-MM-DD 
Physician decision 
XXX / XXX-XX 
76/F/As 
YYYY-MM-DD 
Pregnancy 
XXX / XXX-XX 
55/M/Ca 
YYYY-MM-DD 
Screen failure 
XXX / XXX-XX 
76/F/As 
YYYY-MM-DD 
Study terminated by sponsor 
XXX / XXX-XX 
55/M/Ca 
YYYY-MM-DD 
Technical problems 
XXX / XXX-XX 
76/F/As 
YYYY-MM-DD 
Subject/guardian decision 
XXX / XXX-XX 
55/M/Ca 
YYYY-MM-DD 
Death 
……. 
 
 
 
 
 
 
 


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Section 16.2.2 – Protocol deviations 
Listing 16.2.2-1.1 
Protocol deviations by treatment 
Full Analysis Set 
 
 
Subject Number 
 
Any Protocol 
Deviation? 
 
Type of Deviation 
 
Date of 
Deviation 
(YYYY-MM-
DD) 
 
Visit 
 
Specify Deviation Details 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
XXX-XX 
Yes 
Inclusion criteria 
YYYY-MM-DD 
- 
ABCD 
XXX-XX 
Yes 
Exclusion criteria 
YYYY-MM-DD 
ABCD 
ABCD 
XXX-XX 
Yes 
Discontinuation of Treatment 
YYYY-MM-DD 
ABCD 
ABCD 
XXX-XX 
Yes 
Medication (includes excluded meds) 
YYYY-MM-DD 
ABCD 
ABCD 
XXX-XX 
Yes 
Others 
YYYY-MM-DD 
ABCD 
ABCD 
XXX-XX 
No 
- 
- 
- 
- 
 
 
 
 
 
 
Relaxed 
 
 
 
 
XXX-XX 
Yes 
Exclusion criteria 
YYYY-MM-DD 
- 
ABCD 
XXX-XX 
Yes 
Discontinuation of Treatment 
YYYY-MM-DD 
ABCD 
ABCD 
XXX-XX 
Yes 
Medication (includes excluded meds) 
YYYY-MM-DD 
ABCD 
ABCD 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 16.2.3 – Patients excluded from the efficacy analysis 
Listing 16.2.3-1 Patients excluded from Per-Protocol efficacy analysis by treatment 
Full Analysis Set 
 
 
Subject Number 
Reason for Exclusion from Per-Protocol 
Efficacy Analysis 
 
 
Intensive 
 
XXX-XX 
xxxxxxxxxxxxxxxxx 
XXX-XX 
xxxxxxxxxxxxxxxxx 
XXX-XX 
xxxxxxxxxxxxxxxxx 
XXX-XX 
xxxxxxxxxxxxxxxxx 
XXX-XX 
xxxxxxxxxxxxxxxxx 
XXX-XX 
xxxxxxxxxxxxxxxxx 
 
 
Relaxed 
 
XXX-XX 
xxxxxxxxxxxxxxxxx 
XXX-XX 
xxxxxxxxxxxxxxxxx 
XXX-XX 
xxxxxxxxxxxxxxxxx 
 
 
 
 


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Section 16.2.4 – Demographic data 
Listing 16.2.4-1 Patient Disposition 
Randomised Set 
 
Subject Number 
Informed 
Consent Date 
(YYYY-MM-DD) 
Did the patient 
complete the 
study? 
Date of 
Withdrawal  
(YYYY-MM-DD) 
Date of 
Completion 
(YYYY-MM-DD) 
Reason for Treatment Termination 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
XXX-XX 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
YYYY-MM-DD 
ABCD 
XXX-XX 
YYYY-MM-DD 
No 
YYYY-MM-DD 
- 
ABCD 
XXX-XX 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
YYYY-MM-DD 
ABCD 
XXX-XX 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
YYYY-MM-DD 
ABCD 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
XXX-XX 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
YYYY-MM-DD 
ABCD 
XXX-XX 
YYYY-MM-DD 
No 
YYYY-MM-DD 
YYYY-MM-DD 
ABCD 
XXX-XX 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
YYYY-MM-DD 
ABCD 
XXX-XX 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
YYYY-MM-DD 
ABCD 
 
 
 
 
 
 
  


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Listing 16.2.4-2 Eligibility Criteria 
Randomised Set 
 
Subject Number 
Has the patient met all 
Inclusion Criteria? 
Has the patient met all Exclusion 
Criteria? 
 
 
 
Intensive 
 
 
XXX-XX 
Yes 
Yes 
XXX-XX 
No: Inc 1 
No: Exc 1 
XXX-XX 
Yes 
Yes 
XXX-XX 
No: Inc 2 
No: Exc 2 
 
 
 
Relaxed 
 
 
XXX-XX 
Yes 
Yes 
XXX-XX 
No: Inc 3 
No: Exc 3 
XXX-XX 
Yes 
Yes 
XXX-XX 
No: Inc 4 
No: Exc 4 
 
 
 
  


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Listing 16.2.4-3 Patient demographics by treatment 
Randomised Set 
 
 
Subject Number 
 
 
Gender 
Child-bearing 
Potential 
 
Date of Birth 
 
Age* 
 
Predominant Race 
 
Ethnicity 
 
 
 
 
 
 
 
Intensive 
 
 
 
XXX-XX 
Female 
Able to bear children 
YYYY-MM-DD 
XX 
Caucasian 
Anglo Saxon 
XXX-XX 
Male 
- 
YYYY-MM-DD 
XX 
Black African 
Northern European 
XXX-XX 
Female 
Post Menopausal 
YYYY-MM-DD 
XX 
Asian 
Southern European 
XXX-XX 
Female 
Sterile - of child 
bearing age 
YYYY-MM-DD 
XX 
Caucasian 
Asian Indian 
XXX-XX 
Male 
- 
YYYY-MM-DD 
XX 
Other: xxxxxx 
Other: xxxxxx 
………. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
XXX-XX 
Female 
 
YYYY-MM-DD 
XX 
Caucasian 
Anglo Saxon 
XXX-XX 
Male 
 
YYYY-MM-DD 
XX 
Black African 
Northern European 
XXX-XX 
Female 
 
YYYY-MM-DD 
XX 
Asian 
Southern European 
XXX-XX 
Female 
 
YYYY-MM-DD 
XX 
Caucasian 
Asian Indian 
XXX-XX 
Male 
 
YYYY-MM-DD 
XX 
Black African 
Other: xxxxxx 
………. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.4-4 Patient demographic questions by treatment 
Randomised Set 
 
 
Subject 
Number 
 
Family 
History of 
AMD 
Is yes, was it a first 
degree relative? 
Ever smoked 
cigarettes, pipes or 
cigars 
If the participant smoked in 
the past, when did the 
participant stop smoking? 
 
 
 
 
 
Intensive 
 
 
 
 
XXX-XX 
Yes 
Yes 
Never smoked 
- 
XXX-XX 
Yes 
No 
Smoked in the past 
One year ago or less 
XXX-XX 
Yes 
Yes 
Current smoker 
- 
XXX-XX 
Yes 
No 
Never smoked 
- 
XXX-XX 
Yes 
Yes 
Smoked in the past 
More than one year ago 
………. 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
XXX-XX 
No 
- 
Never smoked 
- 
XXX-XX 
No 
- 
Smoked in the past 
One year ago or less 
XXX-XX 
No 
- 
Current smoker 
- 
XXX-XX 
No 
- 
Never smoked 
- 
XXX-XX 
No 
- 
Smoked in the past 
More than one year ago 
………. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.4-5 Relevant medical history and current medical conditions by treatment 
Randomised Set 
 
 
Subject 
Number 
 
MH 
No 
History Condition 
(REPORTED / Preferred / System 
Organ Class) 
Site 
 
Date of Diagnosis 
(YYYY-MM-DD) 
 
Ongoing? 
 
 
 
 
 
 
Intensive 
 
 
 
XXX-XX 
1 
ABCD  / Acbd / Acbd 
Left eye 
YYYY-MM-DD 
Yes/No 
 
2 
ABCD  / Acbd / Acbd 
Non-ocular 
YYYY-MM-DD 
Yes/No 
 
3 
ABCD  / Acbd / Acbd 
Right eye 
YYYY-MM-DD 
Yes/No 
 
4 
ABCD  / Acbd / Acbd 
Non-ocular 
YYYY-MM-DD 
Yes/No 
XXX-XX 
1 
ABCD  / Acbd / Acbd 
Both eyes 
YYYY-MM-DD 
Yes/No 
……… 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
XXX-XX 
1 
ABCD  / Acbd / Acbd 
Left eye 
YYYY-MM-DD 
Yes/No 
 
2 
ABCD  / Acbd / Acbd 
Non-ocular 
YYYY-MM-DD 
Yes/No 
 
3 
ABCD  / Acbd / Acbd 
Right eye 
YYYY-MM-DD 
Yes/No 
 
4 
ABCD  / Acbd / Acbd 
Non-ocular 
YYYY-MM-DD 
Yes/No 
XXX-XX 
1 
ABCD  / Acbd / Acbd 
Both eyes 
YYYY-MM-DD 
Yes/No 
……… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NK: Not Known; MH No: Medical History Number 
 


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Listing 16.2.4-6 AMD Treatment History (STUDY eye) 
Randomised Set 
 
 
Subject 
Number 
 
FELLOW 
Eye 
Was any treatment 
ever given to the 
fellow eye prior to 
Screening? 
Treatment 
Dose 
Start date of 
treatment 
(YYYY-MM-DD) 
Stop date of 
treatment 
(YYYY-MM-DD) 
Ongoing 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
XXX-XX 
Left 
Yes 
Lucentis 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
XXX-XX 
Right 
Yes 
Eylea 
XX unit 
YYYY-MM-DD 
- 
Yes 
XXX-XX 
Left 
Yes 
Visudyne 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
 
 
 
Avastin 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
XXX-XX 
Left 
No 
- 
- 
- 
- 
- 
……… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
 
 
XXX-XX 
Left 
Yes 
Lucentis 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
XXX-XX 
Right 
Yes 
Eylea 
XX unit 
YYYY-MM-DD 
- 
Yes 
XXX-XX 
Left 
Yes 
Steroids 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
 
 
 
Other 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
XXX-XX 
Left 
No 
- 
- 
- 
- 
- 
……… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NK: Not Known; MH No: Medical History Number 


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Listing 16.2.4-7 AMD Treatment History (FELLOW eye) 
Randomised Set 
 
 
Subject 
Number 
 
FELLOW 
Eye 
Was any treatment 
ever given to the 
fellow eye prior to 
Screening? 
Treatment 
Dose 
Start date of 
treatment 
(YYYY-MM-DD) 
Stop date of 
treatment 
(YYYY-MM-DD) 
Ongoing 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
XXX-XX 
Left 
Yes 
Lucentis 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
XXX-XX 
Right 
Yes 
Eylea 
XX unit 
YYYY-MM-DD 
- 
Yes 
XXX-XX 
Left 
Yes 
Visudyne 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
 
 
 
Avastin 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
XXX-XX 
Left 
No 
- 
- 
- 
- 
- 
……… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
 
 
XXX-XX 
Left 
Yes 
Lucentis 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
XXX-XX 
Right 
Yes 
Eylea 
XX unit 
YYYY-MM-DD 
- 
Yes 
XXX-XX 
Left 
Yes 
Steroids 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
 
 
 
Other 
XX unit 
YYYY-MM-DD 
YYYY-MM-DD 
- 
XXX-XX 
Left 
No 
- 
- 
- 
- 
- 
……… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NK: Not Known; MH No: Medical History Number 


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Listing 16.2.4-8 AMD Treatment at Baseline 
Randomised Set 
 
 
Subject 
Number 
 
Treatment at Baseline 
EYE 
Date of diagnosis of active CNV 
due to wet AMD (YYYY-MM-DD) 
Type of CNV 
Location 
CNV 
classification 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
XXX-XX 
Two treatment naïve eyes 
STUDY – Right 
YYYY-MM-DD 
Subfoveal 
Occult 
 
 
FELLOW - Left 
YYYY-MM-DD 
Juxtafoveal 
Predominantly 
classic 
XXX-XX 
One eye (fellow eye) being treated 
with ranibizumab 
STUDY – Right 
YYYY-MM-DD 
Extrafoveal 
Minimally classic 
 
 
FELLOW - Left 
YYYY-MM-DD 
Note evaluable 
PCV 
XXX-XX 
One eye (fellow eye) being treated 
with anti-VEGF other than 
ranibizumab 
STUDY – Right 
YYYY-MM-DD 
Subfoveal 
RAP 
 
 
FELLOW - Left 
YYYY-MM-DD 
Juxtafoveal 
Note evaluable 
XXX-XX 
Two treatment naïve eyes 
STUDY – Right 
YYYY-MM-DD 
Extrafoveal 
Occult 
 
 
FELLOW - Left 
YYYY-MM-DD 
Note evaluable 
Predominantly 
classic 
……… 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
XXX-XX 
Two treatment naïve eyes 
STUDY – Right 
YYYY-MM-DD 
Subfoveal 
Occult 
 
 
FELLOW - Left 
YYYY-MM-DD 
Juxtafoveal 
Predominantly 
classic 
XXX-XX 
One eye (fellow eye) being treated 
with ranibizumab 
STUDY – Right 
YYYY-MM-DD 
Extrafoveal 
Minimally classic 
 
 
FELLOW - Left 
YYYY-MM-DD 
Note evaluable 
PCV 
……… 
 
 
 
 
 
 
 
 
 
 
 
NK: Not Known; MH No: Medical History Number 


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Section 16.2.5  
Compliance and/or drug concentration data  
Listing 16.2.5-1 Dose administration record by treatment (STUDY eye) 
Safety Set 
 
 
Subject 
Number 
 
Visit 
Was Study Drug 
Administered? 
Date of dosing  
(YYYY-MM-DD) 
Total dose 
administered 
(mg) 
STUDY eye 
treated 
Batch number 
 
 
 
 
 
 
 
XXX-XX 
Baseline 
Yes 
YYYY-MM-DD 
XX 
Left eye 
XXXXXXX 
 
Week n 
Yes 
YYYY-MM-DD 
XX 
Left eye 
Not available 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
Baseline 
Yes 
YYYY-MM-DD 
XX 
Right eye 
XXXXXXX 
 
Week n 
No: xxxxxxx 
- 
- 
- 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                           


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Listing 16.2.5-2 Dose administration record by treatment (FELLOW eye) 
Safety Set 
 
 
Subject 
Number 
 
Visit 
Was treatment 
for FELLOW 
eye given? 
FELLOW eye 
treated 
Date of dosing  
(YYYY-MM-DD) 
Treatment for wet AMD to 
fellow eye 
Total dose 
administered  
 
 
 
 
 
 
 
XXX-XX 
Baseline 
Yes 
Left eye 
YYYY-MM-DD 
xxxxxxxxxxxxx 
XX units 
 
Week n 
Yes 
Left eye 
YYYY-MM-DD 
Not xxxxxxxxxxxxx 
XX units 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
Baseline 
Yes 
Right eye 
YYYY-MM-DD 
xxxxxxxxxxxxx 
XX units 
 
Week n 
No 
- 
- 
 
- 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                           
 


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Listing 16.2.5-3 Medications and significant non-drug therapies prior to start of study drug by treatment 
Randomised Set 
 
 
Subject 
Number 
 
CM 
No 
Concomitant Medication 
(REPORTED / Preferred) 
Reason 
 
 
 
 
Intensive 
 
XXX-XX 
1 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
 
2 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
 
3 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
 
4 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
XXX-XX 
1 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
……… 
 
 
 
 
 
 
 
Relaxed 
 
XXX-XX 
1 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
 
2 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
 
3 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
 
4 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
XXX-XX 
1 
ABCD  / Acbd 
xxxxxxxxxxxxxxxx 
……… 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.5-4 Medications and significant non-drug therapies after start of study drug by treatment 
Full Analysis Set 
 
 
Subject 
Number 
 
CM 
No 
Concomitant Medication 
(REPORTED / Preferred) 
Start Date 
(YYYY-MM-DD) 
Stop Date 
(YYYY-MM-DD) 
Reason 
 
 
 
 
 
 
Intensive 
 
 
 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
2 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
3 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
4 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
……… 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
2 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
3 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
4 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
……… 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.5-5 Medications and significant non-drug therapies after start of study drug by treatment (STUDY EYE) 
Full Analysis Set 
 
 
Subject 
Number 
 
CM 
No 
Concomitant Medication 
(REPORTED / Preferred) 
Start Date 
(YYYY-MM-DD) 
Stop Date 
(YYYY-MM-DD) 
Reason 
 
 
 
 
 
 
Intensive 
 
 
 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
2 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
3 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
4 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
……… 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
2 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
3 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
4 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
……… 
 
 
 
 
 
 
 
 
 
 
 
NOTE: Includes all ocular medications administered to the STUDY eye only. 
 


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Listing 16.2.5-6 Medications and significant non-drug therapies after start of study drug by treatment (FELLOW EYE) 
Full Analysis Set 
 
 
Subject 
Number 
 
CM 
No 
Concomitant Medication 
(REPORTED / Preferred) 
Start Date 
(YYYY-MM-DD) 
Stop Date 
(YYYY-MM-DD) 
Reason 
 
 
 
 
 
 
Intensive 
 
 
 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
2 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
3 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
4 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
……… 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
2 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
3 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
 
4 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
XXX-XX 
1 
ABCD  / Acbd 
YYYY-MM-DD 
YYYY-MM-DD 
xxxxxxxxxxxxxxxx 
……… 
 
 
 
 
 
 
 
 
 
 
 
NOTE: Includes all ocular medications administered to the FELLOW eye only. 
 


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Section 16.2.6 – Individual efficacy response data and other non-safety data  
Listing 16.2.6-1 CF/FA/AF by treatment (STUDY EYE) (CRF Data) 
Full Analysis Set 
 
Subject 
Number 
Visit 
STUDY 
eye 
assessed 
Was CF 
Performed? 
Date CF 
performed 
(YYYY-MM-DD) 
Was FA 
Performed? 
Date FA 
performed 
(YYYY-MM-
DD) 
Presence of 
Retinal 
Haemorrhage 
Was AF 
Performed? 
Date AF 
performed 
(YYYY-MM-
DD) 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Left 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Yes 
Yes 
YYYY-MM-DD 
 
ABCD 
Left 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
No 
Yes 
YYYY-MM-DD 
 
ABCD 
Left 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Evaluable 
Yes 
YYYY-MM-DD 
 
ABCD 
Left 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Yes 
Yes 
YYYY-MM-DD 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Right 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Yes 
Yes 
YYYY-MM-DD 
 
ABCD 
Right 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
No 
Yes 
YYYY-MM-DD 
 
ABCD 
Right 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Evaluable 
Yes 
YYYY-MM-DD 
 
ABCD 
Right 
No 
YYYY-MM-DD 
No 
YYYY-MM-DD 
Yes 
No 
YYYY-MM-DD 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
 
 
AF: Autofluorescence, CF: Colour Fundus Photography, FA: Fluorescein Angiography 


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Listing 16.2.6-2 CF/FA/AF by treatment (FELLOW EYE) 
Full Analysis Set 
 
Subject 
Number 
Visit 
FELLOW 
eye 
assessed 
Was CF 
Performed? 
Date CF 
performed 
(YYYY-MM-DD) 
Was FA 
Performed? 
Date FA 
performed 
(YYYY-MM-
DD) 
Presence of 
Retinal 
Haemorrhage 
Was AF 
Performed? 
Date AF 
performed 
(YYYY-MM-
DD) 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Left 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Yes 
Yes 
YYYY-MM-DD 
 
ABCD 
Left 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
No 
Yes 
YYYY-MM-DD 
 
ABCD 
Left 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Evaluable 
Yes 
YYYY-MM-DD 
 
ABCD 
Left 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Yes 
Yes 
YYYY-MM-DD 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Right 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Yes 
Yes 
YYYY-MM-DD 
 
ABCD 
Right 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
No 
Yes 
YYYY-MM-DD 
 
ABCD 
Right 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
Evaluable 
Yes 
YYYY-MM-DD 
 
ABCD 
Right 
No 
YYYY-MM-DD 
No 
YYYY-MM-DD 
Yes 
No 
YYYY-MM-DD 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
 
 
AF: Autofluorescence, CF: Colour Fundus Photography, FA: Fluorescein Angiography 


Novartis 
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Listing 16.2.6-3 Fluorescein Angiography Assessments by treatment (STUDY EYE) (Central Reading Center Data) 
Full Analysis Set 
 
Subject 
Number 
Visit 
STUDY eye 
assessed 
Parameter 
Result 
 
 
 
 
 
Intensive 
 
 
 
 
XXX-XX 
ABCD 
Left 
Lesion leakage present 
Yes 
 
 
 
Lesions components* 
CNV, blood 
 
 
 
Type of lesion 
Occult 
 
 
 
Location of lesion 
Subfoveal 
 
 
 
CNV present 
Yes 
 
 
 
CNV Location 
Subfoveal 
 
 
 
CNV leakage present 
Yes 
 
 
 
Area of lesion (mm2) 
xx 
 
 
 
Area of CNV (mm2) 
xx 
 
 
 
Geographic Atrophy present 
Yes 
………….. 
 
 
Location of Geographic Atrophy 
Outer Subfield 
 
 
 
Total area of Geographic Atrophy within ETDRS grid 
xx 
Relaxed 
 
 
 
 
………….. 
 
 
 
 


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Listing 16.2.6-4 Colour Fundus Assessments by treatment (STUDY EYE) (Central Reading Center Data) 
Full Analysis Set 
 
Subject 
Number 
Visit 
STUDY eye 
assessed 
Parameter 
Result 
 
 
 
 
 
Intensive 
 
 
 
 
XXX-XX 
ABCD 
Left 
Haemorrhage present 
Yes 
 
 
 
Haemorrhage location 
Central subfield 
 
 
 
Retinal Abnormalities present 
Yes: Drusen 
 
 
 
Retinal Abnormalities Location 
Central 
 
 
 
Retinal Abnormalities Type 
Inflammation 
 
 
 
 
 
 
…….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
………….. 
 
 
 
 


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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Listing 16.2.6-5 Visual Acuity by Treatment (STUDY EYE) 
Full Analysis Set and Per-Protocol 
 
Subject 
Number 
Visit 
Was VA 
Performed? 
Date VA 
performed 
(YYYY-MM-DD) 
Was 
Refraction 
Performed? 
STUDY Eye 
Assessed 
EDTRS chart 
used for 3 
metres lane? 
Total BCVA 
score 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
XXX-XX 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Left eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Left eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Left eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Left eye 
Yes/No 
XX 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Right eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Right eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Right eye 
Yes/No 
XX 
 
ABCD 
Not Done: 
specify 
- 
- 
- 
- 
- 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VA: Visual Acuity, BCVA: Best Corrective Visual Acuity 


Novartis 
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Listing 16.2.6-6 Visual Acuity by Treatment (FELLOW EYE) 
Full Analysis Set 
 
Subject 
Number 
Visit 
Was VA 
Performed? 
Date VA 
performed 
(YYYY-MM-DD) 
Was 
Refraction 
Performed? 
FELLOW 
Eye 
Assessed 
EDTRS chart 
used for 3 
metres lane? 
Total BCVA 
score 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
XXX-XX 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Left eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Left eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Left eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Left eye 
Yes/No 
XX 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Right eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Right eye 
Yes/No 
XX 
 
ABCD 
Yes 
YYYY-MM-DD 
Yes/No 
Right eye 
Yes/No 
XX 
 
ABCD 
Not Done: 
specify 
- 
- 
- 
- 
- 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VA: Visual Acuity, BCVA: Best Corrective Visual Acuity 


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Confidential 
Page 202 
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Listing 16.2.6-7 Optical Coherence Tomography (OCT) by Treatment (STUDY EYE) (CRF Data) 
Full Analysis Set 
 
Subject 
Number 
Visit 
Was 
OCT 
Performe
d? 
Date OCT 
performed 
(YYYY-MM-
DD) 
STUDY 
Eye 
Type of OCT 
(Including subtype if 
high 
definition/spectral 
domain OCT) 
Presence 
of intra-
retinal fluid 
Compared 
to previous 
intra-retinal 
assessment 
Presence of 
sub-retinal 
fluid 
Compared 
to previous 
sub-retinal 
assessmen
t 
>200μm 
height or 
SRF at 
foveal centre 
 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes 
YYYY-MM-DD 
Left 
eye 
Other: Time domain 
Present 
- 
Present 
- 
Yes 
 
ABCD 
Yes 
YYYY-MM-DD 
Left 
eye 
Other: Time domain 
Present 
No change 
Present 
No change 
No 
 
ABCD 
Yes 
YYYY-MM-DD 
Left 
eye 
Other: Time domain 
Absence 
Improved  
Absence 
Improved  
Yes 
 
ABCD 
Yes 
YYYY-MM-DD 
Left 
eye 
Other: Time domain 
Present 
Worse 
Present 
Worse 
No 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes 
YYYY-MM-DD 
Right 
eye 
High definition / 
spectral domain: 
Cirrus 
Present 
- 
Present 
- 
Yes 
 
ABCD 
Yes 
YYYY-MM-DD 
Right 
eye 
High definition / 
spectral domain: 
Cirrus 
Absent 
Improved 
Absent 
Improved 
No 
 
ABCD 
Yes 
YYYY-MM-DD 
Right 
eye 
High definition / 
spectral domain: 
Cirrus 
Can’t 
grade 
- 
Can’t grade 
- 
Yes 
 
ABCD 
Not 
Done: 
specify 
- 
- 
- 
- 
- 
- 
- 
- 
………….. 
 
 
 
 
 
 
 
 
 
 
OCT: Optical Coherence Tomography, SRF: Sub-retinal fluid 


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Confidential 
Page 203 
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Listing 16.2.6-8 Optical Coherence Tomography (OCT) by Treatment (FELLOW EYE) (CRF Data) 
Full Analysis Set 
 
Subject 
Number 
Visit 
Was 
OCT 
Performe
d? 
Date OCT 
performed 
(YYYY-MM-
DD) 
FELLO
W 
 Eye 
Type of OCT 
(Including subtype if 
high 
definition/spectral 
domain OCT) 
Presence 
of intra-
retinal fluid 
Compared 
to previous 
intra-retinal 
assessment 
Presence of 
sub-retinal 
fluid 
Compared 
to previous 
sub-retinal 
assessmen
t 
>200μm 
height or 
SRF at 
foveal centre 
 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes 
YYYY-MM-DD 
Left 
eye 
Other: Time domain 
Present 
- 
Present 
- 
Yes 
 
ABCD 
Yes 
YYYY-MM-DD 
Left 
eye 
Other: Time domain 
Present 
No change 
Present 
No change 
No 
 
ABCD 
Yes 
YYYY-MM-DD 
Left 
eye 
Other: Time domain 
Absence 
Improved  
Absence 
Improved  
Yes 
 
ABCD 
Yes 
YYYY-MM-DD 
Left 
eye 
Other: Time domain 
Present 
Worse 
Present 
Worse 
No 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes 
YYYY-MM-DD 
Right 
eye 
High definition / 
spectral domain: 
Cirrus 
Present 
- 
Present 
- 
Yes 
 
ABCD 
Yes 
YYYY-MM-DD 
Right 
eye 
High definition / 
spectral domain: 
Cirrus 
Absent 
Improved 
Absent 
Improved 
No 
 
ABCD 
Yes 
YYYY-MM-DD 
Right 
eye 
High definition / 
spectral domain: 
Cirrus 
Can’t 
grade 
- 
Can’t grade 
- 
Yes 
 
ABCD 
Not 
Done: 
specify 
- 
- 
- 
- 
- 
- 
- 
- 
………….. 
 
 
 
 
 
 
 
 
 
 
OCT: Optical Coherence Tomography, SRF: Sub-retinal fluid 


Novartis 
Confidential 
Page 204 
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Listing 16.2.6-9 Optical Coherence Tomography (OCT) by treatment (STUDY EYE) (Central Reading Center Data) 
Full Analysis Set 
 
Subject 
Number 
Visit 
STUDY eye 
assessed 
Parameter 
Result 
Comments 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
XXX-XX 
ABCD 
Left 
Central Subfield Foveal Thickness 
xx 
ABCD 
 
 
 
Central Subfield Volume 
xx 
 
 
 
 
Cysts Present? 
Yes 
 
 
 
 
Cyst(s) involving central macula 
Yes 
 
 
 
 
Cysts: Thickness at Center Point 
xx 
 
 
 
 
Vitreomacular traction present 
Yes 
 
 
…….. 
 
Subretinal fluid (within 6x6mm scan) present 
Yes 
 
 
 
 
Intraretinal fluid present 
No 
 
 
 
 
Vitreoretinal Abnormalities 
No 
 
 
 
 
Type of OCT 
HD 
 
 
 
 
GA Measurement* 
xx 
 
 
 
 
Subfoveal SRF (at centrepoint) present** 
Yes 
 
 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
………….. 
 
 
 
 
 
* Where allowable by imaging equipment at site 
** For the relaxed arm, if “Yes”, height “> 200um” or “= or <200um” 


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Page 205 
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Listing 16.2.6-10 
Genotyping Sampling 
Full Analysis Set 
 
Subject 
Number 
Consent 
provided for 
genotyping 
sample 
collection? 
Date of consent 
specific to 
genotyping 
(YYYY-MM-DD) 
Was genotyping 
sample taken? 
Date genotyping 
sample collected 
(YYYY-MM-DD) 
Sample 
Number 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
XXX-XX 
Yes  
YYYY-MM-DD 
Yes  
YYYY-MM-DD 
XXXXXX 
XXX-XX 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
XXXXXX 
XXX-XX 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
XXXXXX 
XXX-XX 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
XXXXXX 
XXX-XX 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
XXXXXX 
XXX-XX 
Yes 
YYYY-MM-DD 
No 
- 
- 
XXX-XX 
Yes 
YYYY-MM-DD 
Yes 
YYYY-MM-DD 
XXXXXX 
………….. 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
 
 
 
 


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Confidential 
Page 206 
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Listing 16.2.6-11 
Genotyping SNPs 
Full Analysis Set 
 
Subject 
Number 
rsXXXXXXXX 
rsXXXXXXXX 
rsXXXXXXXX 
rsXXXXXXXX 
rsXXXXXXXX 
rsXXXXXXXX 
rsXXXXXXXX 
rsXXXXXXXX 
rsXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XXX-XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XXX-XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XXX-XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XXX-XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XXX-XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XXX-XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 207 
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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Section 16.2.7 – Adverse event listings 
Listing 16.2.7-1 Adverse events 
Safety Set 
 
Subject 
Number 
AE 
No 
Adverse Event 
(REPORTED / 
Preferred / System 
Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study Day 
Stop Date 
(YYYY-MM-DD) / 
Study Day 
Duration 
(Days) 
Site 
Severity 
Action Taken 
Relation to 
Study Drug 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Non-
Ocular 
Mild 
ABCD 
Not susp 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
 
 
 
 
 
 
 
 
 
 
NK: Not Known; AE No = Adverse Number                                                                                           
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Relationship to study drug: Not susp=Not suspected, Susp=Suspected 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Day is relative to the first day of treatment (day 1) 


Novartis 
Confidential 
Page 208 
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CRFB002AAU15/RFB002/Ranibizumab 
 
 
Listing 16.2.7-2 Ocular adverse events 
Safety Set 
 
Subject 
Number 
AE 
No 
Adverse Event 
(REPORTED / 
Preferred / System 
Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study Day 
Stop Date 
(YYYY-MM-DD) / 
Study Day 
Duration 
Site 
Severity 
Action Taken 
Relation to 
Study Drug 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Non-
Ocular 
Mild 
ABCD 
Not susp 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
 
 
 
 
 
 
 
 
 
 
NK: Not Known; AE No = Adverse Number                                                                                           
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Relationship to study drug: Not susp=Not suspected, Susp=Suspected 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Day is relative to the first day of treatment (day 1) 


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Confidential 
Page 209 
MAP Module 7.1 
 
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Listing 16.2.7-3 Adverse events suspect to be related to study drug and/or ocular injection 
Safety Set 
 
Subject 
Number 
AE 
No 
Adverse Event 
(REPORTED / 
Preferred / System 
Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study Day 
Stop Date 
(YYYY-MM-DD) / 
Study Day 
Duration 
Site 
Severity 
Action Taken 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Non-
Ocular 
Mild 
ABCD 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
 
 
 
 
 
 
 
 
 
NK: Not Known; AE No = Adverse Number                                                                                           
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Day is relative to the first day of treatment (day 1) 


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Confidential 
Page 210 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
Listing 16.2.7-4 Serious adverse events 
Safety Set 
 
Subject 
Number 
AE 
No 
Adverse Event 
(REPORTED / 
Preferred / System 
Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study Day 
Stop Date 
(YYYY-MM-DD) / 
Study Day 
Duration 
Site 
Severity 
Action Taken 
Relation to 
Study Drug 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Non-
Ocular 
Mild 
ABCD 
Not susp 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
 
 
 
 
 
 
 
 
 
 
NK: Not Known; AE No = Adverse Number                                                                                           
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Relationship to study drug: Not susp=Not suspected, Susp=Suspected 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Day is relative to the first day of treatment (day 1) 


Novartis 
Confidential 
Page 211 
MAP Module 7.1 
 
CRFB002AAU15/RFB002/Ranibizumab 
 
 
Listing 16.2.7-5 Adverse events leading to treatment withdrawal 
Safety Set 
 
Subject 
Number 
AE 
No 
Adverse Event 
(REPORTED / 
Preferred / System 
Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study Day 
Stop Date 
(YYYY-MM-DD) / 
Study Day 
Duration 
Site 
Severity 
Action Taken 
Relation to 
Study Drug 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Non-
Ocular 
Mild 
ABCD 
Not susp 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
 
 
 
 
 
 
 
 
 
 
NK: Not Known; AE No = Adverse Number                                                                                           
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Relationship to study drug: Not susp=Not suspected, Susp=Suspected 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Day is relative to the first day of treatment (day 1) 


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Listing 16.2.7-6 Adverse events leading to treatment interruption 
Safety Set 
 
Subject 
Number 
AE 
No 
Adverse Event 
(REPORTED / 
Preferred / System 
Organ Class) 
Start Date 
(YYYY-MM-DD) / 
Study Day 
Stop Date 
(YYYY-MM-DD) / 
Study Day 
Duration 
Site 
Severity 
Action Taken 
Relation to 
Study Drug 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Non-
Ocular 
Mild 
ABCD 
Not susp 
 
 
 
 
 
 
 
 
 
 
Intensive 
 
 
 
 
 
 
 
 
 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Left 
Mild 
ABCD 
Susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Right 
Mod 
ABCD 
Not susp 
XXX-XX 
X 
ABCD 
YYYY-MM-DD / X 
YYYY-MM-DD / X 
X 
Both 
Sev 
ABCD 
Susp 
 
 
 
 
 
 
 
 
 
 
NK: Not Known; AE No = Adverse Number                                                                                           
Severity: Mild=Mild, Mod=Moderate, Sev=Severe 
Relationship to study drug: Not susp=Not suspected, Susp=Suspected 
Action taken: 1=Study drug dosage adjusted/temporarily interrupted, 2=Study drug permanently discontinued due to this AE 
                      3=Concomitant medication taken, 4=Non-drug therapy given, 5=Hospitalization/Prolonged hospitalization 
Note: Day is relative to the first day of treatment (day 1) 


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Section 16.2.8 – Laboratory measurements 
 
No output 


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Section 16.2.9 – Vital signs, physical findings and other observations related to safety listings 
Listing 16.2.9-1 Vital signs by treatment 
Safety Set 
 
Subject 
Number 
Visit 
Were Vital Signs 
Performed? 
Date of Vital Signs 
Assessment 
(YYYY-MM-DD) 
Systolic Blood 
Pressure 
 (mmHg)* 
Diastolic Blood 
Pressure 
 (mmHg)* 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXH 
XXX 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXX 
XXX 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXXL 
XXX 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXX 
XXX 
………….. 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
ABCD 
Yes/No 
YYYY-MM-DD 
XXX 
XXX 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXX 
XXX 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXX 
XXX 
 
ABCD 
Yes/No 
YYYY-MM-DD 
XXX 
XXX 
………….. 
 
 
 
 
 
*Flags: H=High (Systolic - >180 and increase from baseline of >20, Diastolic - >105 and increase from baseline of >15) 
L=Low (Systolic - <90 and decrease from baseline of >20, Diastolic - <50 and decrease from baseline of >15)  


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Listing 16.2.9-2 Ophthalmic Examinations by treatment (STUDY EYE) 
Safety Set 
 
Subject 
Number 
Visit 
Was OE 
Performed? 
Date OE 
performed 
(YYYY-MM-DD) 
STUDY 
Eye 
assessed 
IOP 
(mmHg) 
Examination 
Result 
 
 
 
 
 
 
 
 
XXX-XX 
Screening 
Yes 
YYYY-MM-DD 
Left eye 
XX 
Cornea 
Iris 
Vitreous 
Disc 
Retina other than AMD 
Lens 
  
Normal 
Abnormal 
Abnormal 
Normal 
Abnormal  
Phakic 
 
 
Baseline 
Yes 
YYYY-MM-DD 
Left eye 
XX 
Changes since previous assessment?  
Cornea 
Iris 
Vitreous 
Disc 
Retina other than AMD 
Lens 
AREDS – Nuclear Sclerosis 
AREDS – Cortical 
AREDS – PSC  
Yes: xxxxxxxx 
Normal 
Abnormal 
Abnormal 
Normal 
Abnormal  
Aphakic 
<2 
>2 
>2 
 
Week n 
Yes 
YYYY-MM-DD 
Left eye 
XX 
…………. 
…………. 
 
Week n 
Yes 
YYYY-MM-DD 
Left eye 
XX 
…………. 
…………. 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
………….. 
 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
OE: Ophthalmic Examination, IOP: Intra Ocular Pressure 


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Listing 16.2.9-3 Ophthalmic Examinations by treatment (FELLOW EYE) 
Safety Set 
 
Subject 
Number 
Visit 
Was OE 
Performed? 
Date OE 
performed 
(YYYY-MM-DD) 
FELLOW 
Eye 
assessed 
IOP 
(mmHg) 
Examination 
Result 
 
 
 
 
 
 
 
 
XXX-XX 
Screening 
Yes 
YYYY-MM-DD 
Left eye 
XX 
Cornea 
Iris 
Vitreous 
Disc 
Retina other than AMD 
Lens 
  
Normal 
Not done 
Abnormal 
Normal 
Abnormal  
Normal 
 
 
Baseline 
Yes 
YYYY-MM-DD 
Left eye 
XX 
Changes since previous assessment?  
Cornea 
Iris 
Vitreous 
Disc 
Retina other than AMD 
Lens 
AREDS – Nuclear Sclerosis 
AREDS – Cortical 
AREDS – PSC  
Yes: xxxxxxxx 
Normal 
Not done 
Abnormal 
Normal 
Abnormal 
Normal 
<2 
>2 
>2 
 
Week n 
Yes 
YYYY-MM-DD 
Left eye 
XX 
…………. 
…………. 
 
Week n 
Yes 
YYYY-MM-DD 
Left eye 
XX 
…………. 
…………. 
………….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXX-XX 
………….. 
 
 
 
 
 
 
………….. 
 
 
 
 
 
 
 
OE: Ophthalmic Examination, IOP: Intra Ocular Pressure 


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Listing 16.2.9-4 Pregnancy test data by treatment 
Safety Set 
 
Subject 
Number 
Was pregnancy test 
done? 
Type of sample 
taken 
Date of sample  
(YYYY-MM-DD) 
Result of Test 
 
 
 
 
 
Intensive 
 
 
 
 
XXX-XX 
Yes 
Urine sample 
YYYY-MM-DD 
Negative 
XXX-XX 
Yes 
Serum sample 
YYYY-MM-DD 
Negative 
XXX-XX 
Yes 
Urine sample 
YYYY-MM-DD 
Negative 
XXX-XX 
Yes 
Serum sample 
YYYY-MM-DD 
Negative 
………….. 
 
 
 
 
 
 
 
 
 
Relaxed 
 
 
 
 
XXX-XX 
Yes 
Urine sample 
YYYY-MM-DD 
Negative 
XXX-XX 
Yes 
Serum sample 
YYYY-MM-DD 
Negative 
XXX-XX 
Yes 
Urine sample 
YYYY-MM-DD 
Negative 
XXX-XX 
No 
- 
- 
- 
………….. 
 
 
 
 
*Flags: H=High (Systolic - >180 and increase from baseline of >20, Diastolic - >105 and increase from baseline of >15) 
L=Low (Systolic - <90 and decrease from baseline of >20, Diastolic - <50 and decrease from baseline of >15)  


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Section 16.2.10 – Listing of subject numbers who reported at least one safety event of special interest by event and 
treatment 
No output 
 
Section 16.2.11 – Case retrieval strategy listing 
No output 
 

SAP_001.pdf: 
Clinical Development 
RFB002/ranibizumab /  NCT01972789
A Phase IV, randomised, controlled, single masked study 
investigating the efficacy and safety of ranibizumab “inject 
and extend” using an intensive retinal fluid retreatment 
regimen compared to a relaxed retinal fluid retreatment 
regimen in patients with wet age-related macular 
degeneration (AMD). 
Detailed Statistical Methodology 
Author(s): 
 
Document type: 
MAP Module 3 
Document status: 
Final, Version 2.0 
Release date: 
19-JUN-2017
Number of pages: 
33 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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SAP Approval 
 
By my signature, I confirm that this SAP has been reviewed and approved for use on the 
CRFB002AAU15 study: 
 
Name 
Title / Company 
Signature 
Date 
 
 
 
 
 
 Novartis 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 6 
2 
Project standards .................................................................................................................. 7 
2.1 
General considerations ............................................................................................. 7 
2.2 
Analysis sets ............................................................................................................ 8 
2.3 
Subgroup definitions ................................................................................................ 9 
2.4 
Assessment windows, baseline and post baseline definitions, missing data 
handling ................................................................................................................... 9 
2.4.1 
Baseline and post-baseline definitions: ................................................... 9 
2.4.2 
Study observation period ....................................................................... 11 
2.4.3 
Missing and implausible dates .............................................................. 11 
2.5 
Subject disposition, background and demographic characteristics ....................... 15 
2.5.1 
Subject disposition ................................................................................ 15 
2.5.2 
Protocol deviations ................................................................................ 15 
2.5.3 
Background and demographic characteristics ....................................... 16 
2.5.4 
Eligibility............................................................................................... 16 
2.5.5 
Baseline Characteristics ........................................................................ 16 
2.5.6 
Medical history ...................................................................................... 19 
2.6 
Study medication ................................................................................................... 19 
2.7 
Prior and Concomitant medication ........................................................................ 21 
2.8 
Efficacy evaluation ................................................................................................ 21 
2.8.1 
Variables ............................................................................................... 21 
2.8.2 
Statistical hypothesis, model, and method of analysis .......................... 23 
2.9 
Safety evaluation ................................................................................................... 29 
2.9.1 
Adverse events ...................................................................................... 30 
2.9.2 
Laboratory data ..................................................................................... 30 
2.9.3 
Vital signs.............................................................................................. 30 
2.9.4 
Electrocardiogram (ECG) ..................................................................... 30 
2.9.5 
Intra-Ocular Pressure (IOP) .................................................................. 31 
2.9.6 
Ophthalmologic Examination ............................................................... 31 
2.9.7 
Meta-analysis ........................................................................................ 31 
2.10 
Interim analyses ..................................................................................................... 31 
2.11 
Data monitoring committee (DMC) ...................................................................... 31 
2.12 
Sample size and power considerations .................................................................. 31 
2.13 
Pharmacokinetic analyses ...................................................................................... 32 
3 
Summary of Changes to Planned Analyses ....................................................................... 32 
3.1 
Statistical Analysis Plan, Version 1.0, 9-April-2017 ............................................. 32 
3.1.1 
Additional baseline efficacy variables .................................................. 32 


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3.1.2 
Additional baseline characteristics analysis .......................................... 32 
3.1.3 
Additional exploratory analyses added ................................................. 32 
4 
References ......................................................................................................................... 33 


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List of tables and figures 
Table 1-1 
Studies covered in the MAP .................................................................... 6 
Figure 1  
Study design ............................................................................................ 7 
Table 2-1  
Analysis set exclusion summary ............................................................. 8 
Table 2.3-3 
Study Assessment Windows ................................................................... 9 
Table 2.7.2-1 
Primary Efficacy Analyses .................................................................... 23 
Table 2.7.2-2 
Secondary Efficacy Analyses ................................................................ 23 
Table 2.7.2-3 
Exploratory Efficacy Analyses ............................................................. 23 
Table 2.7.2.5-1 
Mixed Models ....................................................................................... 26 
Table 2.7.2.8-1 
Logistic Regression Models .................................................................. 28 
 


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1 
Introduction 
Studies covered are listed in Table 1-1. The study design, objective, treatment duration, and 
efficacy variables for this indication may be different from other related studies due to 
different indications and phases of clinical development so that almost every study is unique.  
The main purpose is to provide project-level standards for the statistical analyses of efficacy 
and safety data which are common or similar across studies. This MAP can be used as a 
reference or guidance of statistical methods for future studies not listed in Table 1-1. 
Table 1-1 
Studies covered in the MAP 
Indication
/Study 
Phase/ 
Duration 
Treatment/ dose 
Primary objective 
AMD / 
RFB002 
IV 
(1) Intensive retinal 
fluid retreatment 
regimen 
(2) Relaxed retinal 
fluid retreatment 
regimen 
To test the non-inferiority (visual acuity 
benefit that is not clinically worse) of 
intravitreal ranibizumab when administered to 
resolve IRF or SRF >200 µm under the fovea 
(relaxed retinal fluid management) relative to 
when administered to completely resolve both 
IRF and SRF (intensive retinal fluid 
management) in patients with wet AMD. The 
primary endpoint for the study will be the mean 
change in BCVA from baseline to month 24. 
This is a randomised, multi-centre, non-inferiority trial investigating a relaxed fluid retreatment 
regimen relative to an intensive fluid retreatment regimen (using a non-inferiority margin of 5 
letters on the primary endpoint of mean change in BCVA). After consenting to participate in 
the study, patients will participate in a screening period lasting up to 2 weeks to evaluate patient 
eligibility. After eligibility confirmation at the Baseline Visit, patients will be randomised in a 
1:1 ratio to one of the two treatment arms i.e. intensive retinal fluid regimen or relaxed retinal 
fluid regimen within the appropriate stratum depending on the treatment at baseline for the non-
study eye i.e. none, ranibizumab or other anti-VEGF therapy. Only one eye will be 
selected/treated as the study eye.  
Patients withdrawn from the study prior to completion of the 24 month assessment visit will be 
asked to return for an Early Discontinuation evaluation 30 days +/- 7 days following their last 
study visit.  


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Figure 1  
Study design 
2 
Project standards 
Treatment groups for the analysis 
The group labels for the 2 treatment groups for the analysis are: “Intensive” (Group I) and 
“Relaxed” (Group II). 
2.1 
General considerations 
Descriptive statistics will include n (number of observations), mean, standard deviation, 
median, minimum and maximum for continuous variables, and frequencies and percentages for 
categorical variables.  
The study eye is the eye identified by the investigator according to the protocol inclusion and 
exclusion criteria and recorded as such at the screening visit in the eCRF.  
The efficacy analyses of this study will be based on the study eye data only.   
For non-ocular, study eye, and fellow eye summary tables, figures, and listings will be based 
on all patients included in the analysis/set population under consideration. Unless otherwise 
specified, all confidence intervals (CIs) and p values will be two-sided and will be based on an 
alpha significance level of 0.05.  
Central Reading Centre data will be used for efficacy summary tables and analyses, whilst all 
site and Central Reading Centre data will be included in listings. 
 


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2.2 
Analysis sets 
The following are common analysis sets used across the project.  
Randomized Set: The Randomised Population will consist of all randomised patients. 
Full Analysis Set (FAS): The Full Analysis Set (FAS) compromises all subjects randomised 
and whom have at least one post-baseline efficacy value for BCVA. 
Safety Set: The Safety Set will consist of all patients who received at least one application of 
study treatment and had at least one post-baseline safety assessment. The statement that a 
patient had no adverse events also constitutes a safety assessment.  
Per-Protocol Set: The Per-Protocol Set (PPS) will consist of all patients in the FAS who 
followed the treatment regimen as randomised and completed the study without clinically 
significant protocol deviations.  Clinically significant protocol deviations will be identified 
and documented prior to the database lock.  Refer to “Protocol Deviations” study document 
for further details.1  
In order to derive the analysis set, protocol deviations (defined prior to DB lock; impact on 
analysis defined in this document) and non-protocol deviations (based on the definition of the 
analysis set/according to this document) need to be considered. 
The protocol deviations are mainly used in excluding entire patients or particular data within a 
patient from the Per Protocol Set (PPS) and are described in the Protocol Deviation Plan. 
Furthermore - to derive the analysis sets, non-protocol deviations will be used. Table 2-1 
Analysis set exclusion summary below gives a summary of the non-protocol deviations that 
exclude patients from each analysis set.  
Table 2-1 Analysis set exclusion summary 
Analysis Set (to 
be excluded from) 
Non-Protocol Deviations 
Full Analysis Set 
Not in the Randomized set  
Did not have at least one post-baseline efficacy value for BCVA  
Per Protocol Set 
Not in FAS 
Clinically significant protocol deviation(s) 
Safety Set 
Did not receive at least one study treatment 
Did not record at least one post-baseline safety assessment 
 
All efficacy evaluations will be carried out on the FAS. The analysis for the primary 
efficacy evaluation will be carried out on both the FAS and the PPS population. Analyses for 
secondary and exploratory evaluations will be carried out on the FAS, and may also be carried 
out on the PPS population as part of sensitivity analyses. Within the FAS and PPS, patients 
will be analysed as randomised. 
 
All safety evaluations will be carried out on the Safety set. Within the safety set, patients will 
be analysed as treated. 


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The number and percentage of patients in each analysis set will be summarized based on all 
patients included in the analysis set. 
In addition, a listing will be produced to show the patient inclusion/exclusion into each of the 
analysis sets with the corresponding reason(s) for exclusion. 
Note that additional analysis sets may be derived as part of sensitivity analyses. 
2.3 
Subgroup definitions 
Sub-groups analyses may be included in exploratory and sensitivity analyses. Potential 
sub-groups: 
• Randomisation Strata: Two treatment naïve eyes, one eye (first non-study eye) being 
treated with ranibizumab, and one eye (first non-study eye) being treated with an anti-
VEGF other than ranibizumab. 
• Age Group 
• Sex 
• Baseline BCVA group (>=70 letters, <70 letters) 
• Genotype sampling status 
• Baseline lesion size 
• Baseline IRF and/or SRF 
Sub-group analyses may include descriptive analyses as well as forest plot(s) displaying 
treatment effects within each sub-group. 
2.4 
Assessment windows, baseline and post baseline definitions, 
missing data handling 
Assessment windows to be applied to this study are detailed in Table 2.4-3. 
Table 2.4-3 
Study Assessment Windows 
Period 
Screen Initial Treatment 
Treatment Period 
Visit 
1 
2 
3 
4 
n 
Month 
12 
n 
Month 24 or Early 
Discontinuation 
Weeks (relative to 
Baseline, Day 0) 
 
-2 to 0 
 
Baseline 
 
4 
 
8 
 
v 
 
52 
 
v 
 
104 
Visit window (days) 
 
 
±3 ±3 
±7 
± 14 
± 7 
±14 
n = number of visits as required per study protocol2 section 5.5.4.1 
v = variable. The number of visits will differ dependent on treatment interval as per study protocol3 section 
5.5.4.1 
2.4.1 
Baseline and post-baseline definitions: 
2.4.1.1 
Baseline 
Baseline is defined as the last available non-missing value collected just prior to the start of 
treatment in the study eye.  Where a patient parameter value is missing for Visit 2: 
1. If the patient has entered the treatment period (i.e. received at least one treatment), the 
baseline value for that patient will be imputed with the patient’s Screening value.   


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2. If the patient never entered the treatment period, the baseline value will not be 
imputed.   
Furthermore, patients with screening assessments, who do not enter the treatment period data, 
will only be included in data listings. 
Note: Photography and FA performed no more than 14 days before the Baseline Visit 
will be accepted as the baseline examination (will not need to be repeated unless clinically 
indicated). 
Note: BCVA performed no more than 2 days before the Baseline Visit will be accepted as the 
baseline examination.  In addition, only BCVA data collected as per protocol (e.g. refracted 
ETDRS) will be accepted as the baseline examination. 
2.4.1.2 
Post-baseline 
All assessments obtained after the date of first dose of study drug are considered as 
post-baseline unless otherwise specified.  Missing data for post-baseline values, for example 
due to discontinuation, loss to follow-up, or other types of censoring (e.g. due to rescue 
medication), will not be imputed.  Only subjects with measurements at any given time point 
will be included in the analysis for that given parameter and visit.  Refer to Section 2.4.3 for 
further details regarding the handling of missing dates. 
The study day for a baseline or post-baseline scheduled or unscheduled visit is defined as: 
Study day = (Date of visit) - (date of first treatment ) + 1 
The study day for a scheduled or unscheduled visit before baseline is defined as: 
Study day = (Date of visit) - (date of first treatment) 
2.4.1.3 
Visit Windows 
Output presented by visit will use a derived visit number, based on the number of weeks from 
Day 1; the derived visit number will be calculated using the actual visit date, as opposed to the 
scheduled visit date.  Listings will also include the CRF nominal visit. 
Visit names available will be 4-weekly for the first 12 weeks, and then fortnightly.  For example: 
Week 4, Week 8, Week 12, Week 14, Week 16, Week 18, etc., with each visit having a visit 
window of ± 7 days. 
Month 12 and Month 24 visits will be analysed using the CRF nominal visit window. 
2.4.1.4 
Early Discontinuation 
The standard approach to handling Early Discontinuation visits will be to assign the visit to a 
derived visit number based on the date of termination.  If the Early Discontinuation visit is 
assigned to a visit which already exists, then the assigned visit number will be set to the next 
visit.  
Early Discontinuation visits may also be summarised as a separate distinct visit, in addition to, 
or in place of, the standard approach described in the paragraph above. 
In addition, sensitivity analyses may be conducted to assess the impact of possible biases in 
endpoint analyses due to missing endpoint data for early withdrawal patients. These analyses 
may include Last Observation Carried Forward (LOCF), Baseline Observation Carried Forward 
(BOCF)  and other imputation methods, as detailed further in Section 2.8.2.2. 


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2.4.2 
Study observation period 
The study observation period for each patient will be defined as the period (in days) between 
the date of first treatment in the study eye (Day 1) and the date of the end of study visit + 1 
(day). 
2.4.3 
Missing and implausible dates 
The general approach to handling missing dates is shown below for dates of AEs, medical 
history diagnosis and concomitant treatment.  
2.4.3.1 
Adverse event start date imputation 
AEs with completely missing onset dates will be considered to be treatment emergent. Adverse 
events with partially missing onset dates will also be included as treatment emergent when the 
month (if it exists) and the year occur on or later than the month and year of the initial study 
treatment date. 
Partial AE start dates are imputed with reference to the treatment start date (TRTSTD) as 
outlined in the Imputation table below. Completely missing start dates will not be imputed.  
For individual data listings, any missing or partial AE start dates will always be presented as 
recorded. 
 
 


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The date value is split into day, month, year sections and referenced in the Imputation table as 
outlined below: 
 
Day 
Month 
Year 
Partial AE Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
(TRTSTD) 
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation. 
Comparison of 
Month Section 
MON MISSING 
MON<TRTM 
MON=TRTM 
MON>TRTM 
YYYY 
MISSING 
NC 
NC 
NC 
NC 
YYYY<TRTY 
(D)=01JULYYY 
Before Treatment 
Start 
(C)=15MONYYYY 
Before Treatment 
Start 
(C)=15MONYYYY 
Before Treatment 
Start 
(C)=15MONYYYY 
Before Treatment 
Start 
YYYY=TRTY 
(B)=TRTSTD+1 
Uncertain 
(C)=15MONYYYY 
Before Treatment 
Start 
(A)=TRTSTD+1 
Uncertain 
(A)=01MONYYYY 
After Treatment 
Start 
YYYY=TRTY 
(E)=01JANYYYY 
After Treatment 
Start 
(A)=01MONYYYY 
After Treatment 
Start 
(A)=01MONYYYY 
After Treatment 
Start 
(A)=01MONYYYY 
After Treatment 
Start 
 


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The following table is the legend to the logic matrix. 
Relationship 
Before Treatment Start 
Partial date indicates AE start date prior to 
Treatment Start Date  
After Treatment Start 
Partial date indicates AE start date after 
Treatment Start Date 
Uncertain 
Partial date insufficient to determine 
relationship of AE start date to Treatment 
Start Date 
Imputation Calculation 
NC / Blank Uncertain 
No convention 
(A) After Treatment Start or Uncertain 
MAX(01MONYYYY,TRTSTD+1) 
(B) Uncertain 
TRTSTD+1 
(C) Before Treatment Start 
15MONYYYY 
(D) Before Treatment Start 
01JULYYYY 
(E) After Treatment Start 
01JANYYYY 
2.4.3.2 
Medical history date of diagnosis imputation 
Completely missing dates will not be imputed. Partial dates of diagnosis will be compared to 
the treatment start date. 
• If DIAG year < treatment start date year and DIAG month is missing, the imputed DIAG 
date is set to the mid-year point (01JULYYYY)  
o else if DIAG month is not missing, the imputed DIAG date is set to the mid-
month point (15MONYYYY) 
• If DIAG year = treatment start date year 
o and (DIAG month is missing OR DIAG month is equal to treatment start month), 
the imputed DIAG date is set to one day before treatment start date 
o else if DIAG month < treatment start month, the imputed DIAG date is set to the 
midmonth point (15MON YYYY) 
o else if DIAG month > treatment start month => data error 
• If DIAG year > treatment start date year => data error 


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2.4.3.3 
Concomitant treatment date imputation 
In order to classify a medication as prior or prior/concomitant, it may be necessary to impute 
the start date. Concomitant treatments with partial start dates will have the date or dates 
imputed. Partial concomitant treatment start dates are imputed with reference to the treatment 
start date (TRTSTD) in accordance with the rules outlined below: 
Concomitant treatments with completely missing start dates will not be imputed. As a 
conservative approach, such treatments will be classified as prior/concomitant (i.e. as being 
received on or after the start of study treatment). 
 
Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
(TRTSTD) 
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation. 
Comparison of 
Month Section 
MON MISSING 
MON<TRTM 
MON=TRTM 
MON>TRTM 
YYYY 
MISSING 
(C)  
Uncertain 
(C)  
Uncertain 
(C)  
Uncertain 
(C)  
Uncertain 
YYYY<TRTY 
(D)=01JULYYY 
Before Treatment 
Start 
(A)=15MONYYYY 
Before Treatment 
Start 
(A)=15MONYYYY 
Before Treatment 
Start 
(A)=15MONYYYY 
Before Treatment 
Start 
YYYY=TRTY 
(C) 
Uncertain 
(A)=15MONYYYY 
Before Treatment 
Start 
(C) 
Uncertain 
(B)=01MONYYYY 
After Treatment 
Start 
YYYY=TRTY 
(E)=01JANYYYY 
After Treatment 
Start 
(B)=01MONYYYY 
After Treatment 
Start 
(B)=01MONYYYY 
After Treatment 
Start 
(B)=01MONYYYY 
After Treatment 
Start 
 


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The following table is the legend to the logic matrix. 
Relationship 
Before Treatment Start 
Partial date indicates CMD start date prior to Treatment 
Start Date  
After Treatment Start 
Partial date indicates CMD start date after Treatment Start 
Date 
Uncertain 
Partial date insufficient to determine relationship of CMD 
start date to Treatment Start Date 
Imputation Calculation 
NC / Blank Uncertain 
No convention 
(A) Before Treatment Start 
15MONYYYY  
(B) After Treatment Start 
MAX(01MONYYYY,TRTSTD+1) 
(C) Uncertain 
IF CMDTYP1C IN (1, 3) THEN TRTSTD-1 ELSE IF 
CMDTYP1C IN (. 2) THEN TRTSTD+1 
(D) Before Treatment Start 
01JULYYYY 
(E) After Treatment Start 
01JANYYYY 
2.5 
Subject disposition, background and demographic 
characteristics 
2.5.1 
Subject disposition 
The number of subjects randomized and included in each of the analysis sets will be presented 
by treatment group. The number and percentage of subjects in the Full Analysis Set (FAS) who 
completed the study, who discontinued the study and the reason for discontinuation will be 
presented for each treatment group and all subjects. 
The number of subjects screened only will also be presented. In addition, the reasons for screen 
failures will be provided. 
An additional table will summarise and compare the number of subjects randomized by 
treatment group and site. 
2.5.2 
Protocol deviations 
All clinically significant protocol deviations will be summarized by number and percentage of 
patients with each deviation. Patients with multiple protocol deviations will only be counted 
once at each level of summarization. In addition, a listing of protocol deviations will be 
produced including the date and study day of the deviation occurrence with the accompanying 
deviation code and severity. Deviations will be summarized for the Randomized Set. Refer to 
the protocol deviation plan for the PDs / non-PDs defined for this study. 
Note that protocol deviations may lead to exclusion of data based on a per-patient, per-visit or 
per-variable basis, as described in the protocol deviation plan. 


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2.5.3 
Background and demographic characteristics 
The following background and demographic variables will be analysed using the Randomised 
Set: 
Continuous variables (per eCRF): 
• Age (years) 
Categorical variables (per eCRF): 
• Gender (Male, Female) 
• Race, grouped as  
• Caucasian: Afghan, Caucasian, Egypt, Egyptian, El Salvadore, Greek, Hispanic, 
Israeli, Italian, Maltese, Middle East, Middle Eastern, South American, Turkish, 
Yugoslavian 
• Black African 
• Asian: Asian and Indian;  
• Aboriginal and Torres Strait Islander 
• Pacific Islander 
• Not sure 
• Ethnicity (Anglo Saxon, Northern European, Southern European, Asian Indian, Other) 
For continuous variables, descriptive statistics (mean, median, standard deviation, minimum 
and maximum) will be presented for each treatment group and for all subjects (total).  
For categorical variables, the number and percentage of subjects in each category will be 
presented for categorical variables for each treatment group and all subjects (total).  The number 
and percentage of subjects with missing data will also be presented. 
2.5.4 
Eligibility 
All eligibility data, including inclusion and exclusion criteria, will be listed. 
2.5.5 
Baseline Characteristics 
The following baseline characteristic variables will be analysed using the Randomised Set: 
Categorical baseline variables (per eCRF): 
• Study eye selection (L/R) 
• Prior wet AMD treatment for fellow eye (Yes/No) 
• Prior wet AMD treatment for fellow eye (Lucentis, Eylea, Visudyne, Avastin, Steroids, 
Other) 
• Family history of AMD 
• History of thromboembolic events 
• Smoking history (as reported, as well as grouped with “Never smoked” and “Smoked in 
the past” combined) 
 
 
 


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Continuous baseline efficacy variables: 
• Total BCVA score (per eCRF) 
• OCT assessments (per 
): 
• Central subfield foveal thickness (CSFT) (µm2) 
• Central subfield volume (mm3) 
• FA assessments (per 
): 
• Area of lesion (mm2) 
• Area of CNV (mm2) 
• Area of Geographic atrophy (mm2) 
 
Categorical baseline efficacy variables 
• Visual acuity >=70 letters (20/40) - per eCRF 
• Visual acuity <70 letters – per eCRF 
• OCT assessments (per 
): 
• Intra-retinal fluid (Present, Absent, Can’t grade) (within 6x6mm scan) (also per eCRF) 
• Intra-retinal fluid centre involvement (Present, Absent, Can’t grade) 
• Intra-retinal cysts (Present, Absent) 
• Intra-retinal cysts centre involvement (Present, Absent) 
• Sub-retinal fluid (Present, Absent, Can’t grade) (within 6x6mm scan) (also per eCRF) 
• Sub-retinal fluid centre involvement (Present, Absent, Can’t grade) (within 6x6mm 
scan) 
• Sub-retinal fluid at centrepoint (Present, Absent, Can’t grade) 
• Sub-retinal fluid height at centrepoint (>200um, ≤200um, not applicable) (also per 
eCRF) 
• Morphologic changes (epiretinal membrane, vitreoretinal traction, macular hole, 
atrophy, other) 
 
• FA assessments (per 
): 
• CNV complex (lesion) (Absent, Definite, Questionable etc.) (also per eCRF) 
• CNV complex (lesion) location (subfoveal, juxtafoveal, extrafoveal, can’t grade) 
• CNV complex (lesion) location (subfoveal, juxtafoveal, extrafoveal, can’t grade), by 
presence of fluid central involvement 
• CNV location (subfoveal, juxtafoveal, extrafoveal, can’t grade) (also per eCRF) 
• CNV location (subfoveal, juxtafoveal, extrafoveal, can’t grade), by presence of fluid 
central involvement  
• CNV secondary to (AMD, angioid streaks, idiopathic, pathologic myopia, other) 
• Type of CNV (predominantly class, occult, fibrovascular PED, serous PED, other  
• CNV leakage (Present, Absent) 
• Lesion components (CNV, blood, serous PED, RPE tear, can’t grade, other) 
• Geographic atrophy (Absent, Definite, Can’t grade etc.) 
• Geographic atrophy location (central subfield, inner subfield, outer subfield) 


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• Colour fundus assessments (per 
): 
• Haemorrhage (Absent, definite, Can’t grade, NA) 
• Haemorrhage location (central subfield, inner subfield, outer subfield) 
• Retinal abnormality (drusen, atrophy, fibrosis, PED, other) (Present, Absent) 
• Retinal abnormality location (central, periphery) 
 
Summary statistics will be presented for each treatment group and for all subjects (total) in the 
Randomised Set, for all baseline characteristics (including the baseline values of the main 
efficacy endpoints). 
For continuous variables, descriptive statistics will be presented.   
For categorical variables, the number and percentage of subjects in each category will be 
presented for categorical variables for each treatment group and all subjects (total).  The number 
and percentage of subjects with missing data will also be presented. 
An analysis will be conducted to compare baseline age, visual acuity, lesion size, SRF and IRF 
between those participants who provided a saliva sample and those who did not. 
 
Study Endpoint 
Method of Analysis 
Comparison of baseline visual acuity between 
participants who provided a genotyping saliva sample 
and those who did not 
Mixed Model 
 
Comparison of baseline SRF between participants who 
provided a genotyping saliva sample and those who did 
not 
Logistic regression model  
Comparison of baseline IRF between participants who 
provided a genotyping saliva sample and those who did 
not 
Logistic regression model 
Comparison of age between participants who provided a 
genotyping saliva sample and those who did not 
Mixed Model 
 
Comparison of lesion size between participants who 
provided a genotyping saliva sample and those who did 
not 
Mixed Model 
 
The mixed model analyses will include genotype saliva sample status as a definite class variable 
and treatment group as an optional class variable.  Further details regarding the general mixed 
model approach are detailed in Section 2.8.2.5. 
Logistic Regression analyses will include genotype saliva sample status as the predictor 
variable.  Further details regarding the general logistic regression approach are detailed in 
Section 2.8.2.5. 
 
 


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2.5.6 
Medical history 
Relevant medical history (ocular and non-ocular) and current medical conditions will be 
tabulated by system organ class and preferred term of the MedDRA dictionary. Separate 
tables will be provided for ocular (study eye and fellow eye) and non-ocular histories and 
conditions.  The number and percentage of subjects with each medical condition will be 
provided by treatment group for the Randomised Set. 
Additionally, all information will be listed including the investigator reported term, and the 
diagnosis/surgery date and day.  
2.6 
Study medication 
The following summaries will be presented for the injections in the study eye and the 
fellow treated eye using the Safety Set: 
• Duration of Exposure 
o Descriptive statistics (mean, median, standard deviation, minimum and 
maximum) will be presented using days as the unit.  
• The number of ranibizumab injections presented by treatment group in frequency 
tables by visit and cumulatively. 
Analyses of the treatment exposure and treatment patterns of the two alternative treatment 
regimens over 24 months include:  
• Treatment frequency  
• Total number of injections 
• Reason for interval decision (as defined within disease activity for each arm) 
The number of injections administered per patient for injections in the study eye will be 
summarized. Both the frequency distribution (number of patients with 1 injection, number of 
patients with 2 injections, on up to the maximum number of injections for any one patient for 
the given treatment period) and summary statistics for the number of injections per patient will 
be presented. 
Additionally, a listing of summarized dosing parameters (e.g., total number of injections in the 
study eye) will be provided. A listing will also be provided detailing data related to the study 
observation period. 
Furthermore, to assess visit/treatment frequency and average visit/dosing interval, the following 
summaries will be provided (within the FAS) 
• The number (%) of patients by the maximum visit interval (4, 6, 8, 10 and 12 weeks); a 
visit interval is defined as the difference of the visit week number as from the visit date. 
E.g. if the first visit to be considered is recorded as Week 16 visit and the next visit is 
recorded as Week 22 visit, then the visit interval is 6 weeks; the maximum visit interval 
is evaluated on a patient level, i.e. the longest visit interval within the study for each 
patient. 
 
 


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• The number (%) of patients for whom the visit interval was never decreased, decreased 
once, decreased two times; The decrease of the visit interval is based on a comparison 
with the previous visit interval. E.g. if the previous visit interval was 8 weeks and the 
current visit interval is 6 weeks (4 weeks), then the visit interval was decreased by 2 
weeks (4 weeks). 
• The number (%) of patients by breakpoint interval (4, 6, 8, 10 and 12 weeks); (the 
injection interval equals the visit interval) 
• The number (%) of patients by the number of times the patient returned to monthly 
injections. 
• The number (%) of patients with presence of new haemorrhage, fluid (SRF, IRF) or a 
loss of visual acuity of ≥5 letters related to study indication, by visit and disease activity 
(over all post-baseline visits). 
• The number (%) of patients with presence of vision impairment attributable to disease 
activity related to study indication, by visit (over all post-baseline visits).  
• The number of scheduled and attended post-baseline visits by patients will be 
summarized (i.e. all scheduled and attended visits after baseline). 
• The number of injections by patients will be summarized.  Injections administered on, 
or after, the Month 12 visit, will count towards the 2nd year of treatment. 
• The average time (in days) between visits scheduled for treatment will be summarized; 
the time “delta” between 2 consecutive visits will be calculated as: delta = (Date of visit 
x) - (date of visit x-1) + 1; the average per patients will then be summarized. 
 


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2.7 
Prior and Concomitant medication 
The number and percentage of patients taking concomitant therapies will be summarized by 
preferred term according to the WHO Drug Reference List dictionary using the Safety Set. 
Summaries will be presented over two time periods, in separate tables: therapies received 
prior to the start of study treatment and therapies received after the start of study treatment. 
Categorisation of the time period will be determined based on recorded or imputed start and 
end dates of medications. Rules for imputing incomplete (start and end) dates are described in 
Section 2.4.3.3. 
Medications will be presented in alphabetical order, by ATC codes and grouped by anatomical 
main group (the 1st level of the ATC codes). Tables will also show the overall number and 
percentage of subjects receiving at least one drug of a particular ATC code and at least one drug 
in a particular anatomical main group.  
For both prior and concomitant medications, separate summaries will be provided for 
non-ocular, study eye, and fellow eye. Treatments that are specified as being taken in both 
eyes will be included in summaries for both the study eye and the fellow eye. 
2.8 
Efficacy evaluation 
The primary objective is to evaluate the effectiveness of two treatment regimens by 
assessing the mean change in BCVA from baseline to Month 24 in each treatment group. A 
key secondary endpoint is to evaluate the effectiveness of two treatment regimens by 
assessing the mean change in BCVA from baseline to Month 12 in each treatment group. A 
mixed model (see below) utilising all data will be the primary analysis to assess both these 
endpoints in the one analysis with no imputation for missing data. Supportive and Sensitivity 
analyses will be conducted as described in Section 2.8.2.1. 
Other key secondary variables include the central retina thickness and number of injections at 
Month 12 and Month 24. 
2.8.1 
Variables 
The primary efficacy variable and key secondary variables are: 
• Mean change in BCVA from baseline to month 24 
• Mean change in BCVA from baseline to month 12 
• Mean change in central retinal thickness from baseline to month 12 and month 24 
• Number of injections from baseline to month 12 and 24 


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The additional secondary variables are: 
• Mean change in area of new and existing geographic atrophy from baseline to month 
12 and 24.  
Patients at sites where autofluoresence can be undertaken will be assessed for the 
presence of geographic atrophy at Baseline, visit 4 (week 8) and then again at the 12 
and 24 month visits. If present, the area of geographic atrophy will be estimated. 
o New Geographic Atrophy at month 12 and month 24a (Yes, No) 
o Change in area of geographic atrophy from the visit where geographic atrophy 
was first present 
• Intra-retinal (IRF) and Sub-retinal fluid (SRF) (present/absent) 
At each relevant assessment visit, the patient is examined for the presence/absence of 
IRF and SRF by the central reading centre as per the definitions for their treatment 
arm.  
• The proportion of patients showing no IRF and SRF at month 2, 12 and 24 
• Proportion of patients showing greater than or equal to 15 letters (EDTRS) gain and 
less than 15 letters loss from baseline to month 24.  
• Proportion of patients with SRF as assessed by the 
 CRC and IRF as assessed by 
Investigators at baseline who do not resolve their SRF and IRF by Month 24 
The remaining exploratory variables are: 
• 
Proportion of patients with a) SRF, b) IRF, c) both SRF and IRF, d) neither SRF 
and/or IRF at baseline, month 2, 12 and 24 
• 
Proportion of patients with ≥6/12 visual acuity at baseline, month 12 and month 24 
• 
Proportion of patients with 6/60 or worse visual acuity at baseline, month 12 and 24 
• The proportion of patients with IRF and SRF at baseline who never resolve either their 
IRF or SRF at any visit up to Month 2, 12 and 24. 
• Proportion of patients with SRF at baseline who never resolve their SRF at any visit 
up to Month 2, 12 and 24 (irrespective of their IRF) 
• Proportion of patients with IRF at baseline who never resolve their IRF at any visit up 
to Month 2, 12 and 24 (irrespective of SRF) 
 
 


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2.8.2 
Statistical hypothesis, model, and method of analysis 
Statistical methodologies for efficacy variables are detailed in Table 2.8.2-1 (Primary 
efficacy), Table 2.8.2-2 (Secondary efficacy) and Table 2.8.2-3 (Exploratory efficacy). 
Table 2.8.2-1 
Primary and Key Secondary Efficacy Analyses 
Study Endpoint 
Method of Analysis 
Mean change in BCVA from baseline to 
months 12 and 24 
1. Mixed Modelling (Refer to Section 2.8.2.5) 
2. Summary statistics of change from baseline 
will be presented.  
Mean change in central retinal thickness 
(CRT) from baseline to months 12 and 24 
1. Mixed Modelling (Refer to Section 2.8.2.5) 
2. Summary statistics of change from baseline 
will be presented.  
Mean number of injections from baseline 
to months 12 and 24 
1. Binomial Model 
2. All data will be listed. 
 
Table 2.8.2-2 Additional Secondary Efficacy Analyses 
Study Endpoint 
Method of Analysis 
Geographic Atrophy from Baseline to 
Month 12 / 24 
(newly developed geographic atrophy 
between baseline and Month 24 (Yes/No)) 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 
2. Survival Analysis 
(Refer to Section 2.8.2.10) 
Geographic Atrophy from Baseline to 
Month 12 / 24 
(Change in area of geographic atrophy from 
the visit where geographic atrophy was first 
present) 
1. Mixed Modelling 
(Refer to Section 2.8.2.8) 
 
Proportion of patients showing greater than 
or equal to 15 letters (EDTRS) gain from 
baseline to month 24 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 
Proportion of patients showing less than 15 
letters loss from baseline to month 24 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 
Proportion of patients showing no IRF and 
SRF at month 2, 12 and 24 
1. Logistic regression model  
(Refer to Section 2.8.2.8)  
 
Table 2.8.2-3 Exploratory Efficacy Analyses 
Study Endpoint 
Method of Analysis 
Proportion of patients with SRF, as assessed 
by the 
 CRC, and IRF, as assessed by 
investigators at Baseline, who do not resolve 
their SRF and IRF by Month 24 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 
The proportion of patients with a) SRF b) 
IRF c) both SRF and IRF d) neither SRF or 
IRF at baseline, 2, 12, 24 months 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 


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Proportion of patients with SRF at baseline 
who never resolve their SRF at any visit up 
to Month 2, 12 and 24 (irrespective of their 
IRF) 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 
Proportion of patients with IRF at baseline 
who never resolve their IRF at any visit up 
to Month 2, 12 and 24 (irrespective of SRF) 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 
Proportion of patients with IRF and SRF at 
baseline who never resolve either their IRF 
or SRF at any visit up to Month 2, 12 and 
24. 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 
Proportion of patients who show ≥6/12 
visual acuity at baseline, month 12 and 24 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 
Proportion of patients who show 6/60 or 
worse visual acuity at baseline, month 12 
and 24 
1. Logistic regression model  
(Refer to Section 2.8.2.8) 
Time to Breakpoint 
1. Kaplan Meier Survival Analysis 
(Refer to Section 2.8.2.10) 
2.8.2.1 
Descriptive Summaries 
All data will be listed. 
All continuous data will be summarised by timepoint and treatment group using descriptive 
statistics.  All categorical data will be summarized by timepoint (if appropriate) and treatment 
group by the number (and percentage) of patients in category. 
For all patients, data will be recorded on scheduled visits for treatment. These visits are based 
on a bi-weekly visit grid, however each patient has their own set of scheduled visits which are 
determined by disease activity/visual impairment. Therefore, the number of visits differs 
between patients and as a consequence the number of available assessments/data at each visit 
differs. The time course of efficacy variable data will be presented/summarized as per the 
observed scheduled visits. As this differs between patients “by visit” tables presenting the 
overall time-course will be based on a biweekly time-grid. 
Endpoints for BCVA improvement or BCVA loss will be summarized by presenting the 
number and percentage of patients in each treatment achieving the endpoint. 
The mean BCVA value will be presented graphically by time point and treatment group, 
categorized by baseline BCVA value. The baseline categories will be:  -0.29-0.00, 0.01-0.30, 
0.31-0.60, 0.61-0.90, 0.91-1.20 and 1.21-1.50. The same graph will be presented for the mean 
BCVA change from baseline. 
 
 


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2.8.2.2 
Supportive/Sensitivity Analyses 
The primary endpoint will be assessed using a mixed model as described above with no 
imputation for missing data. Sensitivity analyses may include re-fitting the model with 
missing data imputed using the LOCF and multiple imputation (as detailed further in Section 
2.8.2.3).  
In addition, the primary model will be fitted to the Per-Protocol Set as a supporting 
analysis. Secondary and exploratory models may also be fitted to the Per-Protocol set as 
supporting or sensitivity analyses. 
Secondary endpoints will be assessed with no imputation for missing data.  Sensitivity 
analyses may be conducted; including the re-fitting of models with missing data imputed 
using the LOCF and multiple imputation, if appropriate. Furthermore, the secondary endpoint 
models may be fitted to use the Per-Protocol Set as supporting analyses. 
Statistical models with optional variables may be explored to identify which model(s) 
optimally fit the data.  In addition, ANCOVAs may be used to confirm cross-sectional 
analyses, as applicable. 
Furthermore, one of the secondary outcomes is to explore the percentage of patients with > 15 
letter improvement. This analysis provides a further supporting analysis of the primary 
endpoint. 
2.8.2.3 
Handling of missing values/discontinuations in efficacy analyses 
For the primary analysis, there will be no imputation for missing data. The mixed model 
approach where all values recorded for each patient up to the time of withdrawal (or 
completion) are used is an appropriate model for data missing at random.  
Sensitivity analyses will be conducted to explore the robustness of the data to the methods 
of dealing with missing data. These methods will include LOCF and multiple imputation.  
2.8.2.4 
Centre pooling 
Not Applicable 
 
 


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2.8.2.5 
Mixed Modelling 
The mixed models to be fitted are detailed in Table 2.8.2.5-1.   
Table 2.8.2.5-1 Mixed Models 
 
Model 
Number Outcome Variable 
Predictor/Covariate 
Class Variable 
Random 
Term 
 
Definite 
Optional 
Definite 
Optional 
 
MM_1 
Change in BCVA 
from baseline to 2, 
12 and 24 months 
• Treatment 
• Baseline BCVA 
• Visit (categorical) 
• Treatment by Visit 
Interaction 
• Stratification group 
• Cumulative weeks 
on treatment 
Treatment 
Visit 
Subject 
 
 
 
 
Subject 
MM_2 
Change in BCVA 
from baseline to 2, 
12 and 24 months 
• Treatment 
• Baseline BCVA 
• Visit (categorical) 
• Treatment by Visit 
Interaction 
• Injection frequency 
• Cumulative number 
of weeks on treatment 
• Stratification group 
Baseline: 
• Age 
• Lesion size 
• GA presence 
• Smoking status 
• Genotype saliva 
sample status 
• Baseline BCVA 
(<=70/>70) 
• Baseline IRF 
• IRF 
• Baseline SRF 
• SRF 
• PED 
• SRF resolved (y/n) 
Treatment 
Visit 
Subject 
 
Stratum 
Centre 
 
Subject 
MM_3 
Change in 
Geographic Atrophy 
from baseline to 2, 
12 and 24 months. 
• Treatment 
• Baseline GA area 
• Visit (categorical) 
• Treatment by Visit 
Interaction 
• Cumulative number 
of weeks on treatment 
 
Baseline: 
• Age 
• BCVA 
• Injection frequency 
• Lesion size 
• GA presence 
• Smoking status 
• Genotype saliva 
sample status 
• Baseline BCVA 
(<=70/>70) 
• Baseline IRF 
• IRF 
• Baseline SRF 
• SRF 
• PED 
• SRF resolved (y/n) 
Treatment 
Visit 
Subject 
 
Stratum 
Centre 
 
Subject 


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All results for all patients for will be included for each model, unless otherwise indicated.  
The repeated nature of the data will be modelled by including subject as random effect. The 
Kenward-Roger (KR) correction will be used to compute the denominator degrees of freedom 
to test fixed effects. The least square (LS) mean estimate for intensive retinal fluid 
treatment group (“intensive”) – relaxed retinal fluid treatment group (“relaxed”) will be 
obtained for treatment time = 2 months,  12 months and 24 months. These will be obtained 
with 95% confidence limits. 
In regards to primary efficacy, if the upper 2-sided 95% confidence limit for the least square 
mean for intensive – relaxed mean change in BCVA at 24 months is <5 (the non-inferiority 
margin) then relaxed will be declared non-inferior to intensive. 
2.8.2.6 
Generalised Estimating Equations 
In addition, a model fitting the development of geographic atrophy in the first 12-month period 
or the second 12-month period may be fitted to provide one analysis of the newly developed 
GA over time. This analysis would be undertaken using a generalised estimating equation 
(GEE) logistic regression.  
Absence/Presence of IRF and/or SRF may also be analysed using a GEE logistic regression. 
2.8.2.7 
Analysis of Binomial Data 
The mean number of injections over the 24-month period will be analysed using a Negative 
Binomial model for count type data. The number of injections will be the outcome variable and 
treatment as a class variable. The logarithm length of time each subject is in the study up to 
their 24-month visit will be used as an offset variable. The injection frequency (per year) and 
the difference between injection frequencies (ratio) will be obtained for each treatment group 
along with the corresponding 95% confidence intervals and p-values. The model may be 
expanded to cater for other time points such as 12 months or separate analyses.  
Model 
Number Outcome Variable 
Predictor/Covariate 
Class Variable 
Random 
Term 
 
Definite 
Optional 
Definite 
Optional 
 
MM_4 
Change in CRT from 
baseline to 2, 12 and 
24 months 
• Treatment 
• Baseline CRT 
• Visit (categorical) 
• Treatment by Visit 
Interaction 
• Injection frequency 
• Cumulative number 
of weeks on 
treatment 
• Stratification group 
Baseline:  
Age 
• Lesion size 
• GA presence 
• Smoking status 
• Genotype saliva 
sample status 
• Baseline BCVA 
(<=70/>70) 
• Baseline IRF 
• IRF 
• Baseline SRF 
• SRF 
• PED 
• SRF resolved (y/n) 
Treatment 
Visit 
Subject 
 
Stratum 
Centre 
 
Subject 


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2.8.2.8 
Logistic regression 
The logistic regression models to be fitted are detailed in Table 2.8.2.8-1. 
Table 2.8.2.8-1 
Logistic Regression Models 
Model 
Number 
Outcome Variable 
Predictor/Covariate 
Mandatory 
Optional 
LR_1 
Newly developed geographic 
atrophy between baseline and 
Month 12 / 24 (Yes/No) 
Treatment  
 
Baseline geographic 
atrophy 
Baseline IRF/SRF 
Centre 
LR_2 
≥ 15 letter increase from 
baseline to month 24 (Yes/No) 
Treatment  
 
Baseline BCVA 
Centre 
LR_3 
SRF and IRF at baseline and 
never resolving SRF at any 
visit up to Month 2 (Yes/No) 
Same for Month 12 and 24 
Treatment  
 
Baseline IRF/SRF 
Centre 
LR_4 
Greater than or equal to 15 
letters (EDTRS) gain and less 
than 15 letters loss from 
baseline to month 24 
Treatment  
 
Baseline BCVA 
Centre 
LR_5 
SRF as assessed by the 
 
CRC and IRF as assessed by 
Investigators who do not 
resolve their SRF and IRF by 
Month 24 
Treatment  
 
Baseline IRF/SRF 
Centre 
LR_6 
No IRF and SRF at month 2, 
12 and 24 
Treatment  
 
Baseline IRF/SRF 
Centre 
LR_7 
SRF (as assessed by the 
 
CRC) and IRF (as assessed by 
Investigators) who do not 
resolve their SRF and IRF by 
Month 24 
Treatment  
 
Baseline IRF/SRF 
Centre 
LR_8 
IRF at baseline who never 
resolve their IRF at any visit 
up to Month 2, 12 and 24 
(irrespective of SRF) 
Treatment  
 
Baseline IRF 
Centre 


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Model 
Number 
Outcome Variable 
Predictor/Covariate 
Mandatory 
Optional 
LR_9 
IRF and SRF at baseline who 
never resolve either their IRF 
or SRF at any visit up to 
Month 2, 12 and 24. 
Treatment  
 
Baseline IRF/SRF 
Centre 
LR_10 
Show ≥6/12 visual acuity at 
baseline, Month 2, Month 12, 
month 24 
Treatment  
 
Baseline BCVA 
Centre 
LR_11 
Show 6/60 visual acuity or 
worse at baseline, Month 2, 
Month 12, month 24 
Treatment  
 
Baseline BCVA 
Centre 
 
From each model the adjusted odds ratio for the outcome variable, for intensive compared 
with relaxed treatment, will be obtained with 2-sided 95% confidence limits. 
Using PROC GENMOD to calculate the 95% confidence interval for the odds ratios assumes 
asymptotic normality of the Wald estimate for the regression coefficient. The 95% confidence 
interval for the regression parameter of the relaxed regime treatment effect relative to the 
intensive regime is calculated using an exponential transformation to create the 95% confidence 
interval for the odds ratio.  
All p-values reported on linear hypotheses about regression coefficients will be based on the 
Wald tests from Type III analyses. In the SAS procedure PROC GENMOD, a Type III analysis 
will be performed by adding the model options: TYPE3, DIST=BIN, and LINK=LOGIT. 
The repeated binary data for absence/Presence of IRF and/or SRF may also be assessed using a 
random intercept logistic regression (under the frame work of generalized linear mixed model) 
with robust estimation of SE. 
2.8.2.9 
Genotyping 
Exploratory models will be fitted to investigate the correlation between genotype expression 
and visual acuity and dry retina. Analyses relating to genotype expression will be planned in an 
independent Statistical Methods document, and will also be reported independently. 
2.8.2.10 Time to Event 
Time to event analyses will be conducted using Kaplan Meier. Cox Hazards analysis may also 
be used as deemed appropriate. 
2.9 
Safety evaluation 
Safety parameters will include adverse events, the results of ophthalmic examinations, IOP, 
vital signs, and laboratory results if reported as AE. 
All safety analyses will be conducted within the Safety Set. 


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2.9.1 
Adverse events 
Adverse events (AEs) will be reported by primary system organ class and preferred term 
according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The MedDRA version used for reporting the study will be described in a footnote. 
AEs will be deemed treatment emergent if the onset date is on or after the date of first study 
treatment. Any AEs recorded prior to the start of study treatment will be listed together with 
all other AEs. If any event has an incomplete onset date, this will be handled as described in 
section 2.4.3.1 above. 
The incidence of treatment emergent AEs will be summarized separately for ocular and non-
ocular AEs as follows: 
• All AEs 
• AEs by maximum severity 
• AEs suspected to be related to study drug 
• Serious AEs 
• AEs leading to study treatment discontinuation 
Patients who experienced multiple adverse events for a preferred term will be counted once, 
similarly for patients with multiple adverse events per system organ class. 
All information pertaining to AEs noted during the study will be listed by patient, detailing AE 
(e.g., verbatim given by the investigator as well as the system organ class and preferred term 
according to MedDRA), date of starting and ending, severity, suspected relationship (by the 
investigator) to the study drug / ocular injection, and eye (for ocular events). The AE onset will 
also be shown relative (in number of days) to the day of (first) initial study treatment 
(ranibizumab injection) and relative (in number of days) to the Day 1. 
The following AE listings will be provided: 
• All adverse events, 
• Ocular adverse events  
• Adverse events suspected to be related to study drug and/or ocular injection. 
• Serious adverse events, 
• Adverse events leading to treatment withdrawal 
• Adverse events leading to treatment interruption 
2.9.2 
Laboratory data 
No laboratory evaluations to assess blood or urine parameters will be performed – with the 
exception of pregnancy assessments as described in Section 2.5.5, and DNA genotyping as 
described in Section 2.8. 
2.9.3 
Vital signs 
Vital signs will be listed with values outside the extended normal range flagged.  
Vital signs (sitting systolic and diastolic blood pressure (mmHg)) will also be summarised. 
2.9.4 
Electrocardiogram (ECG) 
No ECG performed during this study. 


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2.9.5 
Intra-Ocular Pressure (IOP) 
IOP measurements will be summarised by treatment group using descriptive of raw data and 
change from baseline.  
Change from baseline will only be summarized for subjects with both baseline and post-baseline 
values and will be calculated as described in Section 0. 
2.9.6 
Ophthalmologic Examination 
Ophthalmic examination data for the study and fellow eye will be listed separately and will 
include: 
• Cornea (Normal, Abnormal) 
• Iris (Normal, Abnormal) 
• Vitreous (Normal, Abnormal) 
• Disc (Normal, Abnormal) 
• Retina other than AMD (Normal, Abnormal) 
• Lens (Phakic, Aphakic, Pseudophakic) 
• AREDS grading; 1st, 2nd and 3rd criteria (Nuclear Sclerosis, Cortical, PSC) 
• Grade categorised as (<2=’none to mild’ or >2=’moderate to severe’) 
2.9.7 
Meta-analysis 
Not Applicable 
2.10 
Interim analyses 
There is no planned interim analysis. 
2.11 
Data monitoring committee (DMC) 
An independent Data Monitoring Committee (DMC) will be used in this study for assessment 
of data at 6 monthly timepoints commencing after 50% patients have completed the Month 
12 visit. The composure of and procedures applied by the DMC is outlined in the data 
monitoring committee charter.4 
2.12 
Sample size and power considerations 
This study is designed as a non-inferiority trial. The non-inferiority limit for the difference 
between groups (change with intensive treatment – change with relaxed treatment) is 5. 
Therefore, if the upper 2-sided 95% confidence limit for the difference between treatments 
(intensive – relaxed) in the change in BCVA (on treatment – baseline) is < 5 the relaxed 
treatment will be declared non-inferior to the intensive treatment. 
Assuming a Standard Deviation (SD) of 15 (as used in the CATT study; Martin et al, 2012) 
and assuming no true difference between treatments, a sample size of 165 patients per group 
provides 80% power assuming analysis will be conducted using a t-test. The sample size of 
165 per group (total of 330) will be randomised (this allows for 15% drop-out based on the 
CATT study which observed an 11% dropout in the ranibizumab as needed group and 16% in 
the bevacizumab as needed group over the two years in the study). Calculations were 
performed using SAS V9.3. 


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2.13 
Pharmacokinetic analyses 
Not applicable 
3 
Summary of Changes to Planned Analyses 
3.1 
Statistical Analysis Plan, Version 1.0, 9-April-2017 
3.1.1 
Additional baseline efficacy variables 
 
Additional baseline efficacy variables added to baseline characteristics analysis. 
 
Protocol:  
Not included 
SAP:  
Section 2.5.5, added: 
• Visual acuity  >=70 letters (20/40) - per eCRF 
• Visual acuity <70 letters – per eCRF 
 
3.1.2 
Additional baseline characteristics analysis 
 
Baseline characteristics analysis added to compare baseline characteristics between subjects 
who did, and did not, provide saliva samples for genotypjng. 
 
Protocol:  
Not included 
SAP:  
Section 2.5.5, added: 
An analysis will be conducted to compare baseline age, visual acuity, 
lesion size, SRF and IRF between those participants who provided a 
saliva sample and those who did not. 
3.1.3 
Additional exploratory analyses added 
 
Additional exploratory endpoints incorporated following review of recently published literature. 
 
Protocol:  
Not included 
SAP:  
Additional exploratory endpoints added in Section 2.8.1: 
• Proportion of patients with a) SRF, b) IRF, c) both SRF and IRF, d) 
neither SRF and/or IRF at baseline, month 2, 12 and 24 
• Proportion of patients with ≥6/12 visual acuity at baseline, month 
12 and month 24 
• Proportion of patients with 6/60 or worse visual acuity at baseline, 
month 12 and 24 
• The proportion of patients with IRF and SRF at baseline who never 
resolve either their IRF or SRF at any visit up to Month 2, 12 and 
24. 


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• Proportion of patients with SRF at baseline who never resolve their 
SRF at any visit up to Month 2, 12 and 24 (irrespective of their 
IRF) 
• Proportion of patients with IRF at baseline who never resolve their 
IRF at any visit up to Month 2, 12 and 24 (irrespective of SRF) 
4 
References 
1 Protocol Deviations, RFB002 / CRFB002AAU15, V1, 21 November 2013. 
2 Clinical Study Protocol, RFB002 / CRFB002AAU15, V2, 11 February 2013.  
3 Clinical Study Protocol, RFB002 / CRFB002AAU15, V2, 11 February 2013.  
4 Data Monitoring Committee Charter, RFB002 / CRFB002AAU15, Version dated 18 
December 2013.