Clinical trial NCT02375971
Conditions: Retinopathy of Prematurity
Keywords: intravitreal ranibizumab laser ablation therapy retinopathy of prematurity preterm infants RAINBOW
Sponsor: Novartis Pharmaceuticals
Start date: 2015-12-30; Completion date: 2017-12-14
Enrollment: 224 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to determine if intravitreal ranibizumab is superior to laser ablation therapy in the treatment of retinopathy of prematurity (ROP).

Detailed description:
The study consisted of a screening period (screening and randomization could occur up to 3 days before the administration of the first investigational treatment), followed by a treatment and follow-up period (Day 1 to Day 169).

Arms: arm 1: 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required arm 2: 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required arm 3: Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed
Interventions: intervention 1: Ranibizumab intervention 2: Laser therapy
Intervention descriptions: intervention 1: Administered as an intravitreal injection intervention 2: Transpupillary diode or frequency-doubled yttrium aluminum garnet (YAG) laser ablative therapy, following anesthesia or sedation

Protocol documents:
Prot_002.pdf: 
Global Clinical Development - General Medicine 
RFB002/Ranibizumab 
Clinical Trial Protocol CRFB002H2301 / NCT02375971
RAINBOW study: a randomized, controlled study 
evaluating the efficacy and safety of RAnibizumab 
compared with laser therapy for the treatment of INfants 
BOrn prematurely With retinopathy of prematurity 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2014-003041-10 
Version number: 
v02 (Clean) 
Development phase: 
3 
Release date: 
01-Feb-2017
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed  
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0, November 2013 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 2 ............................................................................................................................. 9 
Protocol summary .............................................................................................................. 13 
1 
Introduction ....................................................................................................................... 19 
1.1 
Background ............................................................................................................ 19 
1.1.1 
Ranibizumab ......................................................................................... 21 
1.2 
Purpose .................................................................................................................. 24 
2 
Study objectives ................................................................................................................. 24 
2.1 
Primary objective ................................................................................................... 24 
2.2 
Secondary objectives ............................................................................................. 25 
 
 26 
3 
Investigational plan ........................................................................................................... 26 
3.1 
Study design .......................................................................................................... 26 
3.2 
Rationale of study design ...................................................................................... 27 
3.3 
Rationale of dose/regimen, route of administration, and duration of treatment .... 27 
3.4 
Rationale for choice of comparator ....................................................................... 32 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 32 
3.6 
Risks and benefits .................................................................................................. 32 
4 
Population .......................................................................................................................... 34 
4.1 
Inclusion criteria .................................................................................................... 34 
4.2 
Exclusion criteria ................................................................................................... 34 
5 
Treatment ........................................................................................................................... 35 
5.1 
Protocol requested treatment ................................................................................. 35 
5.1.1 
Investigational treatment ....................................................................... 35 
5.1.2 
Additional treatment.............................................................................. 36 
5.2 
Treatment arms ...................................................................................................... 36 
5.3 
Treatment assignment, randomization ................................................................... 36 
5.4 
Treatment masking ................................................................................................ 37 
5.5 
Treating the patient ................................................................................................ 37 
5.5.1 
Patient numbering ................................................................................. 37 
5.5.2 
Dispensing the investigational treatment .............................................. 37 


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5.5.3 
Handling of study treatment .................................................................. 38 
5.5.4 
Instructions for prescribing and administering investigational 
treatment ................................................................................................ 39 
5.5.5 
Permitted dose adjustments and interruptions of investigational 
treatment ................................................................................................ 40 
5.5.6 
Rescue medication ................................................................................ 40 
5.5.7 
Concomitant treatment .......................................................................... 42 
5.5.8 
Prohibited treatment .............................................................................. 42 
5.5.9 
Discontinuation of investigational treatment ........................................ 42 
5.5.10 
Premature patient withdrawal from the study ....................................... 43 
5.5.11 
Loss to follow-up .................................................................................. 43 
5.5.12 
Emergency breaking of assigned treatment code .................................. 44 
5.5.13 
Study completion and post-study treatment .......................................... 44 
5.5.14 
Early study termination ......................................................................... 44 
6 
Visit schedule and assessments ......................................................................................... 44 
6.1 
Information to be collected on screening failures .................................................. 54 
6.2 
Patient demographics/other baseline characteristics ............................................. 54 
6.3 
Treatment exposure and compliance ..................................................................... 54 
6.4 
Efficacy .................................................................................................................. 54 
6.4.1 
Ophthalmic fundus features .................................................................. 54 
 
 56 
6.4.3 
Appropriateness of efficacy assessments .............................................. 56 
6.5 
Safety ..................................................................................................................... 56 
6.5.1 
Ocular examination ............................................................................... 56 
6.5.2 
Vital signs.............................................................................................. 56 
6.5.3 
Respiratory function .............................................................................. 57 
6.5.4 
Monitoring of adverse events (ocular and systemic) ............................ 57 
6.5.5 
Laboratory evaluations .......................................................................... 57 
6.5.6 
Appropriateness of safety measurements .............................................. 58 
6.6 
Other assessments .................................................................................................. 58 
6.6.1 
Systemic ranibizumab concentration .................................................... 58 
 
 59 
6.6.3 
Systemic vascular endothelial growth factor level ................................ 59 
6.6.4 
Hospitalization ...................................................................................... 59 
7 
Safety monitoring .............................................................................................................. 59 
7.1 
Adverse events ....................................................................................................... 59 
7.2 
Serious adverse events ........................................................................................... 61 


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7.2.1 
Definition of a serious adverse event .................................................... 61 
7.2.2 
SAE reporting........................................................................................ 62 
8 
Data review and database management ............................................................................. 63 
8.1 
Site monitoring ...................................................................................................... 63 
8.2 
Data collection ....................................................................................................... 64 
8.3 
Database management and quality control ............................................................ 64 
8.4 
Data Monitoring Committee .................................................................................. 65 
9 
Data analysis ...................................................................................................................... 65 
9.1 
Analysis sets .......................................................................................................... 66 
9.2 
Patient demographics and other baseline characteristics ....................................... 66 
9.3 
Treatments ............................................................................................................. 67 
9.4 
Analysis of the primary variables .......................................................................... 68 
9.4.1 
Variables ............................................................................................... 68 
 
 68 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 70 
9.4.4 
Supportive analyses ............................................................................... 70 
9.5 
Analysis of secondary 
 variables .................................................. 71 
9.5.1 
Efficacy variables .................................................................................. 71 
9.5.2 
Safety variables ..................................................................................... 72 
 
 73 
9.5.4 
Systemic ranibizumab concentration .................................................... 73 
9.5.5 
Pharmacogenetics/pharmacogenomics ................................................. 73 
9.5.6 
Systemic vascular endothelial growth factor level ................................ 73 
 
 74 
9.5.8 
Hospitalization ...................................................................................... 74 
9.6 
Interim analyses ..................................................................................................... 74 
 
 74 
10  Ethical considerations ........................................................................................................ 75 
10.1 
Regulatory and ethical compliance ........................................................................ 75 
10.2 
Informed consent procedures ................................................................................. 75 
10.3 
Responsibilities of the Investigator and IRB/IEC ................................................. 75 
10.4 
Publication of study protocol and results............................................................... 75 
11  Protocol adherence ............................................................................................................ 75 
11.1 
Protocol amendments............................................................................................. 76 
12  References ......................................................................................................................... 76 


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13  Appendix 1: Blood log for systemic ranibizumab / anti-ranibizumab antibody 
samples collection ............................................................................................................. 82 
14  Appendix 2: Blood log for systemic VEGF samples collection ........................................ 82 
 
List of tables 
Table 5-1 
Prohibited Treatment ............................................................................. 42 
 
 46 
 
 47 
 
 49 
 
 51 
 
 52 
 
 53 
 
 67 
Table 13-1 
Time schedule for blood sampling for systemic ranibizumab / anti 
ranibizumab antibody ............................................................................ 82 
Table 14-1 
Time schedule for blood sampling for VEGF ....................................... 82 
 
List of figures 
 
 24 
Figure 3-1 
Study Design ......................................................................................... 27 
 
 29 
 
 30 
 
 
 31 
 


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List of abbreviations 
AE 
adverse event 
AP-ROP 
aggressive posterior retinopathy of prematurity 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical (classification system) 
AUC 
area under the curve 
BEAT-ROP 
Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of 
Prematurity (study) 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
Cmax 
maximum serum concentration 
CTT 
Clinical Trial Team 
DMC 
Data Monitoring Committee 
eCRF 
electronic case report/record form 
EDC 
electronic data capture 
ETROP 
Early Treatment for Retinopathy of Prematurity (study) 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
Hb 
Hemoglobin 
IB 
investigator’s brochure 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KD 
dissociation constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
OC/RDC 
Oracle Clinical/Remote Data Capture 
 
 


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PK 
pharmacokinetic 
PLT 
Platelet count 
PPS 
Per protocol set  
ROP 
retinopathy of prematurity 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
US 
United States of America 
VEGF 
vascular endothelial growth factor 
WHO 
World Health Organization 
WCC 
White Cell Count 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Dose level 
The dose of drug given to the patient (total daily or weekly, etc.) 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e., prior to starting any of the 
procedures described in the protocol) 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls 
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination 
Investigational treatment generally does not include 
protocol specified concomitant background therapies when these 
are standard treatments in that indication 
Investigational treatment 
discontinuation 
Point/time when patient permanently stops taking 
study/investigational treatment for any reason; may or may not 
also be the point/time of premature patient withdrawal 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system 
Patient number  
A number assigned to each patient who enrolls into the study  
Premature withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival 
Protocol 
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study 


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Amendment 2  
Amendment rationale 
The main purpose of this amendment is to: 
 Reduce the number from 300 patients planned to be treated in the study to approximately 
180 patients planned to be randomized
 
 
 
The revised study is considered to provide 
sufficient statistical power to detect clinically meaningful efficacy results, whilst ensuring 
that the study be completed in a reasonable timeframe. 
In addition, further purpose of this amendment is to: 
 Allow results from ophthalmic exams and laboratory evaluations (other than samples 
collected for determination of ranibizumab or systemic VEGF levels) collected up 
 
 of the screening visit to be used for the study in an effort to minimize the need 
of repeated procedures to be performed in this vulnerable study population. 
In addition, this amendment incorporates changes to the protocol language to improve clarity, 
accuracy and ensure better adherence to the protocol. 
Changes to the protocol 
Major changes are made to the protocol in the following sections: 
- Section 4 Population: Information of the study population was changed from 300 patients 
planned to be treated to approximately 180 patients randomized with corresponding changes 
to the number of evaluable patients. 
- Section 5.5.13 Study completion and post-study treatment: The number of patients was 
changed from 300 to 180 patients randomized with corresponding changes to the number of 
evaluable patients. Wording with respect to over recruitment was removed as it is no longer 
relevant. 
- Section 9.4.2
 
 
 
- 
 
 
Other changes are made to the protocol in the following sections: 
- Section 3.6 Risk and benefits: The reference for Zhou et al was updated to now reflect the 
year of the printed publication instead of the online publication with the respective 
information added in Section 12. 


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- Section 6 Visit schedule and assessments: For Table 6-1 a footnote was added
 
. For 
Table 6-2 and Table 6-3 a footnote was added
 
 
- Section 6.3 Treatment exposure and compliance: Clarification was made that for laser 
therapy, IRT will only be contacted for the first administration (first treatment and rescue) but 
not for any supplementary laser treatment administration. 
- Section 6.4.1 Ophthalmic fundus features: RetCam images taken and results of ophthalmic 
exams performed 
 the screening visit can be used. RetCam vendor 
information was removed. 
- Section 6.5.1 Ocular examination: For the screening visit, results from ophthalmic exams 
performed 
 visit can be used. 
- Section 6.5.5 Laboratory evaluations: Allow results from laboratory evaluations which were 
performed 
 visit to be used for 
 visit. 
- Section 6.6.3 Systemic vascular endothelial growth factor level: The wording was revised to 
refer to the Study Operation Manual and Laboratory Manual for information on blood 
collection. 
- Section 8.3 Database management and quality control: Clarification was made between 
centrally and locally processed laboratory samples and RetCam images. 
These changes will be implemented throughout the protocol. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Summary of previous amendments 
Amendment 1 (05-Aug-2015) 
Amendment rationale  
The main purpose of this amendment is to: 


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 Include additional safety assessments as requested by Health Authorities and Institutional 
Review Boards (IRBs)/Independent Ethics Committees during the clinical trial application 
process. This will enhance the safety monitoring. 
 Amend the exclusion criteria to improve clarity. The exclusion criteria #2 was deleted 
because it was redundant with e.g. exclusion 11. The exclusion criteria #11 was amended 
to clarify that clinically significant comorbidities are exclusionary only if they are 
assessed by the investigator to have a clinically relevant impact on study participation, any 
of the study procedures, or on efficacy assessments. 
 Better align the rescue procedures and criteria with current clinical practice including 
changes to the definition of ROP disease that is unchanged, has minimally improved or 
has worsened. 
 Retain patients in the trial for further follow-up in the instances when they are 
administered with prohibited treatment. This will ensure an appropriate safety monitoring 
of these patients. 
In addition, further purpose of this amendment is to: 
 Add nonclinical information requested by Health Authorities (background section). 
 Provide information requested by Health Authorities on case reports of ROP infants 
treated with ranibizumab, in which temporarily reduced serum VEGF levels have been 
reported (risks and benefits section).  
 Remove the efficacy assessment
 
 
 
 
 Specify that measures will be taken to keep randomization data and aggregated statistical 
analysis by treatment confidential from the Clinical Trial Team (CTT) until database lock. 
Data Management Plan was referenced for additional measures to minimize bias related to 
treatment knowledge. 
 Clarify that, in case RetCam digital photography is not available, the use of indirect 
ophthalmoscopy is allowed as an alternative. Specify that indirect ophthalmoscopy can be 
used at the visit following the treatment visit to align with clinical practice. 
 Transfer details of the blood sampling route and laser type to the Study Operation Manual. 
 
 
  
 Specify that odds ratios are used to define superiority. 
In addition, this amendment incorporates multiple changes to the protocol language to 
improve clarity, accuracy and ensure better adherence to the protocol. 
At the time of the finalization of this amendment, the study has not yet started recruitment. It 
is not anticipated that the changes as per this amendment will affect the study population. 
Changes to the protocol 
Major changes are made to the protocol in the following sections: 


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- Section 6.5 Safety: the monitoring of lower leg length and collection of blood pressure, 
hematology, clinical chemistry, urinalysis and respiratory function data was added to the 
safety assessments. 
- Section 4.2 Exclusion criteria: the exclusion criteria #2 was deleted because it was redundant 
with e.g. exclusion 11. The exclusion criteria #11 was amended to clarify that clinically 
significant comorbidities are exclusionary only if they are assessed by the investigator to have 
a clinically relevant impact on study participation, any of the study procedures, or on efficacy 
assessments. 
- Section 5.5.6 Rescue medication: the definitions for ROP disease that is unchanged, has 
minimally improved or has worsened were amended to better reflect clinical practice. Criteria 
to allow the use of ranibizumab 
 were added. 
- Section 5.5.8 Prohibited treatment: the patient is no longer discontinued from the study if 
prohibited treatment is administered. Instead, the patient should be discontinued from further 
investigational treatment but remains in the study for further follow-up. 
These changes will be implemented throughout the protocol. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 


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Protocol summary 
 
Protocol number 
CRFB002H2301 
Title 
RAINBOW study: a randomized, controlled study evaluating the efficacy 
and safety of RAnibizumab compared with laser therapy for the treatment 
of INfants BOrn prematurely With retinopathy of prematurity 
Brief title 
RAINBOW study: RAnibizumab compared with laser therapy for the 
treatment of INfants BOrn prematurely With retinopathy of prematurity 
Sponsor and clinical 
phase 
Novartis; phase 3 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to determine if intravitreal ranibizumab is 
superior to laser ablation therapy in the treatment of retinopathy of 
prematurity (ROP). The study will assess the ability of these treatments to 
lead to regression of active ROP and prevent the development of ocular 
complications that are associated with poor visual outcome. 
Vascular endothelial growth factor (VEGF) plays an important role in the 
pathogenesis of ROP. There is a growing body of evidence supporting 
the use of targeted pharmacologic inhibition of VEGF in the management 
of ROP. Ranibizumab is a recombinant humanized immunoglobulin G1 
kappa isotype monoclonal antibody fragment targeted against human 
VEGF-A; there have been reports of favorable experience with off-label 
use of intravitreal anti-VEGF in the management of ROP. 
Primary objective 
To demonstrate that intravitreal ranibizumab 0.2 mg has superior efficacy 
to laser therapy in the treatment of ROP as measured by the absence of 
active ROP and absence of unfavorable structural outcomes in both eyes 
24 weeks after starting investigational treatment. 
To achieve this outcome, patients cannot fulfill any of the criteria listed in 
“Data Analysis” (below).  
Secondary objectives 
 
Key secondary objectives are: 
 
To evaluate whether intravitreal ranibizumab 0.2 mg has 
superior efficacy to intravitreal ranibizumab 0.1 mg in the 
treatment of ROP as measured by the absence of active ROP 
and absence of unfavorable structural outcomes in both eyes 
24 weeks after starting investigational treatment 
 
To evaluate whether intravitreal ranibizumab 0.1 mg has 
superior efficacy to laser therapy in the treatment of ROP as 
measured by the absence of active ROP and absence of 
unfavorable structural outcomes in both eyes 24 weeks after 
starting investigational treatment 
Other secondary objectives are: 
 
To evaluate the time to intervention with a second modality for 
ROP or development of unfavorable structural outcome, or 
death 


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 
To evaluate the recurrence of ROP receiving any post-baseline 
intervention at 24 weeks or before 
 
To evaluate the ocular and systemic safety of intravitreal 
ranibizumab 0.1 mg and 0.2 mg in the treatment of ROP as 
assessed by ocular examination, monitoring of adverse events 
(AEs) throughout the study, and by the assessment of length, 
weight, head circumference and lower leg length at Baseline, 
Day 85, and Day 169 
 
To evaluate the systemic pharmacokinetics of intravitreal 
ranibizumab in patients with ROP, as evaluated by sparse 
sampling population pharmacokinetic (PK) methods 
 
To evaluate the effects of investigational treatment on systemic 
VEGF levels in patients with ROP, as evaluated by sparse 
sampling population concentration-response methods 
 
To assess the number of ranibizumab administrations needed in 
the treatment of patients with ROP 
 
Study design 
This is a randomized, open-label, 3-arm, parallel-group, superiority study 
evaluating the efficacy and safety of intravitreal ranibizumab 0.1 mg, 
intravitreal ranibizumab 0.2 mg, and laser therapy for the treatment of 
ROP. Patients will receive the assigned investigational treatment on Day 
1 to each eye, followed by visits to assess safety and efficacy at regular 
intervals during the follow-up epoch. 
Patients will be randomized 1:1:1 to 1 of the following 3 treatment arms: 
 
Intravitreal ranibizumab 0.2 mg to both eyes on the day of 
treatment (Baseline), with up to 2 re-treatments allowed for each 
eye if required 
 
Intravitreal ranibizumab 0.1 mg to both eyes on the day of 
treatment (Baseline), with up to 2 re-treatments allowed for each 
eye if required 
 
Laser ablation therapy to both eyes (at Baseline) 
Assessments to address the primary objective will be performed at 
Day 169, which is 24 weeks after starting investigational treatment. 
Population 
The study population will consist of male and female preterm infants with 
bilateral ROP who require treatment. Approximately 180 patients are 
planned to be randomized in the study to provide at least 48 evaluable 
patients in each of the 3 treatment arms (i.e., 144 evaluable patients in 


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total). 
Inclusion criteria 
Patients have to fulfill all of the following criteria prior to receiving the first 
investigational treatment: 
1. Signed informed consent from parent(s) or legal guardian(s), in 
compliance with local requirements 
2. Male or female preterm infants with a birth weight of less than 
1500 g 
3. Bilateral ROP with 1 of the following retinal findings in each eye: 
 
Zone I, stage 1+, 2+, 3 or 3+ disease, or 
 
Zone II, stage 3+ disease, or 
 
Aggressive posterior ROP 
Exclusion criteria 
Patients fulfilling any of the following criteria prior to receiving the first 
investigational treatment are not eligible for inclusion in this study.  
Investigational treatment is not clinically appropriate for the following 
patients: 
1. Have ROP disease characteristic in either eye, other than that 
listed in “Inclusion Criteria” above, at the time of the first 
investigational treatment 
2. Have a history (either the patient or the mother) of 
hypersensitivity to any of the investigational treatments or to 
drugs of similar chemical classes 
Risk of confounding efficacy and/or safety assessments in the following 
patients: 
3. Have received any previous surgical or nonsurgical treatment for 
ROP (e.g., ablative laser therapy or cryotherapy, vitrectomy) 
4. Have been previously exposed to any intravitreal or systemic 
anti-VEGF agent (either the patient or the mother during this 
child’s pregnancy) 
5. Have used (either the patient or the mother) other investigational 
drugs as part of another clinical study (other than vitamins and 
minerals) within 30 days or within 5 half-lives of the other 
investigational drug, whichever is longer 
6. Have ocular structural abnormalities that are assessed by the 
Investigator to have a clinically significant impact on study 
assessments 
7. Have active ocular infection within 5 days before or on the day of 
first investigational treatment 
8. Have a history of hydrocephalus requiring treatment 
9. Have a history of any other neurological conditions that are 
assessed by the Investigator to have a significant risk of severe 
impact on visual function 
10. Have any other medical conditions or clinical significant 
comorbidities or personal circumstances that are assessed by 
the Investigator to have a clinically relevant impact on study 
participation, any of the study procedures, or on efficacy 
assessments (e.g., poor life expectancy, pupil not able to be 
adequately dilated, unable to comply with the visit schedule) 
Investigational and 
reference therapy 
Ranibizumab 
10 mg/mL 
solution 
for 
injection 
(labeled 
as 
“RFB002 0.5 mg/0.05 mL”) supplied in glass vials for single use by 


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Novartis Drug Supply Management. The storage conditions will be 
described on the medication label. 
Conventional laser ablative therapy 
Efficacy assessments 
Ophthalmic fundus features 
These will be assessed in both eyes using images taken by RetCam 
digital photography and/or as assessed by indirect ophthalmoscopy: 
 
Features of active ROP disease: 
 
ROP disease – zone, stage, 
 
characteristics of vascular changes of plus disease 
 
 
 
Extra-retinal vessels 
 
 
 
Features of late sequelae of ROP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety assessments 
 
Ocular examination 
 
Blood pressure 
 
Length, weight, head circumference and lower leg length 
 
Adverse event monitoring (ocular and systemic) 
 
Laboratory parameters (hematology, clinical chemistry and urinalysis) 
 
Requirement for respiratory support 
Other assessments 
 
Assessment of systemic ranibizumab concentration (in patients who 
receive initial ranibizumab treatment and with an odd patient 
identification number) 
 
Assessment of systemic VEGF levels (in patients who receive initial 
ranibizumab treatment and with an even patient identification number 
as well as patients who receive initial laser therapy) 
 
 
 
 
Duration of hospitalization and weight at discharge home 
Data analysis 
The Full Analysis Set analyzed according to intent-to-treat principles will 
be used to assess efficacy. 


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The primary efficacy variable is the absence of active ROP and absence 
of unfavorable structural outcomes in both eyes 24 weeks after starting 
investigational treatment, as assessed by the Investigator. To achieve 
this outcome, patients cannot fulfill any of the following criteria: 
 
Death at or before the 24-week assessment visit 
 
Requires intervention for ROP in either eye at or before the 24-
week assessment visit with a treatment modality other than the 
modality of the first investigational treatment 
 
Have active ROP in either eye at the 24-week assessment visit 
 
 
 
 
 
 
 
 
Have unfavorable structural outcomes in either eye at or before 
the 24-week assessment visit 
 
 
 
 
 
 
 
 
 
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Key words 
Randomized, open-label, controlled study; intravitreal ranibizumab; laser 
ablation therapy; retinopathy of prematurity; preterm infants; RAINBOW 


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1 
Introduction 
1.1 
Background 
Retinopathy of prematurity (ROP) is a vasoproliferative pathologic process that occurs in the 
incompletely vascularized, developing retina of low birth-weight preterm neonates. Incidence 
and severity of ROP were found to rise with degree of prematurity at birth, low gestational 
age and low birth-weight being the main risk factors (Hartnett and Penn 2012, 
Fierson et al 2013). The vascular changes of ROP may be mild and regress completely with 
time without major long-term sequelae, or may increase in severity and lead to macular 
dragging, total retinal detachment, severe visual impairment, and lifelong blindness (Hardy et 
al 2004). Retinopathy of prematurity is a significant cause of blindness in children in both 
developed and developing countries with approximately 50 000 children blind from ROP 
worldwide (Gilbert 2008, Mintz-Hittner et al 2011). 
Ablation of the peripheral avascular retina with cryotherapy was the first standard treatment 
for ROP, with efficacy demonstrated in the CRYO-ROP study (Cryotherapy for Retinopathy 
of Prematurity Cooperative Group 1988). At 15 years after cryotherapy, treated eyes had 40% 
less unfavorable structural outcomes and 30% less unfavorable visual acuity outcomes, as 
compared with the control eyes (Palmer et al 2005). In the 1990s, the use of laser 
photocoagulation to ablate the peripheral avascular retina gained widespread acceptance, and 
this modality has now almost completely replaced cryotherapy. Laser ablation therapy is 
associated with better long-term structural, visual, and refractive outcomes than cryotherapy 
(Connolly et al 2002, Ng et al 2002, Houston et al 2013). 
In 2003, the Early Treatment for Retinopathy of Prematurity (ETROP) study demonstrated 
that early ablation therapy was associated with better visual and structural outcomes at 
9 months, compared to when therapy was initiated at later stages of ROP (Good 2004). The 
authors developed a clinical algorithm to identify for early treatment those eyes with ROP 
characteristics that had the highest risk for retinal detachment and blindness (Type I ROP), 
while minimizing treatment of those eyes with ROP characteristics likely to show 
spontaneous regression (Type II ROP). The results suggested that, in most circumstances, 
peripheral retinal ablation should be considered for any eye with Type I ROP: 
 Zone I, any stage ROP with plus disease 
 Zone I, stage 3 ROP with or without plus disease 
 Zone II, stage 2 or 3 ROP with plus disease 
Conversely, continued serial examinations should be considered for any eye with Type II 
ROP: 
 Zone I, stage 1 or 2 ROP without plus disease 
 Zone II, stage 3 ROP without plus disease 
Treatment should be considered for any eye with Type II ROP if it progresses to Type I status 
(Good 2004). 


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The findings from the ETROP study, incorporating revisions to the ROP classification system, 
provided the basis for current clinical guidelines recommending that the following types of 
ROP should be treated (International Committee for the Classification of Retinopathy of 
Prematurity 2005, Royal College of Paediatrics and Child Health 2008, Fierson et al 2013): 
 Zone I, any ROP with plus disease 
 Zone I, stage 3 ROP without plus disease 
 Zone II, stage 3 ROP with plus disease 
 Aggressive posterior ROP (AP-ROP) 
With respect to zone II stage 2+ ROP, there are conflicting opinions on whether the available 
clinical data support the benefits of early treatment (Royal College of Paediatrics and Child 
Health 2008). Hence, the treatment guidelines for this ROP category differ on whether 
treatment should be initiated (Fierson et al 2013) or allow the decision to treat or monitor 
closely to be made by an experienced ophthalmologist (Royal College of Paediatrics and 
Child Health 2008). 
Despite improvement in the technology and timing of ROP treatment, it remains a leading 
cause of childhood blindness worldwide. The ETROP study reported 14% unfavorable visual 
acuity outcome and 9% unfavorable structural outcome at 9 months despite ablation therapy 
(Good 2004). In addition, laser ablation therapy may not be possible for certain patients. The 
conduct of laser therapy usually requires general anesthesia and adequate visualization of the 
retina, which may be problematic in preterm neonates with associated comorbidities. 
Both cryotherapy and laser therapy ablate the avascular peripheral retina and destroy the 
majority of the retinal cells that produce vascular endothelial growth factor (VEGF), which 
plays an important role in the pathogenesis of ROP (Smith 2008). Because of the role of 
VEGF in ROP, there is a growing body of evidence supporting the use of targeted 
pharmacologic inhibition of VEGF in the management of ROP (Sonmez et al 2008, Sato et al 
2009). There are a number of reports of favorable experience with the off-label use of 
intravitreal bevacizumab or ranibizumab in the management of ROP (Chung et al 2007, 
Travassos et al 2007, Honda et al 2008, Kusaka et al 2008, Lalwani et al 2008, Mintz-Hittner 
and Kuffel Jr 2008, Quiroz-Mercado et al 2008, Ahmed et al 2010, Altinsoy et al 2010, Dorta 
and Kychenthal 2010, Law et al 2010, Lee et al 2010, Nazari et al 2010, Zepeda-Romero et al 
2010, Harder et al 2011, Mintz-Hittner et al 2011, Wu et al 2011, Lin et al 2012, Mota et al 
2012, Castellanos et al 2013, Kim et al 2014). Most reports used approximately 50% of the 
adult intravitreal dose per eye, although efficacy has also been reported with lower doses 
(Harder et al 2011, Kim et al 2014). 
In a prospective, multicenter, randomized clinical study, intravitreal bevacizumab was found 
to be more efficacious than conventional laser ablation therapy among infants with 
stage 3+ ROP (Bevacizumab Eliminates the Angiogenic Threat of ROP (BEAT-ROP) study) 
(Mintz-Hittner et al 2011). The primary outcome of the study was the recurrence of retinal 
neovascularization before 54 weeks postmenstrual age that required re-treatment. It was found 
that among the subgroup of infants with zone I disease the recurrence rate was 6% with 
bevacizumab and 42% with conventional laser therapy. Moreover, bevacizumab therapy 
resulted in a mild anatomical retinal abnormality in only 1 eye of 31 infants, whereas 
conventional laser treatment resulted in a mild anatomical abnormality in 16 eyes, and a 


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severe abnormality in 2 eyes, of 33 infants. Although the differences in outcomes were not 
statistically significant among infants with posterior zone II ROP, the results suggested a 
similar efficacy trend. An interesting finding of the BEAT-ROP study was that treatment with 
bevacizumab appeared to allow for continued vessel growth into the peripheral retina. In 
contrast, ablation therapy destroyed large areas of the peripheral retina and may affect 
associated vascular growth.
 
 
 This was demonstrated when 
patients from the BEAT-ROP study were assessed at a mean age of 2.5 years, with more 
myopia found in eyes that received laser treatment than in eyes that received intravitreal 
bevacizumab (Geloneck et al 2014). 
A number of limitations have been noted in the BEAT-ROP study (Darlow et al 2013). The 
stage 3+ patients who were studied represent only a subset of the types of ROP disease that 
require treatment; a relatively high dose of anti-VEGF was evaluated; a lack of assessment of 
systemic bevacizumab and VEGF levels; and an unexpectedly high failure rate observed in 
the control laser therapy arm. Therefore, despite reports of potential benefits of anti-VEGF in 
the treatment of ROP, a number of questions remain unanswered. There is concern in the 
medical community that preterm neonates with ROP are treated with anti-VEGF agents with 
insufficient evidence of clinical efficacy compared to standard of care therapy, lack of 
understanding of the optimal dose to be used, as well as information on the long-term safety 
impact of intravitreal anti-VEGF use in a developing infant (Lee et al 2011, 
Darlow et al 2013). This is especially the case with bevacizumab, which is not approved for 
intravitreal use. 
1.1.1 
Ranibizumab 
Ranibizumab is a recombinant humanized immunoglobulin G1 kappa isotype monoclonal 
antibody fragment targeted against human VEGF-A. It binds with high affinity to VEGF-A 
isoforms generated by alternative messenger ribonucleic acid (mRNA) splicing, such as 
VEGF121, VEGF165, and their biologically active proteolytic cleavage product VEGF110. 
Physical, Chemical, and Pharmaceutical Properties and Formulation 
Detailed information on the physical, chemical, and pharmaceutical properties of ranibizumab 
is described in the investigator’s brochure (IB). 
Ranibizumab is available as a 10 mg/mL solution for intravitreal injection. Novartis is the 
marketing authorization holder for Lucentis® 10 mg/mL solution for injection in the European 
Union (EMEA/H/C/000715) and worldwide with the exception of the United States of 
America (US). The 10 mg/mL solution for injection is approved and commercialized globally. 
The formulation is presented as a single-use sterile, clear to slightly opalescent, colorless to 
pale yellow and preservative free aqueous solution for intravitreal injection supplied in glass 
vials. All primary packaging materials are standard quality, suitable for packaging sterile 
liquid products, and comply with relevant pharmacopoeial requirements. 
A syringe suitable to inject volumes of 10 µL and 20 µL of the solution into the eye will be 
used. This syringe will be a sterile, single-use disposable syringe intended for medical 


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purposes. The syringe will be individually packaged. The graduations will be spaced such that 
low volumes in the range of several µL can be delivered accurately. A standard injection 
needle (e.g., 30 G, ½ inch stainless steel) as for the adults will be used for the injection in 
premature neonates. 
Neonatal Nonclinical and Clinical Information 
The IB contains information on nonclinical studies of ranibizumab, as well as clinical studies 
in age-related macular degeneration, diabetic macular edema, retinal vein occlusion, and 
pathologic myopia. Additional information relevant to the neonatal use of ranibizumab is 
described below. 
Vascular endothelial growth factor plays an important angiogenic role in the embryo/fetus, 
during the postnatal period and in the adult life. 
The 3 preclinical studies described below involved more extreme inhibition of systemic 
VEGF (e.g. transgenic mice and high dose of systemically administered VEGFR-1 decoy 
construct and VEGF-A antibody) than seen following intravitreal administration of a VEGF 
inhibitor. 
Gerber et al 1999 reported on a conditional VEGF-knock out mouse model; incomplete/partial 
suppression of VEGF beginning at approximately Day 4 after birth was lethal to 38% of mice 
by Day 7. In surviving animals there was reported growth delays and liver maturation was 
delayed. Other organs evaluated (heart, kidney, lung and spleen) appeared small but normal. 
By Day 27 after birth, 10% of mice recovered body weight compared to wild type control 
mice. 
Gerber et al. 1999 also dosed healthy newborn mice with either a mouse VEGFR-1 decoy 
construct (to deplete VEGF-A and VEGF-B), or an isotypic control protein. Weight loss was 
seen at doses as low as 1 mg/kg. The highest dose tested, 25 mg/kg, was lethal (deaths within 
4-6 days of treatment). Target tissues identified were the fat stores (depleted), kidney 
(hemorrhage and altered growth), delayed growth of the lung and liver; and single-cell 
necrosis in the liver, heart, pancreas and spinal ganglia. 
Malik et al. 2006 compared the effects of an anti-VEGF-A antibody and the mouse VEGFR-1 
decoy construct in newborn mice at maximal pharmacodynamics doses. Both biologics 
decreased survival and weight-gain in the mice. Treatment delayed growth and 
vascularization of the liver, spleen, lung, heart, kidneys, and thymus. 
Nonclinical toxicology data (ocular and systemic) on intravitreal administered ranibizumab 
were generated in cynomolgus monkeys that were 2 to 3.5 years old at study start, which is 
equivalent to adolescents/adults in terms of ocular and systemic organ development stage 
(Boothe et al 1985, Kiely et al 1987, Edward and Kaufman 2003, Qiao-Grider et al 2007). In 
monkeys, intravitreal administration of ranibizumab elicited essentially dose-dependent 
intraocular inflammatory responses that, at least in part, were considered to be an immune-
mediated antibody response to a humanized protein, and thus of questionable relevance to 
humans. No systemic adverse effects were recorded in nonhuman primates administered up to 
2 mg/eye for 26 weeks or when the intravitreal doses given to monkeys resulted in levels of 


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systemically circulating ranibizumab that were higher than those observed in the clinical 
situation.  
In pregnant cynomolgus monkeys, intravitreal administration of ranibizumab did not elicit 
developmental toxicity/teratogenicity and had no effect on weight/structure of the placenta. 
Bevacizumab or aflibercept administered intravenously to pregnant animals cause skeletal 
effects to the embryo/fetus (EMEA 2006, EMEA 2013). Therefore, the absence of 
embryo-fetal toxicity with ranibizumab is attributed to the very low systemic exposures after 
intravitreal administration and, potentially, from the inability of the antigen-binding fragment 
to cross the placental barrier due to lack of a crystallizable fragment region (unless anti-
ranibizumab antibodies form and act as carrier proteins, thereby enabling placental transfer 
via binding to the neonatal crystallizable fragment receptor). However, due to its 
pharmacological mode of action, ranibizumab must be regarded as potentially teratogenic and 
embryo-fetal toxic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The dosing regimen proposed in the ROP clinical trial is also comparable to the one currently 
used by physicians treating ROP (age ≥ 26 weeks) with unlicensed anti-VEGF agents such as 
bevacizumab. In these studies, laser therapy performed after bevacizumab administration has 
been reported to increase systemic drug exposures by damaging the natural barrier that 
represents a full-thickness retina (Wu et al 2011). However, no systemic complication 
(cardiovascular, respiratory, neurologic or renal) attributable to bevacizumab treatment 
(0.40-1.25 mg/eye) has been recorded so far in premature neonates (Micieli et al 2009, Law et 
al 2010, Sahin et al 2013, Wu et al 2013). 
1.2 
Purpose  
The purpose of this study is to determine if intravitreal ranibizumab is superior to laser 
ablation therapy in the treatment of ROP. The study will assess the ability of these treatments 
to lead to regression of active ROP and prevent the development of ocular complications that 
are associated with poor visual outcome. 
 
2 
Study objectives 
2.1 
Primary objective 
To demonstrate that intravitreal ranibizumab 0.2 mg has superior efficacy to laser therapy in 
the treatment of ROP.  
The primary efficacy variable is the absence of active ROP and absence of unfavorable 
structural outcomes in both eyes 24 weeks after starting investigational treatment, as assessed 


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by the Investigator. To achieve this outcome, patients cannot fulfill any of the following 
criteria: 
 Death at or before the 24-week assessment visit 
 Requires intervention for ROP at or before the 24-week assessment visit with a treatment 
modality other than the modality of the first investigational treatment 
 Have active ROP in either eye at the 24-week assessment visit  
 
 
 
 
 
 
 
 Have unfavorable structural outcomes in either eye at or before 24-week assessment visit 
 
 
 
 
 
 
 
 
 
2.2 
Secondary objectives 
Key secondary objectives are: 
 To evaluate whether intravitreal ranibizumab 0.2 mg has superior efficacy to intravitreal 
ranibizumab 0.1 mg in the treatment of ROP as measured by the absence of active ROP 
and absence of unfavorable structural outcomes in both eyes 24 weeks after starting 
investigational treatment, as assessed by the Investigator 
 To evaluate whether intravitreal ranibizumab 0.1 mg has superior efficacy to laser therapy 
in the treatment of ROP as measured by the absence of active ROP and absence of 
unfavorable structural outcomes in both eyes 24 weeks after starting investigational 
treatment, as assessed by the Investigator 
Other secondary objectives are: 
 To evaluate the time to intervention with a second modality for ROP or development of 
unfavorable structural outcome or death 
 To evaluate the recurrence of ROP receiving any post-baseline intervention at 24 weeks or 
before 
 To evaluate the ocular and systemic safety of intravitreal ranibizumab 0.1 mg and 0.2 mg 
in the treatment of ROP as assessed by ocular examination, monitoring of AEs throughout 
the study, and by the assessment of length, weight, head circumference and lower leg 
length at Baseline, Day 85, and Day 169 
 To evaluate the systemic pharmacokinetics of intravitreal ranibizumab in patients with 
ROP, as evaluated by sparse-sampling population PK methods 


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 To evaluate the effects of investigational treatment on systemic VEGF levels in patients 
with ROP, as evaluated by sparse-sampling population concentration-response methods 
 To assess the number of ranibizumab administrations needed in the treatment of patients 
with ROP 
3 
Investigational plan 
3.1 
Study design 
This is a randomized, open-label, 3-arm, parallel-group, superiority study evaluating the 
efficacy and safety of intravitreal ranibizumab 0.1 mg, intravitreal ranibizumab 0.2 mg, and 
laser therapy for the treatment of ROP (Figure 3-1). Screening and randomization can occur 
up to 3 days before the administration of the first investigational treatment (Section 6). 
Eligible patients will be those with bilateral ROP with 1 of the following retinal findings in 
each eye: 
 Zone I, stage 1+, 2+, 3 or 3+ disease, or 
 Zone II, stage 3+ disease, or 
 AP-ROP 
Patients will be randomized 1:1:1 to 1 of the following 3 treatment arms: 
 Intravitreal ranibizumab 0.2 mg to both eyes on the day of treatment (Baseline), with up to 
2 re-treatments allowed for each eye if required 
 Intravitreal ranibizumab 0.1 mg to both eyes on the day of treatment (Baseline), with up to 
2 re-treatments allowed for each eye if required 
 Laser ablation therapy to both eyes (at Baseline) 
Details of the investigational treatments are provided in Section 5.5.4. 
Visits to assess safety and efficacy are scheduled at regular intervals during the follow-up 
epoch. Assessments to address the primary objective will be performed at Day 169, which is 
24 weeks after starting investigational treatment. No interim analysis is planned. 


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Figure 3-1 
Study Design 
 
3.2 
Rationale of study design 
 
 
 
 
 
 
 
 
 
 
 
3.3 
Rationale of dose/regimen, route of administration, and duration 
of treatment 
 
 
 
 
 
 
 
 
Treatment and Follow-up Epoch
Randomization (1:1:1) 
Screening 
Epoch  
Laser therapy
Day 169
Intravitreal ranibizumab 0.1 mg
Intravitreal ranibizumab 0.2 mg
Day 1
Day -3 


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3.4 
Rationale for choice of comparator 
Laser ablation of the peripheral avascular retina is the current standard of care treatment for 
ROP (Royal College of Paediatrics and Child Health 2008, Hartnett and Penn 2012). 
Therefore, this treatment modality has been selected as the comparator for intravitreal 
ranibizumab in the clinical study. 
3.5 
Purpose and timing of interim analyses/design adaptations 
No interim analyses are planned for this study. 
3.6 
Risks and benefits 
The risk to patients in this trial will be minimized by compliance with the eligibility criteria, 
study procedures, and close clinical monitoring. 


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This study will be conducted in preterm neonates, which make up a vulnerable population due 
to their age and associated comorbidities. To protect their rights, safety, and well-being, only 
study centers and investigators experienced in managing these patients will be invited to 
participate in the study. 
Both investigational treatments are associated with potential risks and benefits. Ablation of 
the peripheral avascular retina using transpupillary laser therapy is the current standard of care 
treatment for ROP (Royal College of Paediatrics and Child Health 2008, Hartnett and Penn 
2012). However, it may be associated with complications such as bleeding and retinal 
detachment in the posterior segment and inflammation and cataract formation in the anterior 
segment (Houston et al 2013). In the long term, laser therapy may be associated with the 
development of high myopia and it has been reported that 14.3% of ROP patients treated with 
ablation therapy developed unfavorable visual acuity outcomes at 9 months (Good 2004, 
Houston et al 2013). In addition, general anesthesia is often required and this can be 
associated with a number of risks, especially in the very young and those with concurrent 
medical conditions. The risk of laser therapy will be minimized in this study by only selecting 
study centers and investigators experienced in using laser therapy in the treatment of ROP. 
The potential benefits of intravitreal anti-VEGF in the management of ROP have been 
previously described (Section 1.1). Notably, a prospective randomized clinical study 
demonstrated that intravitreal bevacizumab, compared to laser therapy, was more efficacious 
in the treatment of ROP and was associated with less myopia in the long term (Mintz-Hittner 
et al 2011, Geloneck et al 2014). Some potential risks with the use of intravitreal anti-VEGF 
agents in these patients, as identified in published case reports, include the development of 
late retinal detachment and reduction in systemic VEGF levels (Honda et al 2008, Jang et al 
2010, Lee et al 2010, Zepeda-Romero et al 2010, Hu et al 2012, Sato et al 2012, Hoerster et al 
2013). Furthermore, risks associated with the intravitreal injection procedure include 
endophthalmitis, retinal detachment, traumatic cataract, and increased intraocular pressure. 
Serum VEGF levels in ROP infants following ranibizumab have been measured in two studies 
(Hoerster et al 2013 and Zhou et al 2016). Hoerster et al. describe one infant whose VEGF 
levels were reduced 1 week after ranibizumab injection, were further reduced below detection 
limit at week 3 and returned to normal levels at week 4. Zhou et al. measured plasma VEGF 
levels before and 1 day after ranibizumab injection in 5 ROP infants: plasma VEGF levels 
were reduced to between 9% and 37% of pre-dose VEGF levels 1 day after the injection and 
normalized after 1 week. 
Potential risks of systemic inhibition of VEGF include disturbances of organ and neurological 
development, renal impairment, bone abnormalities, and thromboembolic events. These 
effects were observed in studies using animal knockout models, in nonclinical and clinical 
studies with high systemic doses of anti-VEGF agents or in clinical studies of intravitreal anti-
VEGF in adults with predisposing comorbidities. No such systemic adverse effects have been 
reported in the published reports of intravitreal anti-VEGF therapy in ROP. Nonetheless, all 
patients will be monitored during the study for any new onset AEs. 
As with all therapeutic proteins, there is a potential for immunogenicity with ranibizumab. In 
adult patients, the pretreatment incidence of immunoreactivity to ranibizumab was 0% to 5%. 
After monthly dosing with ranibizumab for 6 to 24 months, antibodies to ranibizumab were 


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detected in approximately 1% to 9% of patients. The clinical significance of immunoreactivity 
to ranibizumab is unclear. Among neovascular age-related macular degeneration patients with 
the highest levels of immunoreactivity, some were noted to have iritis or vitritis. Intraocular 
inflammation was not observed in the retinal vein occlusion or diabetic macular edema 
patients with the highest levels of immunoreactivity. The number of administrations of 
ranibizumab in this study is less than that for the treatment of adult conditions. In addition, 
neonates have a less developed adaptive immune response (Adkins et al 2004). Hence, the 
potential risk of immunogenicity in this study population is likely to be low. 
Patients participating in this study will undergo blood collection. The discomfort and risks 
associated with blood collection will be minimized by allowing the samples to be collected at 
the same time as routine clinical samples, when possible. The volume of blood collected will 
be the minimum required for assay conduct. 
An independent Data Monitoring Committee (DMC) will be established to monitor the safety 
of the trial participants, to ensure that the trial is being conducted with the highest scientific 
and ethical standards, and make appropriate recommendations based on the data seen. 
4 
Population 
The study population will consist of male and female preterm infants with bilateral ROP who 
require treatment. Approximately 180 patients are planned to be randomized in the study to 
provide at least 48 evaluable patients in each of the 3 treatment arms, i.e., at least 144 
evaluable patients in total.  
A patient who drops out after they have been randomized but prior to receiving any 
investigational treatment will be replaced by enrolling a new patient and assigning a new 
patient number and a new randomization number.  
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria prior to 
receiving the first investigational treatment: 
1. Signed informed consent from parent(s) or legal guardian(s), in compliance with local 
requirements  
2. Male or female preterm infants with a birth weight of less than 1500 g 
3. Bilateral ROP with 1 of the following retinal findings in each eye: 
 Zone I, stage 1+, 2+, 3 or 3+ disease, or 
 Zone II, stage 3+ disease, or 
 AP-ROP 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria prior to receiving the first investigational 
treatment are not eligible for inclusion in this study. No additional exclusions may be applied 
by the Investigator, in order to ensure that the study population will be representative of all 
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Investigational treatment not clinically appropriate for the following patients: 
1. 
Have ROP disease characteristic in either eye other than that listed in Section 4.1 at the 
time of the first investigational treatment 
2. 
Have a history of hypersensitivity (either the patient or the mother) to any of the 
investigational treatments or to drugs of similar chemical classes 
Risk of confounding efficacy and/or safety assessments in the following patients: 
3. 
Have received any previous surgical or nonsurgical treatment for ROP (e.g., ablative 
laser therapy or cryotherapy, vitrectomy) 
4. 
Have been previously exposed to any intravitreal or systemic anti-VEGF agent (either 
the patient or the mother during this child’s pregnancy) 
5. 
Have used (either the patient or the mother) other investigational drugs as part of another 
clinical study (other than vitamins and minerals) within 30 days or within 5 half-lives of 
the other investigational drug, whichever is longer 
6. 
Have ocular structural abnormalities that are assessed by the Investigator to have a 
clinically significant impact on study assessments 
7. 
Have active ocular infection within 5 days before or on the day of first investigational 
treatment 
8. 
Have a history of hydrocephalus requiring treatment 
9. 
Have a history of any other neurological conditions that are assessed by the Investigator 
to have a significant risk of severe impact on visual function 
10. Have any other medical conditions or clinically significant comorbidities or personal 
circumstances that are assessed by the Investigator to have a clinically relevant impact on 
study participation, any of the study procedures, or on efficacy assessments (e.g., poor 
life expectancy, pupil not able to be adequately dilated, unable to comply with the visit 
schedule) 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
 0.1 mg or 0.2 mg ranibizumab 
Ranibizumab solution for injection will be supplied (open label) in vials. Each vial contains 
ranibizumab in the concentration of 10 mg/mL (RFB002 0.5 mg/0.05 mL). Ranibizumab is 
formulated as a sterile solution aseptically filled in a sterile glass vial for single use only. The 
content of the vial must not be split. The vials will be supplied to each study center by 
Novartis.  
Ranibizumab must be stored according to the label instructions and it must be kept in a secure 
locked facility. 
Each vial will be labeled with the appropriate information. Medication labels will comply 
with the legal requirements and will be printed in the local language. The storage conditions 
for study drug will be described on the medication label. 


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Ranibizumab that is required for re-treatment (in the ranibizumab arms) or for switched 
therapy (in the laser arm) will also be provided by Novartis Drug Supply Management.  
Novartis will provide sufficient supplies of ranibizumab for treatment use to allow for 
completion of the study. 
 conventional laser ablation therapy 
Treatment administration will be detailed in Section 5.5.4 of this protocol. 
5.1.2 
Additional treatment 
No additional types of treatment, beyond the investigational treatments (i.e., ranibizumab and 
laser therapy), are allowed in this trial. 
5.2 
Treatment arms 
Patients will be randomized to 1 of the following 3 treatment arms in a ratio of 1:1:1, 
 
 
 Intravitreal ranibizumab 0.2 mg to both eyes on the day of first treatment, with up to 
2 re-treatments allowed for each eye if required 
 Intravitreal ranibizumab 0.1 mg to both eyes on the day of first treatment, with up to 
2 re-treatments allowed for each eye if required 
 Laser ablation therapy to both eyes on the day of first treatment, with multiple 
supplementary laser treatments if necessary 
Details of the investigational treatments are provided in Section 5.5.4. 
5.3 
Treatment assignment, randomization 
At Visit 1, all eligible patients will be randomized via Interactive Response Technology (IRT) 
to 1 of the 3 treatment arms. After confirming that the patient fulfills all the 
inclusion/exclusion criteria, the Investigator or his/her delegate will contact the IRT. The IRT 
will assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm (i.e., laser treatment arm or ranibizumab 0.1 mg arm or ranibizumab 0.2 mg 
arm) and will specify (at Visit 2) either unique medication numbers for the first packages of 
investigational treatment to be dispensed to the patient in the ranibizumab treatment arms or 
notification to proceed with laser treatment therapy. The randomization number will not be 
communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A patient randomization list will be produced by the IRT 
provider’s randomization team using a validated system that automates the random 
assignment of patient numbers to randomization numbers. These randomization numbers are 
linked to the different treatment arms, which in turn are linked to medication numbers. 
A separate medication list will be produced by or under the responsibility of Novartis Drug 
Supply Management using a validated system that automates the random assignment of 
medication numbers to study drug packs (medication kits). 


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After randomization at Visit 1, the treatment allocation cannot be changed. 
The randomization scheme for patients will be reviewed and approved by a member of the 
Biostatistics Quality Assurance group.  
5.4 
Treatment masking 
This is an open-label study. The investigators and patients/parents/legal guardians are 
unmasked to the treatments administered. However, in order to minimize the potential impact 
of treatment knowledge, randomization data and aggregated statistical analysis done by 
treatment will be kept confidential from the CTT, until the database is locked for the primary 
analysis. Further measures to minimize bias related to treatment knowledge will be provided 
in the Data Management Plan. 
Fundus images taken by RetCam digital photography during the study will be sent to a central 
reading center 
 The reading center will not be provided with 
treatment allocation information and will therefore be masked to the dose of ranibizumab 
administered. 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon the 
parent(s) or legal guardian(s) signing the informed consent form, the patient is assigned a 
patient number by the Investigator. At each site, the first patient is assigned patient number 1, 
and subsequent patients are assigned consecutive numbers (e.g., the second patient is assigned 
patient number 2, the third patient is assigned patient number 3). The Investigator or his/her 
staff will contact the IRT and provide the requested identifying information for the patient to 
register them into the IRT. Only the assigned patient number should be entered in the field 
labeled “Patient ID” on the electronic data capture (EDC) data entry screen (e.g., enter ‘1,’ 
‘2,’ etc). Once assigned to a patient, the patient number will not be reused. If the patient fails 
to be randomized for any reason, the IRT must be notified within 2 days that the patient was 
not randomized. The reason for not being randomized is to be entered on the Screening Log, 
and the Demography/eCRF must also be completed. 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with (open-label) investigational treatment 
(ranibizumab only). The study drug packaging has a 2-part label. A unique medication 
number (kit number) is printed on each part of this label which corresponds to 1 of the 
2 ranibizumab treatment arms. The investigator will identify the study drug package to 


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dispense to the patient by contacting the IRT and obtaining the medication number (kit 
number) as well as the treatment arm assignment. 
Immediately before dispensing the package to the patient, investigator staff will detach the 
outer part of the label from the packaging and affix it to the source document (Drug Label 
Form) for that patient’s unique patient number. 
The investigator/site personnel are responsible for ensuring that no other person will have 
access to the medication and drug administration documentation. 
Immediately before dispensing and administering ranibizumab, study site staff will record the 
medication number, drug name, strength, Packaging Control Number, and expiration date 
from the label in the source document (Drug Accountability Log) containing that patient’s 
unique patient number. 
Before laser ablation, study site staff will record the serial number of the laser onto the source 
document (Laser Log) containing that patient’s unique patient number. 
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment (ranibizumab) 
Investigational treatment (ranibizumab) must be received by a designated person at the study 
site, handled and stored safely and properly, and kept in a secured location to which only the 
Investigator and designees have access. Upon receipt, all investigational treatment must be 
registered in the IRT system and stored according to the instructions specified on the labels. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical 
complaints are to be reported to the respective Novartis Country Pharma Organization Quality 
Assurance. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the medication number. 
The Investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a Drug Accountability Log. Monitoring of drug accountability 
will be performed by monitors during site visits or remotely and at the completion of the trial.  
At the conclusion of the study, and as appropriate during the course of the study, the 
Investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed Drug Accountability Log to the monitor or to the address provided in 
the investigator folder at each site. 
5.5.3.2 
Handling of other study treatment 
Not applicable. 


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5.5.4 
Instructions for prescribing and administering investigational 
treatment 
After confirmation of the patient’s eligibility, the patient will be randomized 1:1:1 through the 
IRT to 1 of the 3 treatment arms, and the Investigator will initiate the investigational treatment 
accordingly. 
On day(s) when study or rescue treatment is to be administered, all assessments must be 
conducted before administration except when specified otherwise in Section 6. 
All investigational treatments (i.e., ranibizumab treatment and laser therapy) during the study 
must be recorded in the Dose Administration Record eCRF. 
Ranibizumab 0.1 mg or 0.2 mg 
Patients randomized to receive ranibizumab 0.1 mg or 0.2 mg will receive a single dose of 
intravitreal ranibizumab to each eye on Day 1 (Table 6-2). 
Instructions on preparation of the aseptic field, preparation of the ranibizumab for injection, 
the intravitreal injection technique to minimize the risk of complications in patients, and 
information on pre- and post-injection procedures, including assessment of central retinal 
artery status after injection (to monitor for increased intraocular pressure), are provided in the 
Study Operations Manual. 
 
 
 
 
 
 
All ranibizumab treatments must 
be recorded in the IRT system. 
Ranibizumab 
 is not to be administered to an eye that has developed stage 4 or 5 
ROP. The development of any complications of ROP, which is assessed by the Investigator as 
not suitable for treatment with ranibizumab or laser, should be managed as appropriate and 
the treatment given documented in the eCRF. 
Laser therapy 
Patients randomized to laser therapy will receive laser treatment to each eye on Day 1 (Table 
6-3). 
Conventional laser ablative therapy will be administered, following anesthesia or sedation. 
Treatment will be applied with near-confluent laser burn spacing (i.e., 0.5 to 1 burn-width 
apart) to the entire retina peripheral to the ROP lesion. In some cases, limited targeted laser 
ablation posterior to the ROP lesion, but immediately adjacent to it, may be appropriate. 
Treatment should be kept well away from the fovea. 
Laser ablation will be as complete as possible. 
 
 


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 Any unscheduled assessments or visits related 
to the supplementary laser treatment will be captured in the eCRF. 
 
 
 
 
 
 
 
 
 
5.5.5 
Permitted dose adjustments and interruptions of investigational 
treatment 
The timing and dose of the investigational treatments are described in Section 5.5.4 and 
Section 5.5.6. There are no other permitted dose adjustments or interruptions of 
investigational treatment. 
5.5.6 
Rescue medication 
For the purpose of determining if a patient fulfills the criteria for ranibizumab re-treatment or 
switching of investigational treatment, the following definitions will be used: 
 Unchanged – No change in ROP disease activity
 
 Minimally improved – A reduction in ROP disease activity
 
 but 
which is minimal in the opinion of the investigator 
 Worsened - An increase in ROP disease activity
 
5.5.6.1 
Patients who receive ranibizumab as initial treatment 
For patients who receive initial ranibizumab treatment, switch over to laser treatment will 
occur in the below situations of unsatisfactory response. Only the eye with ROP that fulfills 
the below criteria will be treated with laser. If both eyes fulfill the criteria, then both eyes will 
be treated with laser. 
 ROP that remains unchanged or has worsened 
 compared to before 
treatment 
 ROP that  has only minimally improved, is unchanged, or has worsened 
 
 compared to before treatment 
 ROP that has worsened, compared to the previous assessment, 
 
Laser therapy will occur within 
 of the ROP fulfilling the above criteria. Use of this 
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in the IRT system. After this treatment, the schedule of assessments is detailed in Table 6-6. 
Supplementary laser treatment is allowed as described in Section 5.5.4, taking the day of the 
switch laser treatment as the reference day. No further investigational ranibizumab treatment 
can be administered to the eye after it has been switched to laser therapy. 
 
 
 
  
 
 
 
 
 
 
 
Ranibizumab treatment is not to be administered to an eye that has developed 
stage 4 or 5 ROP (see Section 5.5.4).  
5.5.6.2 
Patients who receive laser therapy as initial treatment 
For patients who receive initial laser therapy, switch over to ranibizumab 0.2-mg treatment 
will occur in the below situations of unsatisfactory response. Only the eye with ROP that 
fulfills the below criteria will be treated. If both eyes fulfill the criteria, then both eyes will be 
treated. 
 ROP that has worsened 
 compared to before treatment and 
provided laser treatment is complete as judged by the investigator 
 ROP that is only minimally improved, unchanged, or worsens 
 
compared to before treatment 
 ROP that has worsened, compared to the previous assessment, 
 
 
Ranibizumab 0.2 mg treatment will occur within 
 of the ROP fulfilling the above 
criteria. Treatment with ranibizumab 0.2 mg in this case must be recorded in the Dose 
Administration Record eCRF as well as in the IRT system. After this treatment, the schedule 
of assessments is detailed in Table 6-5. 
 
 
 
 
 
 


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Ranibizumab treatment is not to be administered to an eye that has developed 
stage 4 or 5 ROP (see Section 5.5.4). 
 
 
 
 
5.5.7 
Concomitant treatment 
The Investigator should instruct the patient’s parent(s) or legal guardian(s) to notify the study 
site about any new medications the patient takes after the patient was enrolled into the study. 
All medications, procedures, and significant nondrug therapies (including physical therapy 
and blood transfusions) administered after the patient was enrolled into the study must be 
recorded, including those from primary care and any other hospital. 
5.5.8 
Prohibited treatment 
Use of the treatments displayed in Table 5-1 is NOT allowed after the first investigational 
treatment. 
Table 5-1 
Prohibited Treatment 
Medication 
Action to be taken 
Any intravitreal anti-VEGF agent other than the 
investigational drug 
Discontinue the patient from the investigational 
treatment, as this could confound efficacy and 
safety assessments 
Any systemic anti-VEGF agent 
Discontinue the patient from the investigational  
treatment, as this could confound efficacy and 
safety assessments 
Any other nonsurgical treatment of ROP 
Discontinue the patient from the investigational 
treatment as this could confound efficacy and safety 
assessments 
Any surgical treatment of ROP other than 
investigational laser treatment (e.g. cryotherapy, 
vitrectomy) 
Discontinue the patient from the investigational  
treatment, as this could confound efficacy and 
safety assessments 
Any other investigational medicinal product as part 
of another clinical study, except vitamins and 
minerals 
Discontinue the patient from the investigational 
treatment, as there could be potential interactions 
with the investigational treatments and can 
confound the efficacy and safety assessments 
Abbreviations: ROP – retinopathy of prematurity; VEGF – vascular endothelial growth factor 
5.5.9 
Discontinuation of investigational treatment 
The patient’s parent(s) or legal guardian(s) may voluntarily discontinue further investigational 
treatment for any reason at any time.  
The Investigator should discontinue further investigational treatment for a given patient if, on 
balance, he/she believes that continuation would be detrimental to the patient’s well-being.  
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 Use of prohibited treatment, as specified in Table 5-1 
 Any other protocol deviation that results in a significant risk to the patient’s safety 
Patients who discontinue further investigational treatment should NOT be considered 
withdrawn from the study. They should return for assessments as described in Table 6-1. If 
they fail to return for these assessments for unknown reasons, every effort (e.g., telephone, 
email, letter) should be made to contact their parent(s) or legal guardian(s) as specified in 
Section 5.5.11. 
5.5.10 
Premature patient withdrawal from the study 
If parent(s) or legal guardian(s) decide to prematurely withdraw a patient from the study for 
any reason, the investigator must make every effort to perform the assessments for the 
Premature withdrawal visit as described in Table 6-2 and Table 6-3. The Investigator must 
make every effort (e.g., telephone, email, letter) to determine the primary reason for this 
decision and record this information on the Study Completion eCRF. The investigator must 
also contact the IRT to register the patient’s discontinuation from the study. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
Patients who prematurely withdraw from the study will not be replaced. 
5.5.10.1 Withdrawal of consent 
The patient’s parent(s) or legal guardian(s) may voluntarily withdraw consent to participate in 
the study for any reason at any time.  
Withdrawal of consent occurs only when a patient’s parent(s) or legal guardian(s) does not 
want the patient to participate in the study any more, does not want any further visits or 
assessments, does not want any further study related contacts, and does not allow analysis of 
already obtained biologic material. 
Investigational treatment must be discontinued and no further assessments conducted. All 
biological material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient’s parent(s) or legal guardian(s) are not allowed unless 
safety findings require communicating or follow-up. The investigator must also contact the 
IRT to register the patient’s discontinuation from the study. 
5.5.10.2 Premature patient withdrawal 
The patient must be withdrawn from the study under the following circumstances: 
 Any protocol deviation, where continuation in the study may result in a significant risk to 
the patient’s safety 
5.5.11 
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits and their 
parent(s) or legal guardian(s) have not communicated an intention to withdraw the patient, the 
Investigator should show "due diligence" by contacting the patient’s parent(s) or legal 
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documenting in the source documents steps taken to contact the patient, e.g., dates of 
telephone calls, registered letters, etc. A patient should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred. 
5.5.12 
Emergency breaking of assigned treatment code 
Not applicable. This is an open-label study. 
5.5.13 
Study completion and post-study treatment 
The study will be considered completed for an individual patient when he or she completes 
the last scheduled study visit, i.e. Visit 112 or the last additional visit as per protocol or Visit 
199 in the case of premature withdrawal, whichever is the latest. The study as a whole will be 
considered completed when the last patient has had his or her last scheduled study visit. 
It is planned to randomize approximately 180 patients in the study, in order to provide at least 
48 evaluable patients in each treatment arm. Patients who are being screened when the 
required number of randomized patients is met will be allowed to continue in the study. 
Recruitment into the study is not expected to be rapid and, once the approximate number of 
patients is reached, sites can be closed leaving only those with screens ongoing to continue. 
Patients who have received investigational treatment and are prematurely withdrawn from the 
study will not be replaced; a patient who drops out after they have been randomized but prior 
to receiving any investigational treatment will be replaced by enrolling a new patient and 
assigning a new patient number and randomization number (Section 5.5.10.1). 
The Investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. All eligible 
patients will be offered enrollment in an extension study to CRFB002H2301 to monitor long 
term visual outcomes and safety or local standard of care. 
5.5.14 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as for a prematurely withdrawn 
patient. The Investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the patient’s interests. The 
Investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 through Table 6-6 list all of the assessments and indicate with an “x” when the 
visits are performed. When a visit as per the additional assessment schedule coincides with a 
visit as per the main assessment schedule, assessments have to be performed as per the main 
assessment schedule. 
Patients should be seen for all visits on the designated day, with an allowed “visit window” as 
indicated on the relevant assessment schedule tables. 


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Patients can also be assessed by the investigator in addition to the visit schedule, if the 
investigator deems that the additional contact is necessary for the patient’s well-being. Such 
unscheduled visits and assessments will be documented in the eCRF as well as in the 
investigator’s source notes and any information on adverse events will be documented in the 
eCRF. 
At a minimum, patient’s parent(s) or legal guardian(s) will be contacted for safety evaluations 
during the 30 days following the last study visit or following the last administration of 
investigational treatment (whichever is later) (see Section 7.2). Documentation of attempts to 
contact the patient’s parent(s) or legal guardian(s) should be recorded in the source 
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6.1 
Information to be collected on screening failures 
All patients with informed consent obtained from their parent(s) or legal guardian(s) but not 
treated or randomized will have the study completion page for the screening epoch, 
demographics, inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse 
events that are not SAEs will be followed by the Investigator and collected only in the source 
data. 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: 
race and ethnicity (based on that of the mother), start date of the mother’s last normal 
menstrual period, sex, year of birth, gestational age at birth (by completed weeks), birth 
weight, length and head circumference at birth, characteristics of the ROP, and relevant 
medical history/current medical condition (including multiple pregnancy information, birth 
hospital, and Apgar (appearance, pulse, grimace, activity, respiration) scores at 1 and 
5 minutes, and intubation requirement). 
6.3 
Treatment exposure and compliance 
Every time that ranibizumab treatment is to be administered (treatment/re-treatment and 
rescue), IRT needs to be contacted for the medication (kit) number. For laser therapy, IRT 
will only be contacted for the first administration (first treatment and rescue) but not for any 
supplementary laser treatment administered. Information regarding investigational treatment 
administration will be collected in the Dose Administration Record in the eCRF. 
Exposure to ranibizumab treatment will be based on the number of injections by eye and 
overall (as databased on IRT as well as on the Drug Administration Record eCRF). 
Compliance with ranibizumab treatment will be assessed by the field monitor at each visit 
using vial counts and information provided by the pharmacist or by the investigator. 
Exposure to laser treatment will be based on the number of days laser treatment is received 
(baseline and/or supplementary laser treatment) by eye and overall per patient (as databased 
on IRT as well as on the Drug Administration Record eCRF). 
6.4 
Efficacy 
6.4.1 
Ophthalmic fundus features 
The presence of the following fundus features will be assessed in both eyes by the 
Investigator at all study visits, using images taken by RetCam digital photography and/or as 
assessed by indirect ophthalmoscopy (for the screening visit only, images taken up to 2 days 
before the screening visit and satisfying study protocol imaging criteria can also be used; 
similarly, results of ophthalmic exams performed up to 2 days before the screening visit can 
also be used for this visit): 
 Features of active ROP disease: 


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 ROP disease – zone, stage,
, and characteristics of vascular 
changes of plus disease 
 
 Extra-retinal vessels extending from the retina into the vitreous and judged to be a 
sign of active ROP disease 
 Features of late sequelae of ROP: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
When Digital photography is performed, the RetCam system will be used. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional information on the photography protocol will be described in the Central Reading 
Center Manual. 
 
 If digital photography is not available or is not able to be 
performed or does not provide adequate visualization of the fundus during these visits, an 
examination of the fundus will be performed by indirect ophthalmoscopy. Indirect 
ophthalmoscopy can also be used on the visit following the treatment visit. 
 
 evaluation of fundus features after 
 will be by indirect 
ophthalmoscopy. If available, RetCam digital photography will also be performed, where 
possible, if the patient is sedated for the administration of any additional ROP treatment after 
. Both RetCam digital photography (if available) and indirect ophthalmoscopy are 
scheduled to be performed at 
 visit to allow the Investigator to assess the fundus 
using both methods, prior to switching to using indirect ophthalmoscopy only during 
subsequent study visits. 
In addition, images taken by RetCam digital photography during the study will be sent to a 
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6.4.3 
Appropriateness of efficacy assessments  
The fundus features assessed in this study correspond with morphologic evidence of 
persistence or complications resulting from ROP, and are associated with poor visual 
outcome. Similar measures have been used in previous studies assessing treatments for ROP 
(Cryotherapy for Retinopathy of Prematurity Cooperative Group 1988, Good 2004, 
Mintz-Hittner et al 2011). 
6.5 
Safety 
6.5.1 
Ocular examination 
The presence of any other fundus features abnormalities will be assessed in both eyes at all 
study visits (see Section 6.4.1).  
Ocular examination of structures in addition to that of the fundus will be performed at all 
study visits in both eyes, including assessment of anterior ocular structures and the lens.  
For the screening visit, results from ophthalmic exams performed up to 2 days before this visit 
can be used. Information must be included in the source documentation at the study site. 
Clinically significant abnormal findings will be reported as AEs in the eCRF.  
6.5.2 
Vital signs 
6.5.2.1 
Blood pressure 
Blood Pressure measurements are not required by the protocol. Instead, the most recent 
systolic and diastolic blood pressure [mm Hg] measured as part of the routine clinical care 
should be recorded in the eCRF at visits specified in Section 6. 
Information must be included in the source documentation at the study site. Significant 
findings which meet the definition of an Adverse Event must be recorded on the Adverse 
Event section of the CRF. 
6.5.2.2 
Length, weight, head circumference and lower leg length 
For the assessment of length, weight, head circumference and lower leg length, the patient 
should be wearing minimal clothing (e.g., a clean diaper). Hats, shoes, socks, coats, and other 


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items of clothing should be removed. Study staff trained in the assessment of infants will 
perform these assessments.  
Recumbent length in centimeters will be measured using an infantometer or according to local 
clinical practice. Body weight to the nearest gram will be measured using an electronic scale. 
The maximum occipitofrontal head circumference in centimeters will be measured using a 
tape measure. 
The lower leg length (knee-heel length) will be measured to the nearest 0.1 centimeter using a 
sliding caliper or according to local clinical practice. Measurements should always be done on 
the right side, unless a physical deformity affects the right side. 
6.5.3 
Respiratory function 
Patients’ respiratory function will be assessed by collecting the requirement, if any, for 
positive pressure support (positive end expiratory pressure (PEEP)) and oxygen 
supplementation (FiO2). Oxygen saturation will also be collected, if this has been measured 
as part of routine clinical practice. Data should be recorded on the eCRF. 
Information must be included in the source documentation at the study site. Significant 
findings which meet the definition of an Adverse Event must be recorded on the Adverse 
Event section of the CRF. 
6.5.4 
Monitoring of adverse events (ocular and systemic) 
Patients will be monitored throughout the study for AEs. Please refer to Section 7.1 and 
Section 7.2 for details on recording AEs and recording and reporting of SAEs, respectively. 
In this study, the following safety events will be collected as study endpoints only and are not 
to be additionally considered or recorded as an AE or SAE. These specific events are captured 
on the endpoint page of the eCRF only and investigators should not report these on an 
AE/SAE page of the eCRF: 
 
 
 
 
 
 
 
 
 
 
 
6.5.5 
Laboratory evaluations 
No additional laboratory evaluations are required per protocol (e.g., hematology, clinical 
chemistry or urinalysis). Data from tests which were performed as part of routine clinical 
practice will be collected. At visits specified in Section 6, the most recent laboratory values 
for the tests below will be collected on the eCRF, where such data are available. Abnormal 
laboratory test results that meet the criteria of an AE (Section 7.1) must be reported in the AE 
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For the Day 1 visit, results from laboratory evaluations which were performed up to 2 days 
prior to the screening visit can also be used. Information must be included in the source 
documentation at the study site. 
6.5.5.1 
Hematology 
Hematology will include hemoglobin (Hb), white cell count (WCC) and platelet count (PLT). 
6.5.5.2 
Clinical chemistry 
Serum chemistry data will include urea and electrolytes (sodium, potassium, creatinine and 
urea/blood urea nitrogen (BUN)) and liver function tests (bilirubin, albumin, total protein, 
aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP)). 
6.5.5.3 
Urinalysis 
Urinalysis will include urine protein. 
6.5.6 
Appropriateness of safety measurements  
The safety assessments selected are standard for this patient population. 
6.6 
Other assessments 
To minimize the volume of blood collected, each patient will contribute to either systemic 
ranibizumab concentration/ 
 OR systemic VEGF 
level assessment. 
Systemic ranibizumab concentrations/ 
 will be assessed in 
patients who receive initial ranibizumab treatment and with an odd patient identification 
number. 
Systemic VEGF levels will be assessed in patients who receive initial ranibizumab treatment 
and with an even patient identification number, as well as in all patients who receive initial 
laser therapy. 
Blood sampling for the assessments listed in Section 6.6 must be undertaken wherever 
possible. In cases where blood collection is not possible, the reason for this should be 
recorded in the blood collection eCRF. 
6.6.1 
Systemic ranibizumab concentration 
For patients who receive initial ranibizumab treatment and with an odd patient identification 
number, blood samples (Appendix 1) for the determination of ranibizumab concentrations will 
be collected at the following time points: 
 Within 24 hours after the first administration of ranibizumab 
 At Day 15, 
 after the first administration of 
ranibizumab  
 At Day 29, 
 after the first administration of 
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Where possible, timing of the blood collection should coincide with blood collection for other 
non-study purposes. 
A target of 0.8 mL of blood (with a minimum of 0.5 mL) will be collected at each time point 
into a plain, 
 serum tube. 
The blood sample will be collected and processed according to the Study Operation Manual 
and the Laboratory Manual respectively. All sample tubes will be labeled with the study 
number, center and patient identification (patient identification number) and sample number.  
6.6.3 
Systemic vascular endothelial growth factor level 
For patients who receive initial ranibizumab treatment and with an even patient identification 
number and for all patients who receive initial laser therapy, blood samples (Appendix 2) for 
the determination of systemic VEGF levels (i.e., pharmacodynamics) will be collected at the 
following time points: 
 Before the first investigational treatment 
 At Day 15, 
 after the first investigational 
treatment 
 At Day 29, 
 after the first investigational 
treatment 
Where possible, timing of the blood collection should coincide with blood collection for other 
non-study purposes. 
A target of 0.8 mL of blood (with a minimum of 0.5 mL) will be collected at each time point 
and processed according to the Study Operation Manual and the Laboratory Manual 
respectively. All sample tubes will be labeled with the study number, center and patient 
identification (patient identification number), and sample number.  
6.6.4 
Hospitalization 
Duration of hospitalization (from birth to hospital discharge home) and weight at discharge 
from hospital home will be collected. 
7 
Safety monitoring 
7.1 
Adverse events 
An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom, or disease) in a subject or clinical 
investigation patient after providing written informed consent for participation in the study. 


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Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
In this study, the following safety events will be collected as study endpoints only and are not 
to be additionally considered or recorded as an AE or SAE. These specific events are captured 
on the endpoint page of the eCRF only, and investigators must not report these on an AE/SAE 
page of the eCRF: 
 
 
 
 
 
 
 
 
 
 
 
The occurrence of AEs should be sought by non-directive questioning of the patient’s 
parent(s) or legal guardian(s) at each visit during the study. Adverse events also may be 
detected when they are volunteered by the patient’s parent(s) or legal guardian(s) during or 
between visits or through physical examination, laboratory test, or other assessments. Study 
staff, including the Investigator, should make particular effort to follow-up with neonatal 
intensive care unit staff and the neonatologist (if not also the Investigator) to ensure that no 
unreported AEs/SAEs have been overlooked. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least 1 of the 
following criteria: 
 
They induce clinical signs or symptoms  
 
They are considered clinically significant  
 
They require therapy 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline or the previous visit, or values which are considered to be nontypical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patients and identifying AEs. 
Adverse events should be recorded in the Adverse Events eCRF under the signs, symptoms, 
or diagnosis associated with them, accompanied by the following information. 
 Severity 
 Mild: usually transient in nature and generally not interfering with normal activities 
 Moderate: sufficiently discomforting to interfere with normal activities 
 Severe: prevents normal activities 
 Site (non-ocular/ocular) and laterality (bilateral/left eye/right eye), if an ocular AE 
 Relationship to the study treatment (laser or ranibizumab) and to the study procedure (e.g., 
intravitreal injection) 
 Duration (start and end dates) or if the event is ongoing an outcome of not recovered/not 
resolved or recovering/resolving should be reported 


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 Whether it constitutes an SAE (see Section 7.2.1 for definition of an SAE) 
 Action taken with study treatment (none/dose adjusted/temporarily 
interrupted/permanently discontinued/unknown/not applicable) 
 Medication or therapies taken (no concomitant medication or nondrug 
therapy/concomitant medication or nondrug therapy) 
 Outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)  
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the investigational treatment, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the IB or will be communicated between IB updates in the form of investigator 
notifications. This information will be included in the patient informed consent and should be 
discussed with the patient’s parent(s) or legal guardian(s) during the study as needed. 
The Investigator should also instruct each patient’s parent(s) or legal guardian(s) to report any 
new AE (beyond the protocol observation period) that the patient’s parent(s) or legal 
guardian(s), or the patient’s personal physician, believes might reasonably be related to the 
investigational treatment. This information should be recorded in the Investigator’s source 
documents; however, if the AE meets the criteria of an SAE, it must be reported to Novartis. 
7.2 
Serious adverse events 
7.2.1 
Definition of a serious adverse event 
An SAE is defined as any AE (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any 1 of the following criteria: 
 Is fatal or life threatening 
 Results in persistent or significant disability/incapacity 
 Constitutes a congenital anomaly/birth defect 
 Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 Elective or preplanned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission  
 Social reasons and respite care in the absence of any deterioration in the patient’s 
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 Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life threatening in the context of an SAE refers to a reaction in which the patient was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if more severe (see Annex IV, International Conference on Harmonisation 
(ICH)-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes previously listed 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
In this study, the following safety events will be collected as study endpoints only, and are not 
to be considered or recorded as an AE or SAE: 
 
 
 
 
 
 
 
 
 
 
 
All serious and non-serious AEs (except those to be captured as study endpoints, as detailed 
above) are to be captured in the AE page of the eCRF; SAEs also require individual reporting 
to Novartis’ Drug Safety and Epidemiology Department as per Section 7.2.2. 
7.2.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient’s 
parent(s) or legal guardian(s) has provided informed consent and until 30 days after the last 
study visit or following the last administration of investigational treatment whichever is later 
must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs 
experienced after the 30 day period should only be reported to Novartis if the Investigator 
suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the Investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 


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Information about all SAEs (either initial or follow up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form or the electronic Serious Adverse 
Event Form within the Oracle Clinical/Remote Data Capture (OC/RDC) system (where 
available). The Investigator must assess the relationship to each specific component of the 
study treatment (if the study treatment consists of several components).  
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hours of awareness of the SAE to the local Novartis Drug Safety and Epidemiology 
Department. The telephone and fax number of the contact persons in the local department of 
Drug Safety and Epidemiology, specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. Follow-up 
information should be provided using a new paper SAE Report Form stating that this is a 
follow-up to a previously reported SAE. 
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an 
existing SAE. These data will automatically be submitted to Novartis Drug Safety & 
Epidemiology immediately after investigator signature or 24 hours after entry, whichever 
occurs first.  
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated and whether the patient continued or withdrew from study 
participation. Each re-occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the investigational treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for 
Health Authority reporting. Novartis may need to issue an Investigator Notification to inform 
all investigators involved in any study with the same investigational treatment that this SAE 
has been reported. Suspected Unexpected Serious Adverse Reactions will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
European Union Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries. 
Safety events that are collected as study endpoints will not be considered as SAEs and do not 
follow the above expedited reporting process (Section 7.2.1). These events will be monitored 
and reviewed regularly by Novartis or designee and by the DMC. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 


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site to check the completeness of patient records, the accuracy of entries in the eCRFs, the 
adherence to the protocol and to GCP, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization. 
Additionally, a central analytics organization may analyze data, identify risks and trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight. 
The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information in the eCRFs must be traceable to these source documents in the 
patient's file. The Investigator must also keep the original informed consent form signed by 
the patient’s parent(s) or legal guardian(s) (a signed copy is given to the patient’s parent(s) or 
legal guardian(s)). 
The Investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis’ monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, and documentation of SAEs and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the eCRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the patients will be disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control 
Novartis staff will review the data entered into the CRFs by investigational staff for 
completeness and accuracy and instruct the site personnel to make any required corrections or 
additions. Queries are sent to the investigational site using an electronic data query. 
Designated investigator site staff is required to respond to the query and confirm or correct the 
data. If the electronic query system is not used, a paper Data Query Form will be faxed to the 
site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff that 
will make the correction to the database. The signed copy of the Data Query Form is kept at 
the investigator site. 


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Concomitant medications entered into the database will be coded using the latest World 
Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Concomitant procedures, nondrug 
therapies, and AEs will be coded using the latest Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. 
Laboratory samples collected according to Sections 6.6.1, 6.6.2 and 6.6.3, respectively, will 
be processed centrally and the results will be sent electronically to Novartis. Samples taken as 
part of routine clinical practice according to Section 6.5.5, will be analyzed locally and results 
will be entered into the respective eCRFs by designated investigator site staff. 
 
 
Randomization codes and data about all study drug(s) dispensed to the patient will be tracked 
using an IRT. The system will be supplied by a vendor, who will also manage the database. 
The database will be sent electronically to Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unmasked and made available for data analysis. 
Although this is an open-label study, the CTT will not have access to randomization data until 
after database lock (Section 5.4). Any changes to the database after that time can only be 
made after written agreement by Novartis Development Management. 
8.4 
Data Monitoring Committee 
An independent DMC will be established to monitor the safety of the trial participants, to 
ensure that the trial is being conducted with the highest scientific and ethical standards, and 
make appropriate recommendations based on the data seen. 
The DMC charter will include the DMC membership and responsibilities, the timing of DMC 
meetings, the content of the analysis report for the DMC meetings, and the communication 
with the Sponsor. The DMC will only make recommendations for changes in study conduct. 
9 
Data analysis 
The statistical analysis will be performed or directed by the biostatistician at Novartis. 
At all of the time points assessed, continuous variables will be presented based on descriptive 
statistics (mean, standard deviation, median, minimal and maximum values) for the observed 
values and change from Baseline. Binary variables will be presented by percentage and exact 
2-sided 95% confidence interval. Graphical presentations providing 2-sided 95% confidence 
intervals will be displayed as appropriate.  
The baseline value is the last available, non-missing, value collected prior to Baseline (i.e., 
prior to receiving the first investigational treatment for treated patients). If a patient is 
randomized but not treated, then the baseline value for a variable is the last available non-
missing value collected prior to randomization.  


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Further technical details and discussion of the following statistical considerations will be 
provided in the statistical analysis plan (SAP), which will be finalized before the database 
lock.  
9.1 
Analysis sets 
The Screened Set will consist of all patients whose parent(s) or legal guardian(s) has 
provided informed consent. 
The data from patients whose parent(s) or legal guardian(s) has not provided informed 
consent prior to any study procedures will be listed only and will not be used in any analyses. 
The Randomized Set will consist of all randomized patients. 
The Full Analysis Set (FAS) will comprise all patients from the Randomized Set to whom 
treatment regimen has been assigned. Following the intent-to-treat principle, patients will be 
analyzed for efficacy according to the treatment regimen they are assigned to at 
randomization.  
The Per Protocol Set (PPS) will consist of all patients in the Full Analysis Set who follow 
the treatment regimen as randomized and complete the study period for the analysis of the 
primary and key secondary objectives without clinically important protocol deviations. 
Clinically important protocol deviations will be identified and documented prior to the 
database lock. The PPS will be used in a supportive analysis for the primary and key 
secondary efficacy analyses. 
The Safety Set will consist of all patients who receive at least 1 application of investigational 
treatment and have at least 1 post baseline safety assessment. The statement that a patient has 
no AEs also constitutes a safety assessment.  
The Randomized Set will be used to display patient disposition, demographics and baseline 
characteristics, protocol deviations, and medical history. The Full Analysis Set will be used 
for the primary analysis of the efficacy evaluation using the intent-to-treat principle. A patient 
will be considered to be evaluable if following imputation of missing data (Section 9.4.3) the 
patient provides data for the primary analysis. The Safety Set will be used for exposure, the 
safety evaluation, and to display concomitant and rescue medications. 
9.2 
Patient demographics and other baseline characteristics 
Patient demographics and all baseline characteristics (including the baseline values of the 
main efficacy endpoints) will be summarized for each treatment group and for all patients 
(total). 
Descriptive statistics (mean, median, standard deviation, minimum, and maximum) will be 
presented for continuous variables. The number and percentage of patients in each category 
defined in the trial SAP will be presented for categorical variables. 
Relevant medical history and current medical conditions will be tabulated by system organ 
class (arranged alphabetically) and preferred term (arranged by decreasing frequency in the 
ranibizumab 0.2-mg treatment arm) of the latest version of MedDRA. Separate tables will be 
presented for ocular and non-ocular histories and conditions. 


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For the purposes of classifying an eye by ROP disease status, the worst disease present in any 
clock hour of the eye, ranked in descending order from worse to best in Table 9-1, will be 
used to classify the eye at Baseline and during the study. Plus disease is defined as vascular 
tortuosity and dilatation in at least 2 quadrants of the eye (International Committee for the 
Classification of Retinopathy of Prematurity 2005). 
For the purposes of classifying a patient by ROP disease status, the worst eye, ranked in 
descending order from worse to best in Table 9-1, will be used to classify the patient at 
Baseline. If both eyes have the same zone and stage, then the worst eye is the one with the 
greater total number of clock hours with the highest stage; if this is also the same for both 
eyes, than the left eye will be assigned as the worst eye. 
Other relevant baseline information will be summarized as appropriate. 
9.3 
Treatments 
Exposure to investigational treatment will be presented by treatment group. Concomitant 
therapies will be summarized by preferred term according to the latest version of the WHO 


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Drug Reference List dictionary and ATC codes. Separate summaries will be presented for the 
time periods before and after the first investigational treatment. Concomitant therapies taken 
after the first investigational treatment, which are prohibited according to the protocol, will be 
summarized separately.  
9.4 
Analysis of the primary variables 
9.4.1 
Variables 
The primary efficacy variable is the absence of active ROP and absence of unfavorable 
structural outcomes in both eyes 24 weeks after starting investigational treatment, as assessed 
by the Investigator. To achieve this outcome, patients cannot fulfill any of the following 
criteria: 
 Death at or before the 24-week assessment visit 
 Requires intervention for ROP in either eye at or before the 24-week assessment visit with 
a treatment modality other than the modality of the first investigational treatment 
 Have active ROP in either eye at the 24-week assessment visit as defined by the presence 
of any of the following features: 
 
 
 
 
 
 Have unfavorable structural outcomes in either eye at or before the 24-week assessment 
visit as defined by the presence of any of the following features: 
 
 
 
 
 
 
 
 
A patient may be defined as a “success” (favorable outcome) or “failure” (unfavorable 
outcome) for each of the criteria above. Patients will be defined as a “success” for the primary 
efficacy variable only if they are a “success” for each component. Consequently a patient will 
be defined as a “failure” for the primary efficacy variable if they are defined as a “failure” for 
at least one of the criteria above. 
A 2-sided family-wise type I error rate of 5% will be used. Two-sided exact 95% confidence 
intervals will also be presented for the primary variable event rate within each treatment arm. 


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9.4.3 
Handling of missing values/censoring/discontinuations 
Imputation of missing data will only be undertaken if the value of the primary variable is 
missing. The primary analysis of the hypotheses in Section 9.4.2 will be undertaken after 
imputing missing values of the primary variable at 24 weeks after the first investigational 
treatment using a 2-step single imputation approach. 
In the first step, imputation of missing individual criteria related to the occurrence of active 
ROP and unfavorable structural outcomes at Week 24 will be undertaken assuming the 
following: 
 
If the last non-missing value of a criterion is “success”, then the missing value of the 
criterion at Week 24 will stay missing 
 
If the last non-missing value of a criterion is “failure” then the missing value of the 
component at Week 24 will be imputed by ”failure” 
In the second step, the imputed value of the primary variable will then be derived from the 
imputed values of the individual components. The imputed value of the primary variable will 
be set to: 
 
Failure if at least one of the individual criteria  is “failure”. 
 
“Success” if all of the individual criteria are “success”. 
 
Missing if at least one of the individual components is missing and none of the other 
components are “failure”. 
9.4.4 
Supportive analyses 
The robustness of the primary analysis (testing the hypotheses specified in Section 9.4.2) may 
be assessed by: 
 
 
 
 
 
 


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 
 
 
 
  
 
  
 
 
 Other prognostic/predictive factors 
will be defined before first patient first visit. Each prognostic/predictive factor will be 
considered individually. 
9.5 
Analysis of secondary and exploratory variables 
9.5.1 
Efficacy variables 
Secondary efficacy variables include: 
 The criteria that constitute the definition of absence of active ROP and unfavorable ocular 
outcomes at 24 weeks after starting investigational treatment, as assessed by the 
Investigator. 
 Death from any cause at or before the 24-week assessment visit 
 Requirement of intervention for ROP in either eye at or before the 24-week 
assessment visit with a treatment modality other than the modality of the first 
investigational treatment 
 Vessel dilatation of plus disease 
, in either eye 
 
 at the 24-week assessment visit 
 Presence of extra-retinal vessels 
 
 at the 24-week assessment 
visit 
 Presence of retrolental membrane 
 
 at or before the 24-week assessment visit 
 Substantial temporal retinal vessel dragging 
 
 at or before the 24-week assessment visit 
 Posterior retinal fold 
 at or before the 24-week 
assessment visit 
 Retinal detachment 
 at or before the 24-week 
assessment visit 
 Any of the following unfavorable structural outcomes in either eye at or before 24 weeks 
after the first investigational treatment, as assessed by the Investigator: 
 
 The time after the first investigational treatment to the first occurrence of one of the 
following: 
 Death 


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 Intervention for ROP with a treatment modality other than the modality of the first 
investigational treatment 
 An unfavorable structural outcome in either eye as defined by the presence of any of 
the following features: 
 
 
 
 
 
 
 
 
 Requirement of 
 ranibizumab treatments in each eye by patient 
 Recurrence of ROP receiving any post-baseline intervention at 24 weeks or before 
 
  
Descriptive statistics will be produced for binary efficacy variables. The proportion of patients 
and the proportion of eyes satisfying the condition (e.g., those that have evidence of vessel 
dilatation of plus disease) will be given by treatment arm.  
Exact 2-sided 95% confidence intervals will be given for the proportion of patients satisfying 
the binary efficacy variable condition by treatment arm. Kaplan-Meier plots will be provided 
for time to event variables. 
9.5.2 
Safety variables 
Safety analyses will be conducted on data from Safety set. Adverse events, vital signs 
measurements, requirement for respiratory support, the presence of fundus features 
abnormalities and laboratory evaluations will be summarized and listed. 
Adverse events will be deemed treatment emergent if the onset date is on or after the date of 
first investigational treatment. Any AEs recorded prior to the start of investigational treatment 
will be listed only.  
Only treatment-emergent AEs will be summarized by presenting, for each treatment arm and 
overall, the number and percentage of patients having any AE, having any ocular AE, and 
having any systemic AE. Adverse events will be presented by primary system organ class 


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(arranged alphabetically) and preferred term (arranged by decreasing frequency in the 
ranibizumab 0.2 mg treatment arm) using the most recent version of MedDRA available. 
Patients who experienced multiple AEs for a preferred term will be counted once, similarly 
for patients with multiple AEs per system organ class.  
All other information collected (e.g., severity, relationship to study procedures and 
investigational treatment [ranibizumab/laser]) will be tabulated and listed as appropriate. 
Deaths, SAEs, and AEs leading to permanent discontinuation of investigational treatment will 
be listed separately and, if appropriate, summarized by primary system organ class and 
preferred term. 
Vital signs, requirement for respiratory support and laboratory evaluations will be 
summarized by presenting descriptive statistics of raw values and change from baseline by 
visit and treatment group. Shift tables will be used, as appropriate, to compare baseline and 
post-baseline categorical safety parameters. Other safety data will be summarized and listed 
as appropriate. 
9.5.4 
Systemic ranibizumab concentration 
All patients providing pharmacokinetic serum samples will be included in the PK analysis 
population. Individual ranibizumab concentrations versus time profiles will be displayed 
graphically. Ranibizumab concentration-time data will be evaluated by population PK 
methods to describe ranibizumab exposure and will be compared to exposure in adults from 
previous studies. 
9.5.5 
Pharmacogenetics/pharmacogenomics  
Not applicable. 
9.5.6 
Systemic vascular endothelial growth factor level 
All patients providing VEGF plasma samples will be included in the VEGF analysis 
population. 
The detailed VEGF concentration-time pattern after ranibizumab administration in neonates is 
unknown. If possible, VEGF concentration-time profiles will be evaluated by population 
concentration-response methods (e.g., an indirect-response model) and compared to the 
concentration-time pattern in patients in the control treatment group.  


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9.5.8 
Hospitalization 
The duration of hospitalization and the weight at hospital discharge will be summarized and 
tabulated. 
9.6 
Interim analyses 
There will be no interim analyses during the trial. 


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10 
Ethical considerations 
10.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH harmonised tripartite guidelines for GCP with applicable local regulations (including 
European Directive 2001/20/EC, US 21 CFR, and Japanese Ministry of Health, Labor, and 
Welfare), and with the ethical principles laid down in the Declaration of Helsinki. 
10.2 
Informed consent procedures 
An eligible patient may only be included in the study after his/her parent(s) or legal 
guardian(s) has provided written (witnessed, where required by law or regulation), 
IRB/IEC approved informed consent. Informed consent must be obtained before conducting 
any study-specific procedures (i.e., all of the procedures described in the protocol). The 
process of obtaining informed consent should be documented in the patient source documents.  
Novartis will provide to Investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the Investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval. 
10.3 
Responsibilities of the Investigator and IRB/IEC  
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion 
from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, 
patient recruitment procedures (e.g., advertisements), and any other written information to be 
provided to patients. Prior to study start, the Investigator is required to sign a protocol 
signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access 
to all relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
Investigator must inform Novartis immediately that this request has been made. 
10.4 
Publication of study protocol and results  
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures, and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 


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Investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the clinical 
study report. 
11.1 
Protocol amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring should be followed. 
12 
References 
References are available upon request. 
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Altinsoy HI, Mutlu FM, Gungor R, Sarici SU [2010] Combination of laser photocoagulation 
and intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic 
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Castellanos MA, Schwartz S, García-Aguirre G, et al [2013] Short-term outcome after 
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Chung EJ, Kim JH, Ahn HS, et al [2007] Combination of laser photocoagulation and 
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Connolly BP, Ng EY, McNamara JA, et al [2002] A comparison of laser photocoagulation 
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microangiopathy. N Engl J Med; 358(11):1129-36. 
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_Public_assessment_report/human/002392/WC500135744.pdf (Accessed 17 Sep 2014) 
Fierson WM, American Academy of Pediatrics Section on Ophthalmology, American 
Academy of Ophthalmology, American Association for Pediatric Ophthalmology and 
Strabismus [2013] Screening examination of premature infants for retinopathy of prematurity. 
Pediatrics; 131(1):189-95. 
Geloneck MM, Chuang AZ, Clark WL, et al [2014] Refractive outcomes following 
bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical 
trial. 
JAMA 
Ophthalmol; 
Published 
online 
August 
07, 
2014 
(doi:10.1001/jamaophthalmol.2014.2772) 


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Gerber HP, Hillan KJ, Ryan AM, et al [1999] VEGF is required for growth and survival in 
neonatal mice. Development; 126(6):1149-59. 
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population of babies at risk and implications for control. Early Hum Dev; 84(2):77-82. 
Glade Bender JL, Adamson PC, Reid JM, et al [2008] Phase I trial and pharmacokinetic study 
of bevacizumab in pediatric patients with refractory solid tumors: a Children’s Oncology 
Group Study. J Clin Oncol; 26(3):399-405. 
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results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial. 
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prematurity. J Ocul Pharmacol Ther; 27(6):623-7. 
Hardy RJ, Good WV, Dobson V, et al [2004] Multicenter trial of early treatment for 
retinopathy of prematurity: study design. Control Clin Trials; 25(3):311-25. 
Hartnett ME, Penn JS [2012] Mechanisms and management of retinopathy of prematurity. 
N Engl J Med; 367(26):2515-26. 
Hoerster R, Muether P, Dahlke C, et al [2013] Serum concentrations of vascular endothelial 
growth factor in an infant treated with ranibizumab for retinopathy of prematurity. Acta 
Ophthalmol; 91(1):e74-5. 
Honda S, Hirabayashi H, Tsukahara Y, et al [2008] Acute contraction of the proliferative 
membrane after an intravitreal injection of bevacizumab for advanced retinopathy of 
prematurity. Graefes Arch Clin Exp Ophthalmol; 246(7):1061-3. 
Houston SK, Wykoff CC, Berrocal AM, et al [2013] Laser treatment for retinopathy of 
prematurity. Lasers Med Sci; 28(2):683-92. 
Hu J, Blair MP, Shapiro MJ, et al [2012] Reactivation of retinopathy of prematurity after 
bevacizumab injection. Arch Ophthalmol; 130(8):1000-6. 
International Committee for the Classification of Retinopathy of Prematurity [2005] The 
international classification of retinopathy of prematurity revisited. Arch Ophthalmol; 
123(7):991-9. 
Jang SY, Choi KS, Lee SJ [2010] Delayed-onset retinal detachment after an intravitreal 
injection of ranibizumab for zone 1 plus retinopathy of prematurity. J AAPOS; 14(5):457-9. 
Jin K, Zhu Y, Sun Y, et al [2002] Vascular endothelial growth factor (VEGF) stimulates 
neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA; 99(18):11946-50. 
Kiely PM, Gillard-Crewther S, Nathan J, et al [1987] A comparison of ocular development of 
the Cynomolgus monkey and man. Clin Vision Sci; 1(3):269-80. 
Kim J, Kim SJ, Chang YS, et al [2014] Combined intravitreal bevacizumab injection and zone 
I sparing laser photocoagulation in patients with zone I retinopathy of prematurity. Retina; 
34(1):77-82. 


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Kitamoto Y, Tokunaga H, Tomita K [1997] Vascular endothelial growth factor is an essential 
molecule for mouse kidney development: glomerulogenesis and nephrogenesis. J Clin Invest; 
99(10):2351-7. 
Kusaka S, Shima C, Wada K, et al [2008] Efficacy of intravitreal injection of bevacizumab for 
severe retinopathy of prematurity: a pilot study. Br J Ophthalmol; 92(11):1450-5. 
Lalwani GA, Berrocal AM, Murray TG, et al [2008] Off-label use of intravitreal bevacizumab 
(Avastin) for salvage treatment in progressive threshold retinopathy of prematurity. Retina; 
28(3 Suppl):S13-8. 
Law JC, Recchia FM, Morrison DG, et al [2010] Intravitreal bevacizumab as adjunctive 
treatment for retinopathy of prematurity. J AAPOS; 14(1):6-10. 
Lee JY, Chae JB, Yang SJ, et al [2010] Effects of intravitreal bevacizumab and laser in 
retinopathy of prematurity therapy on the development of peripheral retinal vessels. Graefes 
Arch Clin Exp Ophthalmol; 248(9):1257-62. 
Lee SJ, Kim ET, Yoo BC, et al [2011] Plasma level of vascular endothelial growth factor in 
retinopathy of prematurity after intravitreal injection of bevacizumab (E-abstract). Invest 
Ophthalmol Vis Sci; 52:3165A. Available from: 
http://abstracts.iovs.org//cgi/content/abstract/52/6/3165?sid=eb0ddfe6-4592-4281-aeb5-
974ff09f645a 
Lin CJ, Chen SN, Hwang JF [2012] Intravitreal ranibizumab as salvage therapy in an 
extremely low-birth-weight infant with rush type retinopathy of prematurity. Oman J 
Ophthalmol; 5(3):184-6. 
Malik AK, Beldwin ME, Peale F, et al [2006] Redundant roles of VEGF-B and PlGF during 
selective VEGF-A blockade in mice. Blood; 107(2):550-7.Micieli JA, Surkont M, Smith AF 
[2009] A systematic analysis of the off-label use of bevacizumab for severe retinopathy of 
prematurity. Am J Ophthalmol; 148(4):536-43. 
Mintz-Hittner HA, Kennedy KA, Chuang AZ, et al [2011] Efficacy of intravitreal 
bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med; 364(7):603-15. 
Mintz-Hittner HA, Kuffel RR Jr [2008] Intravitreal injection of bevacizumab (Avastin) for 
treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina; 
28(6):831-8. 
Mota A, Carneiro A, Breda J, et al [2012] Combination of intravitreal ranibizumab and laser 
photocoagulation for aggressive posterior retinopathy of prematurity. Case Rep Ophthalmol; 
3(1):136-41. 
Nazari H, Modarres M, Parvaresh MM, et al [2010] Intravitreal bevacizumab in combination 
with laser therapy for the treatment of severe retinopathy of prematurity (ROP) associated 
with vitreous or retinal hemorrhage. Graefes Arch Clin Exp Ophthalmol; 248(12):1713-8. 
Ng EY, Connolly BP, McNamara JA, et al [2002] A comparison of laser photocoagulation 
with cryotherapy for threshold retinopathy of prematurity at 10 years: Part 1. Visual function 
and structural outcome. Ophthalmology; 109(5):928-34. 


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Palmer EA, Hardy RJ, Dobson V et al [2005] 15-year outcomes following threshold 
retinopathy of prematurity: Final results from the multicenter trial of cryotherapy for 
retinopathy of prematurity. Arch Ophthalmol; 123(3):311-8. 
Qiao-Grider Y, Hung LF, Kee CS, et al [2007] Normal ocular development in young rhesus 
monkeys (Macaca mulatta). Vision Res; 47(11):1424-44. 
Quiroz-Mercado H, Martinez-Castellanos MA, Hernandez-Rojas ML, et al [2008] 
Antiangiogenic therapy with intravitreal bevacizumab for retinopathy of prematurity. Retina; 
28(3 Suppl):S19-25. 
Royal College of Paediatrics and Child Health, Royal College of Ophthalmologists, British 
Association of Perinatal Medicine, BLISS [2008] Guideline for the Screening and Treatment 
of Retinopathy of Prematurity. UK Retinopathy of Prematurity Guideline. May 2008. 
Ryan AM, Eppler DB, Hagler KE, et al [1999] Preclinical safety evaluation of rhuMAb 
VEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol; 27(1):78-86. 
Şahin A, Şahin M, Cingü AK, et al [2013] Intravitreal bevacizumab monotherapy for 
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Sato T, Kusaka S, Shimojo H, et al [2009] Vitreous levels of erythropoietin and vascular 
endothelial growth factor in eyes with retinopathy of prematurity. Ophthalmology; 
116(9):1599-603. 
Sato T, Wada K, Arahori H, et al [2012] Serum concentrations of bevacizumab (Avastin) and 
vascular endothelial growth factor in infants with retinopathy of prematurity. Am J 
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Smith AR, Hennessy JM, Kurth MA, et al [2008] Reversible skeletal changes after treatment 
with bevacizumab in a child with cutaneovisceral angiomatosis with thrombocytopenia 
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Smith LE [2008] Through the eyes of a child: understanding retinopathy through ROP the 
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Zepeda-Romero LC, Liera-Garcia JA, Gutierrez-Padilla JA, et al [2010] Paradoxical 
vascular-fibrotic reaction after intravitreal bevacizumab for retinopathy of prematurity. Eye 
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13 
Appendix 1: Blood log for systemic ranibizumab / 
 samples collection 
Table 13-1 
Time schedule for blood sampling for systemic ranibizumab / 
 
 
Study day 
Dose Ref ID 
Sample ID 
Blood volume (mL) 
Day 1 (within 24h after the 1st 
administration of ranibizumab) 
1 
101 
0.8 (target), 0.5 (minimum) 
Day 15a (7-21 days after the 1st 
administration of ranibizumab) 
1 
102 
0.8 (target), 0.5 (minimum) 
Day 29a (22-28 days after the 1st 
administration of ranibizumab) 
1 
103 
0.8 (target), 0.5 (minimum) 
a  sample to be collected before any investigational treatment on this visit 
14 
Appendix 2: Blood log for systemic VEGF samples 
collection 
Table 14-1 
Time schedule for blood sampling for VEGF 
Study day 
Dose Ref 
ID 
Sample 
ID 
Blood volume (mL) 
Day 1 (before the 1st-administration of 
investigational treatment) 
1 
201 
0.8 (target), 0.5 (minimum) 
Day 15a (7-21 days after the 1st 
administration of investigational treatment) 
1 
202 
0.8 (target), 0.5 (minimum) 
Day 29a (22-28 days after the 1st 
administration of investigational treatment) 
1 
203 
0.8 (target), 0.5 (minimum) 
a sample to be collected before any investigational treatment on this visit 
 

SAP_003.pdf: 
Clinical Development
RFB002/Ranibizumab 
RFB002H2301 / NCT02375971
RAINBOW study: a randomized, controlled study evaluating the efficacy 
and safety of RAnibizumb compared with laser therapy for the treatment 
of INfants BOrn prematurely With retinopathy of prematurity
RAP Module 3 – Detailed Statistical Methodology
Author:
 
Document type:
RAP Documentation
Document status:
Amendment 3
Release date:
Jan 24 2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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List of tables
Table 2-1
Analysis sets used for specific analyses................................................10
Table 2-2
Major Protocol Deviations....................................................................10
Table 2-3
Non-Protocol Deviation Classification Criteria....................................11
Table 2-4
Ranking of Retinopathy of Prematurity Disease...................................12
Table 2-5
Allocation of premature withdrawal visit .............................................13
Table 2-6
Display of the baseline parameters .......................................................20
Table 2-7
Category of refractive error...................................................................30


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Table of contents
List of tables ........................................................................................................................2
Table of contents .................................................................................................................3
1
Statistical methods planned in the protocol and determination of sample size...................7
2
Statistical and analytical plans.............................................................................................7
2.1
Changes to the planned analyses in the protocol.....................................................7
7
2.3
General considerations.............................................................................................8
2.4
Analysis data sets.....................................................................................................8
2.5
Assessment windows, baseline and post baseline definitions, missing data 
handling .................................................................................................................11
2.5.1
Baseline definition and post-baseline definitions .................................11
2.5.2
The last scheduled study visit ...............................................................13
2.5.3
Additional assessment visit schedule....................................................13
2.5.4
Unscheduled visits ................................................................................14
2.5.5
Missing dates.........................................................................................14
2.5.6
Missing baseline data............................................................................17
2.5.7
Missing post-baseline data....................................................................17
2.5.8
Data for permanent study treatment discontinuation ............................19
2.6
Subject disposition, background and demographic characteristics .......................19
2.6.1
Subject disposition ................................................................................19
2.6.2
Background and demographic characteristics.......................................20
2.6.3
Medical history......................................................................................21
2.6.4
Study medication...................................................................................21
2.6.5
Concomitant medication .......................................................................22
2.6.6
Surgery and procedures.........................................................................22
2.6.7
Prohibited treatment..............................................................................23
2.7
Efficacy evaluation................................................................................................23
2.7.1
Analysis for the primary and key secondary objectives........................23
2.7.2
Analysis of secondary variables............................................................27
.28
2.8
Safety evaluation ...................................................................................................28
2.8.1
Risk Management Plan (RMP) adverse events.....................................28
2.8.2
Adverse Events......................................................................................29
2.8.3
Vital signs..............................................................................................30
30


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2.8.5
Laboratory data .....................................................................................30
2.9
Other analysis ........................................................................................................30
30
2.9.2
Pharmacokinetic analysis......................................................................31
2.9.3
Pharmacogenetics/Pharmacogenomics .................................................31
2.9.4
Systemic vascular endothelial growth factor level................................31
31
2.9.6
Hospitalization ......................................................................................31
2.10
Interim analysis......................................................................................................32
32
2.12
Data monitoring committee (DMC) ......................................................................33
33
3
Reference...........................................................................................................................34
34
34
36
36
37
37
37
39


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
Amendment 1
1.
PD table updated, and non-PD table added.
2.
Sections of Determination of sample size updated, 
according to the plan of a reduced sample size.
3.
Sections 2.5.1 and 4 updated to consider a sequential 
testing approach.
4.
Efficacy analysis imputation rules updated according to 
protocol
5.
Combined (ocular and non-ocular) AE tables excluded as 
these are redundant
6.
RMP risk tables and listing included
7.
Section 2.4.4 revised according to TFL shell, and the 
definition of number of days laser treatment received added
8.
Output on rescue medication included
9.
Data reporting rules of additional assessment visits updated
10. SAS code for 95% CI of proportions using Clopper-Pearson 
method included
11. ROP zone information for primary efficacy analysis changed 
to CRF source
 
12. Data exclusion rules for certain PDs updated, resulted from 
alignment made at a meeting
13. AE outputs and safety observation period revised, by 
removing the separate sets of before/after switch
14. PK and anti-VEGF analyses removed, and will be included 
in a separate report
15. Lab summary tables removed due to heterogeneity of data 
collected at local labs.
16. Prohibited medication will not be displayed separately, as 
these will be identified manually. Instead, they will be shown 
as part of the PDs in the PD outputs.
17. CTSD required outputs added.
Amendment 2
1.
Revised the definition of number of days laser treatment 
received, added the definition of duration of laser treatment
2.
Imputation rules in Section 2.4.7.1 clarified
3.
Definitions of PK set and VEGF population set added. 
Outputs of PKPD added in Sections 2.8.x
 
6.
One deviation text updated
Amendment 3
1. Sensitivity analysis to the primary analysis included, with a 
modified imputation rule – Imputation rule 2.


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List of abbreviations
AE
Adverse event 
AP-ROP
Aggressive posterior retinopathy of prematurity 
ATC
Anatomical Therapeutic Chemical (classification system)
BEAT-ROP
Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of 
Prematurity (study) 
BL
Baseline 
CSR
Clinical study report 
DAR
Drug Administration Record
DMC
Data Management Committee
eCRF 
Electronic case report/record form
FAS
Full analysis set 
IRT
Interactive Response Technology 
MedDRA
Medical Dictionary for Regulatory Activities 
PD
Protocol deviation 
PK
Pharmacokinetic
PPS
Per-protocol set 
PT
Preferred term
RAP
Reporting analysis plan 
RMP
Risk management plan
ROP
Retinopathy of prematurity 
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SI
International System of Units 
SOC
System organ class 
VEGF
Vascular endothelial growth factor
WHO
World Health Organization


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1
Statistical methods planned in the protocol and 
determination of sample size
This Report and Analysis Plan (RAP) describes the statistical analysis according to Section 9 
of the study protocol and along with any additional analyses, specifications or deviations from 
the protocol planned.
This document is written in the future tense. It will be reviewed and updated (including 
conversion to past tense) for entry into the clinical study report (CSR) after the analysis has 
taken place. The analyses described in this document will be conducted using SAS version 9.4 
or later 
2
Statistical and analytical plans
The planned analysis is described in Section 9 of the Study Protocol (Appendix 16.1.1). 
This is an open-label study where the CTT team is not masked to the patient level clinical or 
PK data. However, to minimize the impact of assignment knowledge, aggregated statistical 
analysis done by treatment arm will be kept confidential from the CTT until DBL. Therefore,
the CTT will not have access to the DMC closed session outputs. 
Dry runs will be performed by assigning dummy variable to the three treatment groups so that
each dummy group will have a randomly assigned mixture of patients from both dose groups. 
2.1
Changes to the planned analyses in the protocol
 
 
 
 
 
Therefore, in the primary efficacy analysis, stratification 
 
information recorded at the screening visit from the CRF page. In addition, a sensitivity 
analysis will be performed 
 
. 
 
 
 
The population PK and VEGF analyses mentioned in Sections 9.5.4 and 9.5.6, respectively, of 
the protocol will be described in a separate report, other than in the CSR.


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2.3
General considerations 
All analyses will be based on the assessments according to the investigator. 
 
 
Study treatment refers to both study ranibizumab and laser therapy. In this document, patient 
and subject are used interchangeably in the document.
During the study, the patient can switch treatment (also called rescue treatment). A patient 
randomized to ranibizumab can receive switch/rescue laser therapy in either eye; a patient 
randomized to laser therapy can receive switch/rescue ranibizumab 0.2 mg in either eye.
Assessments documented in the database that occur as “bilateral” will be summarized and 
listed for each eye separately. To facilitate derivations and analysis based on eye, database 
records for bilateral will be split into two records containing identical information as the 
original record with the exception of the laterality which shall be recoded to “Right” and 
“Left”, respectively.
Change from baseline will only be summarized for patients with both baseline and post-
baseline values for the relevant visit and will be calculated as:
Change from baseline = post-baseline value – baseline value
Descriptive statistics (mean, median, standard deviation, lower quartile (Q1), upper quartile 
(Q3), minimum and maximum values) will be presented for continuous variables. The number 
and percentage of patients in each category defined will be presented for categorical variables.
If a confidence interval is presented for the proportion of a categorical variable, then the exact 
Clopper-Pearson method will be used to calculate the 2-sided 95% confidence interval. 
All data will be listed/summarized by patient unless otherwise specified. 
2.4
Analysis data sets 
The following data sets are defined for the trial.
The Screened Set will consist of all patients whose parent(s) or legal guardian(s) has 
provided informed consent.
The data from patients whose parent(s) or legal guardian(s) has not provided informed 
consent prior to any study procedures will be listed only and will not be used in any analyses.


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This is expected to occur extremely rarely and would be regarded as violation of good clinical 
practice. 
The Randomized Set will consist of all randomized patients.
The Full Analysis Set (FAS) will comprise all patients from the Randomized Set to whom 
treatment regimen has been assigned. Following the intent-to-treat principle, patients will be 
analyzed for efficacy according to the treatment regimen they are assigned to at randomization.
The Per Protocol Set (PPS) will consist of all patients in the Full Analysis Set who follow 
the treatment regimen as randomized and complete the study period for the analysis of the 
primary and key secondary objectives without clinically important protocol deviations. 
Clinically important protocol deviations will be identified and documented prior to the 
database lock in the latest version of the Data Review Plan.
The Safety Set (SAF) will consist of all patients who receive at least one application of study 
treatment and have at least one post baseline safety assessment. The statement that a patient 
has no AEs also constitutes a safety assessment. Reports using safety set will be by initial 
treatment received at baseline. 
 
The VEGF Set will consist of all patients who provide valid VEGF plasma samples. Reports 
using the VEGF Set will be by initial treatment received at baseline.
The PK Set will consist of all patients who provide valid pharmacokinetic serum samples. 
Report using the PK Set will be by initial treatment received.


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Table 2-1 shows the analyses sets to be used for specific analyses.
Table 2-1
Analysis sets used for specific analyses
Screened 
set
Rando-
mized Set
FAS
PPS
SAF
PK 
Set
VEGF 
Set
 
 
Screen failures 
x
Demographics and 
baseline 
characteristics
x
Patient disposition
x
Protocol deviations
x
Medical history
x
Primary efficacy 
analysis 
x
Other efficacy 
analyses 
x
Subgroup analyses
x
Sensitivity analyses 
x
x
Concomitant 
medication 
x
Safety analyses
x
Exposure 
x
Prior medication
x
Hospitalization 
x
PK
x
VEGF 
x
Table 2-2 and Table 2-3 defines the rules for subject classification in the analysis sets based 
on important CSR reportable protocol deviation IDs and non-protocol deviation classification 
criteria.
Table 2-2
Major Protocol Deviations
PD ID
Deviation Text
Data exclusion
INCL01
Informed consent is not obtained before study related assessment 
performed
Exclude from 
Randomized set, FAS, 
SAF, and PPS
INCL02
Patient did not satisfy protocol specified weight criteria
Exclude from PPS
INCL03
Absence of indication to be studied in either eye (as defined in the 
protocol)
Exclude from PPS
EXCL01
Presence of ROP disease characteristics which is exclusionary in 
either eye
Exclude from PPS
EXCL02
Prohibited medication or procedure indicated in protocol exclusion 
criteria (with potential impact on key efficacy assessments)
Exclude from PPS


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PD ID
Deviation Text
Data exclusion
EXCL03
Medical/ocular history or conditions indicated in protocol exclusion 
criteria (with potential impact on key efficacy assessments)
Exclude from PPS
TRT01
Wrong dose/wrong treatment given
Exclude from PPS
TRT02
Non-adherence to dosing algorithm as per protocol, except for 
valid medical reasons (re-treated wrongly, switched wrongly)
Exclude from PPS
WITH01
Patient was not discontinued from the investigational treatment 
despite administration of prohibited concomitant medications and 
procedures
Exclude from PPS
WITH02
Patient was not withdrawn from the study despite withdrawal of 
consent
Exclude from 
Randomized set, FAS, 
SAF, and PPS
WITH03
Patient was not discontinued from study treatment despite PD 
with a significant risk to the patient’s safety
Exclude from PPS
OTH1
Any other protocol deviation with impact on primary efficacy 
endpoint or key secondary efficacy endpoint
Exclude from PPS  
COMD01
Prohibited concomitant medications and procedures taken during 
the study (with impact on efficacy)
Exclude from PPS
Table 2-3
Non-Protocol Deviation Classification Criteria
Analysis Set
Non-PD criteria that cause patients to be excluded
Randomized set
Not randomized
FAS
Not in the RAN
Mis-randomized
PPS
Not in the FAS
Did not complete the study
SAF
Did not receive at least one study treatment
Did not record at least one post-Baseline safety assessment
In addition, it should be noted that the analysis data sets for this study are based on the 
Novartis Clinical Data Standards.
2.5
Assessment windows, baseline and post baseline definitions, 
missing data handling
2.5.1
Baseline definition and post-baseline definitions 
Baseline (day 1) for treated patients is the date of the first study treatment in either eye. 
The baseline value for efficacy and safety variables is the last available, non-missing value 
collected prior to baseline (i.e., prior to receiving the first study treatment for treated patients). 


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If a patient is randomized but not treated, then the baseline value for a variable is the last 
available non-missing value collected prior to or on the day of randomization.
Baseline assessments may be recorded on the day of the baseline visit or randomization. The 
assessments, according to the protocol, conducted before the first study treatment at the 
baseline visit will be used when deriving baseline values recorded at the baseline visit.
All data collected after day 1 are defined as post-baseline.
The study day relative to baseline for a scheduled or unscheduled visit which is on or after the 
date of first study treatment in either eye is defined as
Study day = (Date of visit) – (date of first study treatment in either eye) + 1
The study day relative to baseline for a scheduled or unscheduled visit which is before the 
date of first study treatment in either eye is defined as
Study day = (Date of visit) – (date of first study treatment in either eye)
 
 
 


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Plus disease is defined as vascular tortuosity and dilatation in at least 2 quadrants of the eye 
(International Committee for the Classification of Retinopathy of Prematurity 2005). 
 
 
 
 
2.5.2
The last scheduled study visit 
The last scheduled study visit will be the latest of (premature withdrawal Visit 199, Visit 112, 
last additional assessment visit as per protocol). 
The study day for the premature withdrawal Visit 199 will be allocated to the nearest planned 
main visit. If data for the nearest planned main visit already exist then the premature 
withdrawal visit will be assigned to the next main visit. In case the Visit 199 happens on the 
same day as a scheduled visit, then Visit 199 will be re-mapped to the next visit number of 
that scheduled visit. All applicable assessments will be captured by scheduled visit, while visit 
199 only contains the assessments specific to premature withdrawal visits. 
 
 
2.5.3
Additional assessment visit schedule 
The additional assessment visits are triggered by a post-baseline treatment (re-treatment with 
ranibizumab or switch treatment with ranibizumab or laser therapy) (see Section 6 of 
Protocol). When a visit as per the additional assessment schedule coincides with a visit as per 


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the main assessment schedule, assessments have to be performed as per the main assessment 
schedule.
For analyses by visit, only data of planned main visits will be reported. For analyses up to a 
certain time point, data of both planned main visits and additional assessment visits up to that 
time point will be considered. E.g., analyses on outcomes at or before 24 weeks after the first 
study treatment will not consider data collected at additional assessment visits after the 
planned main visit of week 24, 
 All data collected at additional assessment visits 
will be listed.   
2.5.4
Unscheduled visits
All data collected at unscheduled visits will be listed. 
All safety and exposure to treatment data collected at unscheduled visits will be considered.
Efficacy collected at unscheduled visits will not be used except when imputing missing 
primary variable values as Section 2.5.7. 
Other data collected at unscheduled visits will not be used for tables and graphs analyzing 
post-baseline data when reporting by scheduled visit.
2.5.5
Missing dates 
The general approach to handling missing dates is shown below for dates of AEs (Section 
2.5.5.1 and Section 2.5.5.2), medical history diagnosis (Section 2.5.5.3), and concomitant 
treatment (Section 2.5.5.4 and Section 2.5.5.5). The imputation of missing dates for surgery or 
procedures will use the same rules as for concomitant treatment.
The detailed algorithms will appear in Programming Dataset Specifications.
For the purpose of date imputation, the treatment follow up period date is defined as the last 
available visit date.
2.5.5.1
Adverse event end date imputation
If the AE end date month is missing, the imputed end date should be set to the earliest of the 
(treatment follow up period date, 31DECYYYY, date of death).
If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(treatment follow up period date, last day of the month, date of death).
If AE year is missing or AE is ongoing, the end date will not be imputed. If the imputed AE 
end date is before the corresponding AE start date then the AE end date will be set to the AE 
start date.
2.5.5.2
Adverse event start date imputation
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.


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Partial AE start dates are imputed with reference to the treatment start date (TRTSTD) as 
outlined in the Imputation table below. 
Before imputing the AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min (informed consent date, earliest visit date).
2. Else AE start reference date = treatment start date
Completely missing start dates will not be imputed. As a conservative approach, such adverse 
events will be defined as treatment emergent.
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) = 01JULYYYY
Before Treatment 
Start
(C) = 
15MONYYYY
Before 
Treatment Start
(C) = 
15MONYYYY
Before 
Treatment Start
(C) = 
15MONYYYY
Before 
Treatment Start
YYYY = 
TRTY
(B) = AE start 
reference date + 1 
day
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
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
AE start reference date+1
(C) Before Treatment Start
15MONYYYY
(D) Before Treatment Start
01JULYYYY
(E) After Treatment Start
01JANYYYY


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If complete (imputed) AE end date is available and the imputed AE start date is greater than 
the (imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end 
date.
2.5.5.3
Medical history date of diagnosis imputation
Completely missing dates and partially missing end 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)

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 

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

else if DIAG month < treatment start month, the imputed DIAG date is set to the mid-
month point (15MON YYYY)

else if DIAG month > treatment start month => data error

If DIAG year > treatment start date year => data error
2.5.5.4
Concomitant treatment end date imputation
If the concomitant treatment end date year value is missing, the date uncertainty is too high to 
impute a reliable date.  Therefore, if the concomitant treatment end year value is missing or 
ongoing, the imputed concomitant treatment end date is set to NULL.
Else, if the concomitant treatment end date month is missing, the imputed end date should be 
set to the earliest of the (treatment follow up period date, 31DECYYYY, date of death).
If the concomitant treatment end date day is missing, the imputed end date should be set to the 
earliest of the (treatment follow up period date, last day of the month, date of death).
If the imputed concomitant treatment end date is before the existing concomitant treatment 
start date, use the concomitant treatment start date as the imputed concomitant treatment end 
date.
2.5.5.5
Concomitant treatment start date imputation 
In order to classify a medication as prior and prior/concomitant, it may be necessary to impute 
the start date. Completely missing start dates will be set to one day prior to treatment start date. 
As a conservative approach, such treatments will be classified as prior and concomitant (and 
summarized for each output). 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: 
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date (TRTSTD)
Not used
TRTM
TRTY


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The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY MISSING
(C)
Uncertain
(C)
Uncertain
(C)
Uncertain
(C)
Uncertain
YYYY < TRTY
(D) = 01JULYYYY
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
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
No convention
(A) Before Treatment Start
15MONYYYY
(B) After Treatment Start
MAX( 01MONYYYY, TRTSTD+1 )
(C) Uncertain
TRTSTD-1
(D) Before Treatment Start
01JULYYYY
(E) After Treatment Start
01JANYYYY
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date.
2.5.6
Missing baseline data
Missing baseline data will not be imputed. This includes variables which are not allowed to be 
collected according to local regulations (e.g. race in France).
2.5.7
Missing post-baseline data 
Observations with values ‘not done’, ‘not evaluable’, ‘not applicable’ will be treated as 
missing values. 


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2.5.7.2
Safety data
Apart from AE and concomitant medication dates, missing post-baseline safety data will not 
be imputed.


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2.5.7.3
Other data
Missing data for other variables such as PK will not be imputed unless otherwise specified.
2.5.8
Data for permanent study treatment discontinuation 
Patients that permanently discontinue study treatment will remain in the study and all planned 
assessments should be conducted. No change to the planned analyses will be made for such 
patients that do not receive a prohibited treatment (as defined in Section 5.5.8 of the protocol). 
As specified in Table 2-2, patients that receive a prohibited treatment will be excluded from 
the PPS. In addition, the data for these patients will be censored in the FAS at the date of the 
first administration of such treatment. If there is a large (or disproportionate across treatment 
arms) number of patients that receive a prohibited treatment then a sensitivity analysis will be 
conducted without censoring the data. 
2.6
Subject disposition, background and demographic 
characteristics
Outputs for subject disposition, background and demographic characteristics will be reported 
by the randomized set presented for each randomized treatment arm and total.
No tests for differences in background and demographic characteristics among treatment arms 
will be performed.
2.6.1
Subject disposition
The number and percentage (based on the number of patients within each randomized 
treatment arm) of patients who complete the study will be displayed by randomized treatment 
and overall. The primary reason for premature study discontinuation and permanent study 
treatment discontinuation will be displayed by randomized treatment and overall. 
The total number of patients screened and the number of patients screened, but not 
randomized will be shown. The primary reason for screening failures will be summarized. 
The number of patients randomized but did not receive treatment will also be summarized by 
randomized treatment. 
The number of patients with PDs and non-PDs according to the applicable SOP will be 
presented. The results of the PDs will be grouped using the broad categories defined in the 
applicable SOP, which currently are:

Eligibility: Patient did not satisfy entry criteria 

Withdrawal: Patient developed study/treatment withdrawal criteria during the study, but 
was not withdrawn 

Study Drug: Patient received the wrong treatment or incorrect dose  

Concomitant Medication: Patient took an excluded concomitant medication 

Other reportable protocol deviation 
The number of patients within each of the analysis sets used in the study will be given.
Patients with PDs and non-PDs leading to data exclusion from analysis sets will be listed.


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Patients removed from the randomized set will not appear in the summary of protocol 
deviations. These patients will be documented in the output summarizing the patients 
excluded from analysis sets.
2.6.2
Background and demographic characteristics
Descriptive statistics (mean, median, standard deviation, minimum and maximum, quartiles 1
and 3) will be presented for the continuous variables. The number and percentage of patients 
will be presented for categorical variables. Table 2-6 shows the allocation of baseline 
parameters into groups and which are displayed as continuous and/or categorical variables. 
Thresholds to convert continuous to categorical variables will be given in RAP Module 7.1.
Table 2-6
Display of the baseline parameters
Demogra
phic
ROP characteristics  and 
relevant medical history
Contin-
uous 
Cate-
gorical
Race
x
x
Ethnicity (based on that of mother)
x
x
Sex 
x
x
Gestational age at birth (week)
x
x
x
Chronological age at baseline (week)
x
x
Postmenstrual age at baseline (week)
x
x
Birth weight (g)
x
x
x
Birth length (cm)
x
x
x
Head circumference at birth (cm)
x
x
x
ROP disease status by patient 
x
x
ROP disease status by eye (worst/best)
x
x
Time from first diagnosis of ROP 
(weeks)
x
x
x
Chronological age and Post-menstrual age will be calculated from core study baseline as 
below: 
 


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2.6.3
Medical history 
Medical history outputs will be based on the randomized set displayed by treatment and 
overall. The reporting level will be by patient (not eye). Separate tables will be provided for 
ocular and non-ocular histories and conditions.
Relevant medical history and current medical conditions will be tabulated by system organ 
class (SOC) and preferred term (PT) of the latest Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary. The SOCs will be presented in alphabetical order. Preferred terms will 
be ordered within each SOC by decreasing proportion in the ranibizumab 0.2 mg treatment 
arm.
2.6.4
Study medication
Exposure will be calculated for patients in the SAF. Note that only study ranibizumab, and 
laser treatment as collected in the Drug Administration Record (DAR) eCRF panel will be 
included. Treatments collected as a concomitant medication will not be included in the study 
medication analysis.  
Exposure to ranibizumab is defined as the number of injections of ranibizumab received by 
worst/best eye (as defined in Section 2.3) and by patient. For example, a patient who only 
receives ranibizumab treatment in both eyes at baseline will be recorded as having received 
two ranibizumab injections in total. If the patient additionally receives a single ranibizumab 
injection in only one eye at a later date then the total number of ranibizumab injections will be 
recorded as three in total. 
The total number of ranibizumab injections will be summarized by worst/best eye and by 
patient by initial treatment received at baseline. 
The number of days laser treatment was received will also be displayed. By considering only 
laser treatment recorded on the DAR page (not the ConMed page), count the number of days 
laser treatment received in the following way.

Each laser treatment for either eye received not on the same day will be counted as 1 
day (Laser treatment is considered to have been received if on the DAR laser page, 
‘number of laser applications’ is not entered as 0 or NA);

 
 
 


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In addition, duration of the safety observation period will be summarized by treatment group
(initial treatment received at baseline). Safety observation period (days) is defined as: date of 
last visit – date of first study treatment  in either eye +1.
Moreover, number of patients requiring 
ranibizumab treatments by ROP 
zone and combined, and number of days laser treatment received will be summarized by eye 
and by subject for SAF and FAS.
2.6.5
Concomitant medication 
Separate listings and summaries will be produced for ocular and non-ocular for both prior and 
concomitant medication according to the investigator’s response to the relevant CRF page. 
Prior medications are defined as those taken and stopped prior to the date of first study 
treatment. Any medication given at least once on or after the first study treatment date will be 
defined as a concomitant medication including those which were started before first study 
treatment date and continued after first study treatment date. Prior or concomitant medication
will be identified based on recorded or imputed start dates of medication taking. The rules for 
imputing incomplete start and end dates are described in Section 2.5.5.4 and Section 2.5.5.5
respectively. Medications with start date equal to that of first study treatment will be classified 
as concomitant.  
Medications will be identified by preferred term (PT) according to the latest World Health 
Organization (WHO) Drug Reference List dictionary and ATC code. Tables will show the 
overall number and percentage of patients within the treatment arm receiving at least one dose 
of the medication ordered by decreasing frequency in the ranibizumab 0.2 mg treatment arm. 
2.6.6
Surgery and procedures
Surgery and procedures will be displayed together and separately from concomitant 
medications.
The same approach will be taken to display surgeries and procedures as specified for 
concomitant medications in section 2.5.5. 


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2.6.7
Prohibited treatment
Analysis of concomitant medications that are prohibited as per protocol (shown in protocol 
Table 5-1) and given during the conduct of the study as well as significant non-drug therapies 
will be addressed by the currently planned outputs of the Protocol deviations. No separate 
outputs will be produced related specifically to prohibited medications, as stated in the 
protocol.
2.7
Efficacy evaluation
2.7.1
Analysis for the primary and key secondary objectives 
2.7.1.1
Primary objective and key secondary objectives 
The primary objective is to demonstrate that:

Intravitreal ranibizumab 0.2 mg has superior efficacy to laser therapy in the treatment of 
ROP as measured by the absence of active ROP and absence of unfavorable structural 
outcomes in both eyes 24 weeks after starting study treatment, 
 
 
The key secondary objectives are to demonstrate that:

The intravitreal ranibizumab 0.1 mg has superior efficacy to laser therapy in the treatment 
of ROP as measured by the absence of active ROP and absence of unfavorable structural 
outcomes in both eyes 24 weeks after starting study treatment, 
 

The intravitreal ranibizumab 0.2 mg has superior efficacy to intravitreal ranibizumab 0.1 
mg in the treatment of ROP as measured by the absence of active ROP and absence of 
unfavorable structural outcomes in both eyes 24 weeks after starting study treatment, 
 
2.7.1.2
Primary efficacy variable 
The primary efficacy variable is the absence of active ROP and absence of unfavorable 
structural outcomes in both eyes 24 weeks after starting study treatment, 
 
 To achieve this outcome, patients cannot fulfill any of the following criteria:

Death at or before the 24-week assessment visit

Requires intervention for ROP in either eye at or before the 24-week assessment visit with 
a treatment modality other than the modality of the first study treatment

Have active ROP in either eye at the 24-week assessment visit 
 

Have unfavorable structural outcomes in either eye at or before the 24-week assessment 
visit 


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A patient may be defined as a “success” (favorable outcome) or “failure” (unfavorable 
outcome) for each of the criteria above. Patients will be defined as a “success” for the primary 
efficacy variable only if they are a “success” for each component. Consequently a patient will 
be defined as a “failure” for the primary efficacy variable if they are defined a “failure” for at 
least one of the criteria above.
A 2-sided family-wise type I error rate of 5% will be used. Two-sided exact 95% confidence
intervals will be presented for the primary variable event rate within each treatment arm, 
overall and by zone (see Section 2.11). 


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2.7.1.4
Handling of missing primary efficacy variable
Please refer to Section 2.5.7.1. 
2.7.1.5
Supportive analysis for primary efficacy 
The robustness of the primary analysis (testing the hypotheses specified in Section 2.7.1.3)
may be assessed by:

Repeating the primary analyses using the Per Protocol Set

Repeating the primary analyses without imputing missing data at Week 24

Repeating the primary analyses imputing  missing primary efficacy variable at Week 24 
with ”success” 

Repeating the primary analyses imputing missing primary efficacy variable at Week 24 
with “failure”

Repeating the primary analyses with imputation rule 2
The primary efficacy variable will also be assessed by a binary logistic regression model by 
using treatment arm 
as factors. The odds ratio 
of the primary variable will be displayed (with values greater than one in favor of 
ranibizumab) with its two-sided 95% confidence interval and one-sided p-value. If the number 
of events of some cells is very small (<5 for at least one cell), then exact logistic regression 
will be used to assess the primary efficacy variable (Please refer to Section 4.2 for SAS code).  
 
The subgroup and its interaction with treatment will be added to the binary logistic regression 
model above and the p-value for the subgroup by treatment interaction term will be displayed. 


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The binary logistic model with treatment arm and ROP zone will be fitted to each subgroup 
level separately and the odds ratio of the primary variable with its two-sided 95% confidence 
interval will be presented. 
2.7.2
Analysis of secondary variables 
All secondary efficacy analyses will be performed on the FAS based on observed data unless 
otherwise specified. No imputation of missing data will be undertaken on secondary efficacy 
variables. 
2.7.2.1
Binary variables 
The following binary variables will be summarized giving the number and percentages (with 
Clopper-Pearson exact 2-sided 95% confidence interval) for each treatment arm overall and 
by zone

Each of the components that constitute the definition of primary variable will be presented. 
Note that if a patient switches treatment then each of the other components will be defined 
as “failure”.

Each of the following unfavorable structural outcomes in either eye at or before 24 weeks 
after the first study treatment, 

Recurrence of ROP receiving any post-baseline intervention at 24 weeks or before 
2.7.2.2
Time-to-event variable 
The time from the first study treatment to the first occurrence of one of the following event:

Death

Intervention for ROP with a treatment modality other than the modality of the first study
treatment 


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
An unfavorable structural outcome 
 
will be evaluated using data collected at all visits from baseline until the last study visit 
inclusive. 
 
Please refer to Section 4.3 for SAS code. 
2.8
Safety evaluation
Safety analyses will be conducted on data from SAF by initial treatment received. Adverse 
events, vital signs measurements, requirement for respiratory support and laboratory 
evaluations will be summarized and listed.
The safety observation period (days) for treated patients begins at the first administration of 
study treatment in either eye. It finishes at the last study visit. 
Safety observation period (days) is defined as 
date of last study visit–date of first study treatment in either eye + 1
The safety observation period [days] will be summarized by treatment for patients in the SAF. 
2.8.1
Risk Management Plan (RMP) adverse events
The number and percentage of patients who report adverse events (AEs) as safety risks (based 
on selected preferred terms) by the current version of the Risk Management Plan (RMP) at the 
time of database lock, will be summarized by risk categories for ocular and systemic safety 
risks separately for patients who receive monotherapy and those who receive both treatment 
modalities. In addition, the analysis will include number and percentage of patients with each 
of the preferred terms that define each of the safety risk categories. Detailed specifications to 


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identify which MedDRA preferred terms belong to which risk category will be added later –
based on the valid RMP at that time-point. 
A listing for AEs of safety risk by preferred term will also be produced.
2.8.2
Adverse Events 
As a default, no summary tables for AEs that occur prior to the first study treatment in either 
eye will be produced.
Adverse events that occur prior to the first study treatment in either eye will be listed for 
patients in the randomized set using the randomized treatment. 
Adverse events will be deemed treatment emergent if the AE start time is on or after the time 
of dose of the first study treatment. When an AE’s start date is equal to the date of first study
treatment and either the start time of AE or the first treatment time is missing, AEs are defined 
as treatment emergent. As stated in Section 2.5.5, adverse events with completely missing 
start date will be defined as treatment emergent.
The number of patients with AE and the incidence rates will be tabulated by treatment using 
the latest MedDRA SOCs and PTs. The SOCs will be presented in alphabetical order and PTs 
will be ordered within the SOC by decreasing proportion in the ranibizumab 0.2 mg treatment 
arm. Patients who experienced multiple AEs for a preferred term will be counted once, 
similarly for patients with multiple AEs per system organ class. Separate In-text tables will 
display the frequency of AEs at the SOC and PT levels. Post-text table will commonly display 
the frequency of AEs at the PT levels within the relevant SOC.
Only treatment-emergent AEs will be summarized, separately for ocular and non-ocular AEs 
(according to the investigator’s response to the AE CRF form). All AE tables will be 
summarized separately by initial study treatment received at baseline, and by patients who 
switch/do not switch treatment modality after receiving the initial study treatment at baseline. 
All AE tables will show the frequency and crude incidence rate by initial study treatment 
received at baseline and total. The following AE tables will be produced for ocular and non-
ocular AEs separately.

All adverse events regardless of study treatment or procedure relationship 

Serious adverse event, regardless of study treatment or procedure relationship 

All adverse events suspected to be related with study treatment or procedure

Serious adverse event suspected to be related with study treatment or procedure 

All adverse events causing permanent study treatment discontinuation 

All adverse events causing permanent study discontinuation 

All adverse events by maximum severity (mild, moderate, severe)
In addition, the following summaries will be produced.

Primary reasons for deaths

Deaths, SAE, or AE leading to permanent study treatment discontinuation 
All AEs, deaths, SAEs, and AEs leading to permanent study drug discontinuation will be 
listed separately. 


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In addition, CTSD required tables will be presented as part of the CSR, i.e.: deaths and serious 
adverse events by system organ class and preferred term, non-serious adverse events by 
system organ class and preferred term.
2.8.3
Vital signs 
Vital signs (weight, body length, head circumference, lower leg length, and blood pressure 
(systolic/diastolic)) will be summarized by presenting summary statistics (n, mean, median, 
standard deviation, min, max, quartiles 1 and 3) of values and change from baseline at days 85 
and 169 
 
 by treatment arm.
2.8.5
Laboratory data 
Laboratory assessments (hematology, chemistry, urinalysis) are collected at local labs with 
heterogeneity across different labs. Therefore, only listings will be provided for each 
individual at baseline, days 85 and 169 by treatment arm.
2.9
Other analysis 
2.9.1.1
Electrocardiogram (ECG)
Not applicable


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2.9.2
Pharmacokinetic analysis 
For patients who receive initial ranibizumab treatment and with an odd patient identification
number, blood samples (Appendix 1) for the determination of ranibizumab concentrations will
be collected at the following time points:
Within 24 hours after the first administration of ranibizumab
At Day 15, 
At Day 29, 
All patients providing valid pharmacokinetic serum samples will be included in the PK 
analysis population. Individual ranibizumab concentrations versus time profiles, as well as 
mean and SD plot over time will be displayed graphically. Moreover, a summary table will be 
provided. 
2.9.3
Pharmacogenetics/Pharmacogenomics
Not applicable. 
2.9.4
Systemic vascular endothelial growth factor level 
For patients who receive initial ranibizumab treatment and with an even patient identification
number and for all patients who receive initial laser therapy, blood samples (Appendix 2) for
the determination of systemic VEGF levels (i.e., pharmacodynamics) will be collected at the
following time points:
Before the first investigational treatment
At Day 15, 
At Day 29, 
All patients providing valid VEGF plasma samples will be included in the VEGF analysis
population. Individual VEGF concentrations versus time profiles, as well as mean and SD plot 
over time will be displayed graphically. Summary statistics table will be presented for VEGF 
samples.
2.9.6
Hospitalization 
The duration of hospitalization and the weight at hospital discharge will be summarized and 
tabulated by treatment. 


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2.10
Interim analysis
There will be no interim analyses during this trial. 


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2.12
Data monitoring committee (DMC)
An independent DMC will be established to monitor the safety of the trial participants to 
ensure that the trial is being conducted with the highest scientific and ethical standards and 
make appropriate recommendations based on the data seen.
Refer to the DMC charter which includes the DMC membership and responsibilities, the 
timing of DMC meetings, the content of the analysis report for the DMC meetings, and the 
communication with the Sponsor. The DMC will only make recommendations for changes in 
study conduct.


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3
Reference 
1. A note on the power of Fisher’s least significant difference procedure, Meier U., 
Pharmaceutical Statistics, 2006; 5 (4): 253-63. 


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