Conditions: Retinopathy of Prematurity (ROP)
Keywords: open-label, long-term, extension study, intravitreal ranibizumab, laser ablation therapy, retinopathy of prematurity, preterm infants, RAINBOW
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the long term efficacy and safety of intravitreal ranibizumab compared with laser ablation therapy in patients who were treated for retinopathy of prematurity (ROP) in the core study CRFB002H2301 (NCT02375971)

Detailed description:
This was a multicenter, open-label extension study where the Visual Acuity (VA) assessment at the child's 5th birthday visit was performed. The study had 2 distinct periods (Epochs). Treatment with study ranibizumab (either as retreatment after ranibizumab had already been injected in the same eye or as switch ranibizumab treatment from study laser therapy administered in the core study) was permitted for eligible eyes with recurrence/worsening of ROP up to and including Week 40 from the baseline visit in the core study (Epoch 1). The remainder of the extension study up to the 5th birthday visit (Epoch 2) was observational, with no study treatment planned to be administered.

In the core study, patients were randomized to 1 of the 3 treatment arms (ranibizumab 0.2 mg, ranibizumab 0.1 mg, and laser). Treatment arm assignment and patient identifier in the extension study remained the same as in the core study.

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 therapy

Interventions: intervention 1: Ranibizumab
Intervention descriptions: intervention 1: 1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine
RFB002/Ranibizumab
Clinical Trial Protocol CRFB002H2301E1 / NCT02640664
RAINBOW extension study: an extension study to evaluate 
the long term 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:
2014-004048-36 (PIP number: 000527-PIP04-13)
Version number:
v02 (Clean)
Clinical trial phase:
III
Release date:
10-Jul-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 03 (August 2015)


Novartis
Confidential
Page 2
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................4
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 2 ......................................................................................................................9
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.1.1
Ranibizumab .........................................................................................16
1.2
Purpose ..................................................................................................................19
2
Study objectives and endpoints .........................................................................................19
2.1
Primary objective(s)...............................................................................................19
2.2
Secondary objective(s)...........................................................................................19
19
2.4
Objectives and related endpoints...........................................................................19
3
Investigational plan ...........................................................................................................25
3.1
Study design...........................................................................................................25
3.2
Rationale for study design .....................................................................................25
3.3
Rationale for dose/regimen, route of administration and duration of treatment....26
3.4
Rationale for choice of comparator .......................................................................26
3.5
Purpose and timing of interim analyses/design adaptations..................................26
3.5.1
Interim analysis 1 ..................................................................................26
3.5.2
Interim analysis 2 ..................................................................................27
3.6
Risks and benefits..................................................................................................27
4
Population..........................................................................................................................29
4.1
Inclusion criteria ....................................................................................................29
4.2
Exclusion criteria...................................................................................................30
5
Treatment...........................................................................................................................30
5.1
Study treatment......................................................................................................30
5.1.1
Investigational and control drugs..........................................................30
5.1.2
Additional treatment..............................................................................30
5.2
Treatment arms......................................................................................................30
5.3
Treatment assignment and randomization.............................................................31
5.4
Treatment blinding.................................................................................................31


Novartis
Confidential
Page 3
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
5.5
Treating the patient................................................................................................31
5.5.1
Patient numbering .................................................................................31
5.5.2
Dispensing the study drug.....................................................................31
5.5.3
Handling of study and additional treatment..........................................31
5.5.4
Instructions for prescribing and taking study treatment........................32
5.5.5
Permitted dose adjustments and interruptions of study treatment ........33
5.5.6
Rescue medication ................................................................................33
5.5.7
Concomitant medication .......................................................................34
5.5.8
Prohibited medication ...........................................................................34
5.5.9
Emergency breaking of assigned treatment code..................................34
5.6
Study Completion and Discontinuation.................................................................35
5.6.1
Study completion and post-study treatment..........................................35
5.6.2
Discontinuation of Study Treatment.....................................................35
5.6.3
Premature patient withdrawal from the study.......................................35
5.6.4
Loss to follow-up ..................................................................................36
5.6.5
Early study termination by the sponsor.................................................36
6
Visit schedule and assessments .........................................................................................36
6.1
Information to be collected on screening failures..................................................42
6.2
Patient demographics/other baseline characteristics .............................................42
6.3
Treatment exposure and compliance .....................................................................42
6.4
Efficacy..................................................................................................................42
6.4.1
Ophthalmic fundus features ..................................................................42
6.4.2
Ocular and visual function ....................................................................43
6.4.3
Visual Acuity (VA)...............................................................................43
6.4.4
Appropriateness of efficacy assessments..............................................44
6.5
Safety.....................................................................................................................44
6.5.1
Ocular examination...............................................................................44
6.5.2
Vital signs..............................................................................................44
6.5.3
Health status..........................................................................................45
6.5.4
Laboratory evaluations..........................................................................45
6.5.5
Appropriateness of safety measurements..............................................45
46
46
7
Safety monitoring..............................................................................................................46
7.1
Adverse events.......................................................................................................46
7.2
Serious adverse events...........................................................................................48


Novartis
Confidential
Page 4
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
7.2.1
Definition of SAE .................................................................................48
7.2.2
SAE reporting........................................................................................49
7.3
Reporting of study treatment errors.......................................................................50
8
Data review and database management.............................................................................51
8.1
Site monitoring ......................................................................................................51
8.2
Data collection.......................................................................................................51
8.3
Database management and quality control............................................................51
8.4
Data Monitoring Committee..................................................................................52
8.5
Adjudication Committee........................................................................................52
9
Data analysis......................................................................................................................52
9.1
Analysis sets ..........................................................................................................53
9.2
Patient demographics and other baseline characteristics.......................................53
9.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................53
9.4
Analysis of the primary variable(s) .......................................................................54
9.4.1
Variable(s).............................................................................................54
9.4.2
Statistical model, hypothesis, and method of analysis..........................54
9.4.3
Handling of missing values/censoring/discontinuations.......................55
9.4.4
Sensitivity analyses ...............................................................................55
9.5
Analysis of secondary variables ............................................................................55
9.5.1
Efficacy variables..................................................................................55
9.5.2
Safety variables .....................................................................................56
57
9.7
Interim analyses.....................................................................................................57
9.8
Sample size calculation..........................................................................................59
10 Ethical considerations........................................................................................................59
10.1
Regulatory and ethical compliance........................................................................59
10.2
Informed consent procedures.................................................................................59
10.3
Responsibilities of the investigator and IRB/IEC..................................................59
10.4
Publication of study protocol and results...............................................................59
11 Protocol adherence ............................................................................................................60
11.1
Protocol Amendments ...........................................................................................60
12 References .........................................................................................................................60
List of tables
Table 2-1
Objectives and related endpoints ..........................................................20


Novartis
Confidential
Page 5
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Table 5-1
Study ranibizumab dose in Extension study based on treatment 
received at the baseline visit in core study (CRFB002H2301).............33
Table 5-2
Treatment which prohibits further use of study ranibizumab...............34
Table 6-1
Main Assessment Schedule...................................................................38
Table 6-2
Additional Assessment Schedule – Treatment with Ranibizumab .......41
List of figures
Figure 1-1
Predicted Systemic Exposure After Anti-VEGF Treatment, 
Classified Based on Toxicological Outcomes.......................................18
Figure 3-1
Study design..........................................................................................25


Novartis
Confidential
Page 6
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
List of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANOVA
Analysis of variance
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical (classification system)
BEAT-ROP
Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity 
(study)
BUN
Blood urea nitrogen
CFR
US Code of Federal Regulations 
CPO
Country Pharma Organization
CRF
Case Report/Record Form (paper or electronic)
CTT
Clinical Trial Team
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
eCRF
electronic Case Report/Record Form
EMA
EEA
ETDRS
European Medicines Agency
European Economic Area
Early Treatment Diabetic Retinopathy Study
ETROP
Early Treatment for Retinopathy of Prematurity (study)
EU
GCP
GDPR
European Union
Good Clinical Practice
General Data Protection Regulation
Hb
Hemoglobin
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IRB
Institutional Review Board
IRT
Interactive Response Technology
MedDRA
Medical dictionary for regulatory activities 
OC/RDC
Oracle Clinical/Remote Data Capture
PIP
EU Pediatric Investigation Plan
PLT
Platelet count
ROP
Retinopathy of Prematurity
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reactions
VA
Visual Acuity 


Novartis
Confidential
Page 7
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
VEGF
Vascular endothelial growth factor
WCC
White Cell Count
WHO
World Health Organization 
WoC
Withdrawal of Consent


Novartis
Confidential
Page 8
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Glossary of terms
Assessment
A procedure used to generate data required by the study
Chronological age
A child’s chronological age is its age referring to the date of birth
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Corrected age
A child’s corrected age is its chronological age corrected for its 
prematurity, i.e. calculated by subtracting the number of weeks of
prematurity from the chronological age
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures 
described in the protocol)
Epoch
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Patient/subject ID
A unique number assigned to each patient upon signing the informed 
consent
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation
When the investigator permanently stops to administer study treatment 
to the patient prior to the defined study treatment completion date
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
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a patient’s 
parent(s) or legal guardian(s) does not want the patient to participate 
in the study any longer and does not allow any further collection of 
personal data.


Novartis
Confidential
Page 9
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Amendment 2
Amendment rationale
The main purpose of this amendment is to:

Include the requirement for masked VA assessments to be performed at the child’s 5th
birthday visit following a Health Authority request.
Changes to the protocol
Major changes are made to the protocol in the following sections:

Protocol summary and Section 3.1 “Study Design”: The sections were amended to update 
language that the VA assessor conducting the child’s 5th year birthday visit will be masked 
to treatment.

Section 5.4 “Treatment Blinding”: The section was amended to update the study design 
open label language and clarify that the VA assessor conducting the child’s 5th year 
birthday visit will be masked to treatment.

Section 6.4.3 “Visual Acuity (VA)”: The section was amended to require a masked 
assessor to perform VA assessments at the child’s 5th birthday visit.
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.
IRB/ 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 and Health Authority 
approval according to local regulations prior to implementation.
The changes herein do NOT affect the trial specific global model consent form.
Summary of previous amendments
Amendment 1 (31-Jul-2018)
Amendment rationale
The main purpose of this amendment is to:

Collect additional visual function data following EU national scientific advice meeting.
In addition, further purpose of this amendment is to:

Update the primary hypothesis testing to also include a scenario where the primary 
efficacy variable of the core study (CRFB002H2301) does not meet the pre-defined 
statistical significance level: In this case, the primary objective will only be analyzed 
using descriptive statistics.
Changes to the protocol
Major changes are made to the protocol in the following sections:


Novartis
Confidential
Page 10
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1

Section 6 “Visit schedule and assessments”: A supplemental visit and additional vision 
tests at the child’s 2 and 3 years’ corrected age visits were added to assess visual function.

“Protocol summary”, Section 9.4 “Analysis of the primary variable(s)” and Section 9.5
“Analysis of secondary variables”: Wording updated to reflect the change in the analysis 
of the primary objective
Other changes are made to the protocol in the following sections:
Section 5.6.3.1 “Withdrawal of informed consent” was updated to reflect the new requirements 
of the General Data Protection Regulation (GDPR) within the European Economic Area (EEA).
Section 6.4.3 “Visual Acuity” was updated, details of VA assessment were removed for clarity.
In addition, this amendment incorporates editorial changes to the protocol language to enhance 
consistency and clarity 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.
IRB/ 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 and Health Authority 
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.


Novartis
Confidential
Page 11
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Protocol summary
Protocol number
CRFB002H2301E1
Title
RAINBOW extension study: an extension study to evaluate the long term 
efficacy and safety of RAnibizumab compared with laser therapy for the
treatment of INfants BOrn prematurely With retinopathy of prematurity
Brief title
RAINBOW extension study
Sponsor and Clinical 
Phase
Novartis; Phase 3
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to evaluate the long term efficacy and safety 
of intravitreal ranibizumab compared with laser ablation therapy in patients 
who were treated for retinopathy of prematurity (ROP) in the core study 
CRFB002H2301
Primary Objective(s) 
To evaluate the visual function of patients, by assessing the visual acuity 
in the better-seeing eye at the patient’s fifth birthday
Secondary Objectives

To evaluate the safety outcomes by analyzing the type, frequency 
and severity of ocular and non-ocular Adverse Events (AEs)

To evaluate the visual function by assessing the visual acuity in the 
worse-seeing eye at the patient’s fifth birthday

To evaluate the absence of active ROP at 40 weeks and 52 weeks 
post baseline visit in the core study

To evaluate the absence of ocular structural abnormalities at 40 
weeks post baseline visit in the core study, at the patient’s 2 years 
corrected age and fifth birthday

To evaluate the recurrence of ROP up to 40 weeks and 52 weeks 
post baseline visit in the core study

To assess the number of ranibizumab injections received in the 
treatment of patients with ROP up to 40 weeks post baseline visit in 
the core study

To evaluate the refraction in each eye at the patient’s 2 years’ 
corrected age and fifth birthday

To evaluate the physical development at the patient’s 2 years’ 
corrected age and fifth birthday

To evaluate the health status at the patient’s 2 years’ corrected age 
and fifth birthday (respiratory function, hearing function, duration of 
hospitalization, and weight at discharge from hospital)
Study design
This is a multicenter open-label extension study where the VA assessment 
at the child's 5th birthday visit will be performed by an assessor who is 
masked to study treatment. Patients who have successfully completed the 
24-week core study CRFB002H2301 are eligible for entry into the study.
Treatment with study ranibizumab will be permitted for eligible eyes up to 
and including week 40 from the baseline visit in the core study 
(CRFB002H2301) [Epoch 1]. The remainder of the extension study [Epoch 
2] is observational.
Population
The study population will consist of male and female preterm 
infants/children who have successfully completed the CRFB002H2301 


Novartis
Confidential
Page 12
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
core study. These patients received intravitreal ranibizumab and/or laser 
therapy for retinopathy of prematurity in the core study.
Key Inclusion criteria
Patients have to fulfill all of the following criteria at baseline of the extension 
study prior to receiving the first study related procedure:
1.
Signed informed consent from parent(s) or legal guardian(s), in 
compliance with local requirements
2.
The patient successfully completed the core study CRFB002H2301, 
as defined by providing assessments at the Visit 112 or, if 
appropriate, at the last of the additional assessment visits as per 
protocol in CRFB002H2301, whichever is latest
3.
The patient received study treatment in both eyes at baseline of 
study CRFB002H2301
Key Exclusion criteria
Patients fulfilling any of the following criteria at study entry are not eligible 
for inclusion in this study:
1.
Patient has a medical condition or personal circumstance which 
precludes study participation or compliance with study procedures, as 
assessed by the Investigator
2.
Patient has been discontinued from the core study CRFB002H2301 
at any time
Study treatment
Ranibizumab 10 mg/mL solution for injection (labeled as 
“RFB002 0.5 mg/0.05 mL”) supplied in glass vials for single use by 
Novartis Drug Supply Management. The storage conditions will be 
described on the medication label.
Efficacy assessments
Ophthalmic fundus features
These will be assessed in both eyes by indirect ophthalmoscopy:

Features of active ROP disease:

ROP disease – zone, stage, extent by clock hours, and 
characteristics of vascular changes of plus disease (extent by 
quadrants and severity)

Extra-retinal vessels judged to be active

Features of late sequelae of ROP/ ocular structural abnormalities:

Retrolental membrane obscuring the view of the posterior pole

Substantial temporal retinal vessel dragging causing abnormal 
structural features

Posterior retinal fold involving the macula

Retinal detachment involving the macula

Retinal detachment not involving the macula

Pre-retinal fibrosis

Optic disc pallor

Optic disc swelling

Pigmentary disturbance in the macula

Atrophic changes in macula
Ocular and visual function: refraction
Visual acuity (VA)

Assessment of VA in each eye


Novartis
Confidential
Page 13
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Key safety 
assessments

Ocular examination

Standing/sitting height, weight, head circumference

Adverse event monitoring (ocular and systemic); number of 
hospitalization/ prolongation due to Serious Adverse Event (SAE)

Health status (respiratory function, hearing function, duration of 
hospitalization and weight at first discharge home)
Data analysis
Three planned analyses will be conducted in the study. 

Interim analysis 1 will provide descriptive statistics for a subset of 
patients to evaluate ocular structural abnormalities. This is to comply 
with the plan for specific follow-up in the Pediatric Investigation Plan. 

Interim analysis 2 will be conducted on all patients at their 2 years’ 
corrected age to report on the progress of the study to the scientific 
community.

The final analysis will be conducted at the completion of the study.
Additional interim analyses may be conducted on safety or efficacy data 
as required.
All analyses will be carried out on the Extension Safety Set and displayed 
by the original study treatment received in the core study CRFB002H2301 
unless otherwise specified. One-sided p-values and two sided 95% 
confidence intervals will be displayed without adjusting for multiplicity.
If the primary hypothesis testing of the core study shows statistical 
significance, the primary objective of the extension study will be assessed 
by testing for the superiority of ranibizumab 0.2 mg to laser of the visual 
acuity for the better-seeing eye at the patient’s fifth birthday. An analysis 
of variance, with treatment group as a factor, stratified by the ROP zone 
defined at baseline in the core study will be performed using the Cochran-
Mantel-Haenszel test. A two-way analysis of variance with treatment group 
and zone as factors will be used to estimate least squares means and 95% 
confidence intervals for visual acuity in the better-seeing eye within and 
between treatment groups. If statistical significance in the core study 
cannot be shown, only descriptive statistics will be provided for the 
comparison between ranibizumab 0.2 mg and laser.
The same approach will be used for inference conducted on continuous 
secondary efficacy variables. Inference conducted on binary secondary 
efficacy variables will use the
Cochran-Mantel-Haenszel test for 
proportions stratified by the ROP zone defined at baseline in the core 
study.


Novartis
Confidential
Page 14
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Descriptive statistics will be used to summarize other variables. All data 
will be listed.
Key words
Open-label, long-term, extension study; intravitreal ranibizumab; laser 
ablation therapy; retinopathy of prematurity; preterm infants; RAINBOW


Novartis
Confidential
Page 15
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
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. 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). ROP 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).
In the 1990s, the use of laser photocoagulation to ablate the peripheral avascular retina gained 
widespread acceptance as standard of care treatment for ROP (Connolly et al 2002, Ng et al. 
2002, Houston et al. 2013, Good 2004). However, despite improvement in the technology and 
timing of ROP treatment, ROP remains a leading cause of childhood blindness worldwide.
Laser therapy ablates the avascular peripheral retina and destroys the majority of the retinal 
cells that produce vascular endothelial growth factor (VEGF), which is postulated to play an 
important role in the initiation and progression 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).
Results from a prospective, multicenter, randomized clinical study (BEAT-ROP study) (Mintz-
Hittner et al. 2011) suggest that intravitreal bevacizumab may be more efficacious than 
conventional laser ablation therapy among infants with stage 3+ ROP. 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 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. If anti-VEGF agents allow more normal retinal vascularization to 
occur, it is anticipated that the rate of abnormal visual acuity, restricted visual fields, refractive 
errors, amblyopia, and strabismus may be reduced. 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). 
Therefore, despite reports of potential benefits of anti-VEGF in the treatment of ROP, a number 
of questions remain unanswered and require further study to better understand the clinical 
efficacy of anti-VEGF agents compared to standard of care laser therapy, the optimal dose to 


Novartis
Confidential
Page 16
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
be used, as well as more information on the long-term safety of intravitreal anti-VEGF use in a 
developing infant (Lee et al. 2011, Darlow et al. 2013). It is also important to collect more 
evidence on the longer term efficacy and safety outcomes in this patient group.
The study CRFB002H2301 is a randomized, open-label, three-arm parallel-group study to 
determine if intravitreal ranibizumab is superior to laser ablation therapy in the treatment of 
ROP. In addition, two doses of ranibizumab are investigated (0.1 mg and 0.2 mg). The study 
will assess the ability of these treatments to lead to regression of active ROP and prevention of 
the development of ocular complications that are associated with poor visual outcome 24 weeks 
after the first study treatment (intravitreal ranibizumab or laser ablation therapy).
This study, CRFB002H2301E1, is an extension study to evaluate the long term efficacy and 
safety of intravitreal ranibizumab compared with laser ablation therapy in ROP patients who 
successfully completed the core study (CRFB002H2301).
1.1.1
Ranibizumab
Ranibizumab is a recombinant humanized immunoglobulin (Ig) G1 kappa isotype monoclonal 
antibody fragment targeted against human VEGF-A.
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 accurately deliver 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 purposes. The syringe will be individually packaged. 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.






Novartis
Confidential
Page 19
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
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 evaluate the long term efficacy and safety of intravitreal 
ranibizumab compared with laser ablation therapy in patients who were treated for ROP in the 
core study CRFB002H2301. All patients who successfully completed the CRFB002H2301 
study will be invited to participate in this extension study CRFB002H2301E1.
The first study interim analysis will be conducted to comply with the plan for specific follow-
up as agreed with the Pediatric Committee at the European Medicines Agency in the Pediatric 
Investigation Plan (see Section 3.2).
2
Study objectives and endpoints
All objectives will be assessed by the original study treatment received at baseline in the core 
study CRFB002H2301 unless otherwise specified. 
2.1
Primary objective(s)
To evaluate the visual function of patients by assessing the visual acuity in the better-seeing eye 
at the patient’s fifth birthday (see Table 2-1).
2.2
Secondary objective(s)
See Table 2-1.
2.4
Objectives and related endpoints


Novartis
Confidential
Page 20
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Table 2-1
Objectives and related endpoints
OBJECTIVE
Endpoint Title, Description and Reporting Time Frame for analysis and Unit 
of Measure
Stat Analysis Section
Primary
To evaluate the visual function of 
patients, by assessing the visual 
acuity in the better-seeing eye at the 
patient’s fifth birthdaya,e
Title: visual acuity in the better-seeing eye at the patient’s fifth birthday
Unit of Measure: visual acuity score (Lea symbols optotypes)
Description: see Section 6.4.3
Time Frame: at the patient’s fifth birthdaye
See Section 9.4
Secondary
To evaluate the safety outcomes by 
analyzing the type, frequency and 
severity of ocular and non-ocular 
Adverse Eventsb
Title: ocular and non-ocular Adverse Events
Unit of Measure: number and percentage of patients having e.g. any AE; number of 
hospitalization/ prolongation of hospitalization due to SAE
Description: see Section 7
Time Frame: from the 1st study treatment in the core study up to 40 weeks post 
baseline visit in the core study, the patient’s 2 years’ corrected age and the 
patient’s fifth birthday
See Section 9.5.2
To evaluate the visual function by 
assessing the visual acuity in the 
worse-seeing eye at the patient’s 
fifth birthdaya
Title: visual acuity in the worse-seeing eye at the patient’s fifth birthday
Unit of Measure: visual acuity score (Lea symbols optotypes)
Description: see Section 6.4.3
Time Frame: at the patient’s fifth birthday
See Section 9.5.1
To evaluate the absence of active 
ROP at 40 weeks and 52 weeks 
post baseline visit in the core study
Title: absence of active ROP
Unit of Measure: number and percentage of patients
Description: see Section 3.5.1
Timeframe: at 40 weeks and 52 weeks post baseline visit in the core study
See Section 9.5.1
To evaluate the absence of ocular 
structural abnormalities at or before
40 weeks post baseline visit in the 
core study, at the patient’s 2 years 
corrected age and fifth birthday
Title: absence of all ocular structural abnormalities
Unit of Measure: number and percentage of patients
Description: the absence of all ocular structural abnormalities listed in Section 3.5.1
in both eyes
See Section 9.5.1


Novartis
Confidential
Page 21
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
OBJECTIVE
Endpoint Title, Description and Reporting Time Frame for analysis and Unit 
of Measure
Stat Analysis Section
Time Frame: at or before 40 weeks post baseline visit in the core study, at or 
before the patient’s 2 years corrected age, at or before the patient’s fifth birthday
Title: absence of each ocular structural abnormality as listed in Section 3.5.2
considered individually
Unit of Measure: number and percentage of patients 
Time Frame: at or before week 40, at or before the patient’s 2 years’ corrected age, 
at or before the patient’s fifth birthday
To evaluate the recurrence of ROP 
up to 40 weeks and 52 weeks post 
baseline visit in the core study
Title: recurrence of ROP
Unit of Measure: number and percentage of patients with recurrence of ROP
Description: Recurrence of ROP is defined as ROP receiving any intervention after 
the 1st study treatment in the core studyd.
Time Frame: up to 40 weeks and 52 weeks post baseline visit in the core study
See Section 9.5.1
To assess the number of 
ranibizumab injections received in 
the treatment of patients with ROP 
up to and including 40 weeks post 
baseline visit in the core study
Title: number of ranibizumab injections
Unit of Measure: number of ranibizumab injections
Description: as per title
Time Frame: up to and including 40 weeks post baseline visit in the core study
See Section 9.5.2
To evaluate the refraction in each 
eye at the patient’s 2 years’ 
corrected age and fifth birthdaya
Title: refraction in each eye
Unit of Measure: diopters
Description: see Section 6.4.2
Time Frame: at the patient’s 2 years corrected age, patient’s fifth birthday
See Section 9.5.1
To evaluate the physical 
development at the patient’s 2 
years’ corrected age and fifth 
birthdayb
Title: standing/sitting height, leg length, weight
Unit of Measure: centimeter, gram (as appropriate)
Description: see Section 6.5.2.2; leg length will be derived from standing/sitting 
height difference
Time Frame: at the patient’s 2 years corrected age, at the patient’s fifth birthday
Title: head circumference
See Section 9.5.2






Novartis
Confidential
Page 24
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
OBJECTIVE
Endpoint Title, Description and Reporting Time Frame for analysis and Unit 
of Measure
Stat Analysis Section
a - Variable corresponding to “ocular effects” in the plan for specific follow-up in the Pediatric Investigation Plan (EMA)
b - Variable corresponding to “clinical outcomes” in the plan for specific follow-up in the Pediatric Investigation Plan (EMA)
c - Variable corresponding to “neurodevelopmental outcomes” in the plan for specific follow-up in the Pediatric Investigation Plan (EMA)
d - Supplementary laser treatments (as per CRFB002H2301 study protocol) are considered part of the complete laser treatment
e - At the visit as close as possible to the child’s fifth birthday (see Table 6-1)


Novartis
Confidential
Page 25
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
3
Investigational plan
3.1
Study design
This is a multicenter open-label extension study (Figure 3-1) where the VA assessment at the 
child's 5th birthday visit will be performed by an assessor who is masked to study treatment.
Patients who have successfully completed the 24-week core study CRFB002H2301 are eligible 
for entry into the study (see Section 4). Visit 201/ baseline visit of the extension study can occur 
on the same day as the last visit in the CRFB002H2301 study.
Treatment with study ranibizumab (either as re-treatment after ranibizumab has already been 
injected in the same eye or as switch ranibizumab treatment from study laser therapy 
administered in the core study) will be permitted for eligible eyes up to and including the visit 
week 40 from the baseline visit in the core study (RFB002H2301) (equal to week 16 from the 
baseline visit in extension study, when the baseline visit in extension study coincides with the 
week 24 visit in the core study) [Epoch 1]. The remainder of the extension study [Epoch 2] is 
observational.
Assessment visits will be performed regularly throughout the Epoch 1 and 2, up to the last study 
visit as close as possible to the patient’s fifth birthday. The assessments related to the primary 
objective will be performed at the patient’s fifth birthday. Two interim analyses are planned, 
see Section 3.5. Additional interim analyses may be conducted on safety or efficacy data as 
required.
Figure 3-1
Study design
3.2
Rationale for study design
The patient population will be described in more detail in the Section 4 below.
This multicenter extension study is designed to provide long term efficacy and safety data of 
ranibizumab treatment compared with laser ablation therapy in ROP patients. A follow-up 
duration until patients are 5 years of age will also provide the opportunity for a robust 


Novartis
Confidential
Page 26
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
assessment of the visual function of the patients as well as of their physical growth and cognitive 
status. Late recurrence of ROP is not expected beyond 40 weeks after the first study treatment 
(in the core study CRFB002H2301), therefore the treatment period ends with the end of the 
Epoch 1. Interim analyses will be performed using a snapshot of the database available at the 
cut-off points. The first interim analysis will be conducted to comply with the plan for specific 
follow-up in the Pediatric Investigation Plan (EMA) and to support the inclusion of information 
related to the treatment of ROP in the Lucentis product information (in EU: Summary of 
Product Characteristics (SmPC)). The second interim analysis will be conducted to evaluate 
efficacy and safety data and report on the progress of the study to the scientific community 
during the course of the study. Additional interim analyses may be conducted on safety or 
efficacy data as required.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Treatment with study ranibizumab is permitted in the Epoch 1 for eligible eyes who have 
recurrence / worsening of ROP disease, in the opinion of the investigator.
The duration of the Epoch 1 (when treatment with study ranibizumab is permitted) is up to and 
including 40 weeks after the first study treatment in the core study CRFB002H2301. This 
reflects that late recurrence of ROP is not expected beyond this time point.
3.4
Rationale for choice of comparator
There is no comparator in the present extension study. Laser ablation of the peripheral avascular 
retina has been selected as the comparator for intravitreal ranibizumab in the core clinical study 
CRFB002H2301. This treatment modality is the current standard of care treatment for ROP in 
many countries (Royal College of Paediatrics and Child Health 2008, Hartnett and Penn 2012).
3.5
Purpose and timing of interim analyses/design adaptations
3.5.1
Interim analysis 1
The first interim analysis will be performed when the last patient has completed the last visit in 
core study CRFB002H2301 or when at least half of the patients enrolled in CRFB002H2301 
have completed the visit corresponding to 40 weeks after the first study treatment (in the core 
study CRFB002H2301), whichever is the latest.
The purpose of the first interim analysis is to provide some longer term data on ocular structural 
abnormalities. This is to comply with the plan for specific follow-up in the Pediatric 
Investigation Plan (EMA). Therefore, the absence of ocular structural abnormalities will be 
evaluated as defined by the absence of all of the following fundus features in both eyes at or 
before week 40 after the first study treatment in the core study CRFB002H2301:

Substantial temporal retinal vessel dragging causing abnormal structural features/ macular 
ectopia

Retrolental membrane obscuring the view of the posterior pole

Posterior retinal fold involving the macula

Retinal detachment involving the macula


Novartis
Confidential
Page 27
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Additional objectives of the interim analysis 1 are:

to explore the absence of active ROP in both eyes as defined by the absence of all of the 
following features:

Vessel dilatation of plus disease in at least 2 quadrants (some persisting tortuosity is 
allowed)

Extra-retinal vessels extending from the retina into the vitreous and judged to be a 
sign of active ROP disease

to explore the recurrence of ROP

to explore the number of ranibizumab injections

to explore the safety outcomes by analyzing the type, frequency and severity of ocular and 
non-ocular Adverse Events
3.5.2
Interim analysis 2
The interim analysis 2 will be performed when the last patient has completed the visit which 
corresponds to the patient’s 2 years’ corrected age.
The rationale for the second interim analysis is given in Section 3.2.
The purpose of the second interim analysis is to evaluate the absence of all ocular structural 
abnormalities as defined in Section 3.5.1 at the patient’s 2 years’ corrected age.
Other objectives of the second interim analysis are:

to evaluate the absence of each ocular structural abnormality considered individually, i.e.

Each ocular structural abnormality as listed above in Section 3.5.1

Retinal detachment not involving the macula

Pre-retinal fibrosis

Optic disc pallor

Optic disc swelling

Pigmentary disturbance in the macula

Atrophic changes in the macula

to evaluate the safety outcomes by analyzing the type, frequency and severity of ocular 
and non-ocular Adverse Events
Further objectives are to evaluate clinical and cognitive outcomes as per Table 2-1.
Additional details for the interim analyses are provided in Section 3.2 and the statistical 
considerations in Section 9.7.
3.6
Risks and benefits 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures and close clinical monitoring.
This study will be an extension of the core study CRF002H2301 conducted in preterm infants 
who received intravitreal ranibizumab injection and/or laser therapy for retinopathy of 


Novartis
Confidential
Page 28
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
prematurity. For eligible patients, the patient’s parent(s) or legal guardian(s) will be invited to 
allow the patient to continue in the extension study. This is a vulnerable patient 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 core and extension studies.
Study ranibizumab can be administered during the Epoch 1 of the extension study to patients 
who, in the opinion of the investigator, have a recurrence / worsening of ROP disease. This is 
to ensure study treatment is still available for potential late ROP recurrences following anti-
VEGF treatment (Chen 2014, Hu et al 2012). Patients not eligible for study ranibizumab 
treatment will receive the Standard of Care therapy as per local clinical practice. Based on 
published literature, late recurrences of ROP following anti-VEGF therapy are not expected 
beyond week 40 post-baseline treatment. The remainder of the extension study (Epoch 2) is 
therefore observational.
Treatment with investigational ranibizumab is associated with potential risks and benefits.
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 (the current Standard of 
Care therapy in most countries), was more efficacious in the treatment of ROP to reduce the 
number of recurrences and was associated with less myopia in the long term (Mintz-Hittner et 
al 2011, Geloneck et al 2014). Based on published information, more than 800 infants with ROP 
have received ranibizumab or other anti-VEGF intravitreal injections. Ranibizumab treatment 
has the potential advantage versus laser therapy of being able to treat ROP without causing 
widespread damage to the peripheral retina, thereby enabling peripheral retinal vascularization 
to continue in the eye, preserving the visual fields.
In adults, ranibizumab has been shown to improve vision and help prevent visual loss in adults 
with age related macular degeneration, visual impairment due to pathologic myopia or diabetic 
macular edema or retinal vein occlusion.
Potential risks with the use of intravitreal anti-VEGF agents, 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, Zhou et al. 2015). Hoerster et al. 2013 described 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. 2015 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 may include disturbances of organ and 
neurological development, renal impairment, bone abnormalities, and thromboembolic events. 


Novartis
Confidential
Page 29
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
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 
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.
An independent Data Monitoring Committee (DMC) was established to monitor the safety of 
the trial participants in the core study and will continue evaluations in this extension study until 
the last patient has completed visit 301 (i.e. week 52 after the 1st study treatment in the core 
study) or discontinued the study (see Section 8.4), to ensure that the trial is being conducted 
with the highest scientific and ethical standards, and make appropriate recommendations based 
on the data seen.
Epoch 2 is observational. Patients will receive standard of care therapy as needed and as per 
local clinical practice and will be followed-up to monitor long term efficacy and safety 
outcomes of ranibizumab treatment as compared to laser ablation therapy. This will address an 
unmet need of the medical community to understand the long term benefits and risks of 
ranibizumab treatment compared to laser therapy in the treatment of ROP.
4
Population
The study population will consist of male and female preterm infants/children who have 
successfully completed the CRFB002H2301 study.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria at baseline 
of the extension study prior to receiving the first study related procedure (including 
investigational treatment):
1. Signed informed consent from parent(s) or legal guardian(s), in compliance with local 
requirements
2. The patient successfully completed the core study CRFB002H2301, as defined by 
providing assessments at the Visit 112 or, if appropriate, at the last of the additional 
assessment visits as per protocol in CRFB002H2301, whichever is latest
3. The patient received study treatment in both eyes at baseline of study CRFB002H2301


Novartis
Confidential
Page 30
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
4.2
Exclusion criteria
Patients fulfilling any of the following criteria at study entry 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 eligible patients.
1. Patient has a medical condition or personal circumstance which precludes study 
participation or compliance with study procedures, as assessed by the Investigator
2. Patient has been discontinued from the core study CRFB002H2301 at any time
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
5.1.1.1
Epoch 1

0.1 mg and 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 by Novartis Drug Supply 
Management.
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.
Novartis will provide sufficient supplies of ranibizumab to allow for completion of Epoch 1.
Treatment administration is detailed in Section 5.5.4 of this protocol.
5.1.1.2
Epoch 2
There is no investigational/ control drug in Epoch 2.
5.1.2
Additional treatment
No additional treatment is included in this trial.
5.2
Treatment arms
Treatment arm assignment will remain the same as in the core study.


Novartis
Confidential
Page 31
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
5.3
Treatment assignment and randomization
At visit 201 (extension baseline), the investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. Treatment arm 
assignment and patient identifier will remain the same as in the core study.
During Epoch 1, the investigator or his/her delegate will contact the IRT upon decision to 
administer study treatment. IRT will specify a unique medication number for the package of 
study drug to be dispensed to the patient.
The investigator must contact the IRT to register the patient’s completion of Epoch 1.
5.4
Treatment blinding
This is an open-label study where the VA assessment at the child's 5th birthday visit will be 
performed by an assessor who is masked to study treatment.
The investigators, 
patients/parents/legal guardians and the Clinical Trial Team (CTT) are unmasked to the 
treatments administered during the core and extension studies. The measures defined in the 
core study CRFB002H2301 to minimize bias related to treatment knowledge will remain
implemented by the CTT until the core study clinical database is locked. They will be provided 
in the Data Management Plan.
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 patient identifier will remain the same in the extension study as in the core 
study CRFB002H2301. The investigator should contact the Novartis medical monitor in case 
of special circumstances (e.g. site transfer).
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.
5.5.2
Dispensing the study drug
Each study site will be supplied by Novartis with (open-label) study drug.
The study drug packaging has a 2-part label. A unique medication number (kit number) is 
printed on each part of this label. Investigator staff will identify the study drug package(s) to 
dispense to the patient by contacting the IRT and obtaining the medication number(s).
Immediately before dispensing the package to the patient, investigator staff will detach the tear-
off label from the packaging and affix it to the source document (Drug Label Form) for that 
patient’s unique subject number.
5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment
Study 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 


Novartis
Confidential
Page 32
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
investigator and designees have access. Upon receipt, all study treatment must be 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 CPO 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 study 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 study 
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 (e.g. after 
completion of Epoch 1), the investigator will return all unused study treatment, packaging, drug 
labels, and a copy of the completed drug accountability log to the Novartis monitor or to the 
Novartis address provided in the investigator folder at each site.
5.5.3.2
Handling of additional treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
0.1 mg and 0.2 mg ranibizumab
On day(s) when study treatment is administered, all assessments must be conducted before 
administration except when specified otherwise in Section 6.
All study treatment administration during the study must be recorded in the Dose 
Administration Record eCRF.
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 are provided in the study operation manual.
Treatment with ranibizumab (either as re-treatment after ranibizumab has already been injected 
in the same eye or as switch ranibizumab treatment from study laser therapy administered in 
the core study) will be permitted for eligible eyes up to and including the study visit occurring 
40 weeks after the first study treatment in the core study CRFB002H2301 (Epoch 1). The 
following rules apply:

Treatment with investigational ranibizumab will only be permitted for recurrence / 
worsening of ROP, as judged by the investigator. Details (e.g. reason) must be 
documented in the CRF.

No further investigational ranibizumab treatment can be administered to the eye after it 
was switched to study laser therapy (in the core study CRFB002H2301). If the other eye 
was not switched to study laser therapy (in the core study CRFB002H2301) then this eye 
could be administered ranibizumab re-treatment.


Novartis
Confidential
Page 33
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1

A maximum of 3 study ranibizumab treatments can be administered to each eye 
throughout the core and extension studies (i.e. including injections received in the core 
study CRFB002H2301 and extension study CRFB002H2301E1).

The minimum time interval between ranibizumab injections in the same eye is 28 days.

Only the eye which needs treatment will be treated. If both eyes need treatment, then both 
eyes will be treated.

Investigational 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, should be managed as 
appropriate and the treatment given documented in the eCRF.

Investigational ranibizumab treatment must be discontinued for a patient under 
circumstances listed in Table 5-2.

No further investigational ranibizumab treatment can be administered if the patient was 
discontinued from study treatment in the core study CRFB002H2301.
The dose of study ranibizumab to be administered (if the above rules apply) will be as follows:
Table 5-1
Study ranibizumab dose in Extension study based on treatment 
received at the baseline visit in core study (CRFB002H2301)
Treatment received at the baseline visit
in Core study (CRFB002H2301)
Ranibizumab dose
in Extension study (CRFB002H2301E1)
RBZ 0.1mg
RBZ 0.1mg
RBZ 0.2mg
RBZ 0.2mg
Laser
RBZ 0.2mg
After treatment with investigational ranibizumab, the visits as per Additional Assessment 
Schedule in Table 6-2 will be performed. All study ranibizumab treatments must be recorded 
in the IRT system.
Patients with recurrence / worsening of ROP, in the opinion of the investigator, who are not 
eligible or suitable for treatment with ranibizumab should be treated with Standard of Care
therapy as per local clinical practice. Details of any treatments or procedures should be 
documented in the CRF.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Investigational treatment dose adjustments and/or interruptions are not permitted.
5.5.6
Rescue medication
Patients with recurrence/worsening of ROP (as judged by the investigator) who are not eligible 
or suitable for treatment with ranibizumab as per Section 5.5.4 should be treated with Standard 
of Care therapy, considering instructions for study treatment discontinuation in Table 5-2. 
Details of any treatments or procedures must be recorded in the Concomitant medications or 
Surgical and medical procedures CRF as applicable.


Novartis
Confidential
Page 34
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
5.5.7
Concomitant medication
The investigator must instruct the patient’s parent(s) or legal guardian(s) to notify the study site 
about any new medications the patient takes since the patient completed the core study and 
throughout the extension study. All medications and procedures (including physical therapy and 
blood transfusions) administered when the patient was enrolled into the extension study and 
after must be recorded in the prior and concomitant medications eCRF or the surgical and 
medical procedures eCRF as appropriate.
Concomitant medications which are ongoing at the time of the last visit in the core study 
CRFB002H2301 must be recorded, and entries in the extension study database should match 
those in the core study database as appropriate.
For patients whose baseline visit of the extension study does not occur on the same day as the 
last visit in the CRFB002H2301 core study, relevant medications and procedures (e.g. related 
to ocular treatment) which started after the last visit in the core study and before the baseline
visit in the extension study will also be recorded.
Each concomitant drug and procedures must be individually assessed against all treatments in 
Table 5-2. If in doubt the investigator should contact the Novartis medical monitor before 
allowing a new medication to be started.
From Visit 301, concomitant medications/ non-drug therapies related to common childhood 
infections and accidents/injuries if they are not SAEs (Section 7.1) are not required to be 
reported in the CRF.
5.5.8
Prohibited medication
There is no prohibited medication in this study, however, the use of the treatments in Table 5-
2 will prohibit further use of investigational ranibizumab. These rules apply from the last visit 
in the core study.
Table 5-2
Treatment which prohibits further use of study ranibizumab
Medication
Action to be taken
Any intravitreal anti-VEGF agent other than the 
investigational drug
Discontinue study treatment
Any systemic anti-VEGF agent
Discontinue study treatment
Any other nonsurgical treatment of ROP
Discontinue study treatment
Any surgical treatment of ROP (e.g. cryotherapy, 
vitrectomy, laser)
Discontinue study treatment
Any other investigational medicinal product as 
part of another clinical study, except vitamins 
and minerals
Discontinue study treatment
Abbreviations: ROP – retinopathy of prematurity; VEGF – vascular endothelial growth factor
5.5.9
Emergency breaking of assigned treatment code
Not applicable. This is an open-label study.


Novartis
Confidential
Page 35
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
5.6
Study Completion and Discontinuation
5.6.1
Study completion and post-study treatment
A patient will be considered to have completed the study when the patient has completed the
last visit planned in the protocol.
Continuing care according to Standard of Care therapy as per local clinical practice should be 
provided by investigator and/or referring physician based on patient availability for follow-up.
5.6.2
Discontinuation of Study Treatment
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration (i.e. during Epoch 1), and can be initiated by either the patient’s 
parent(s) or legal guardian(s) or the investigator.
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued for a patient under the following circumstances:

Patient’s parent(s) or legal guardian(s) wish

Use of treatment as per Table 5-2

Any situation in which study treatment administration might result in a safety risk to the 
patient
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return for assessments as described in Table 6-1. The 
investigator must determine the primary reason for the patient’s premature discontinuation of 
study treatment and record this information on the Dosage Administration eCRF.
After study treatment discontinuation, all data should be collected as per Table 6-1 and, at a 
minimum, in abbreviated visits, the following data should be collected at clinic visits or via 
telephone visits according to the study visit schedule:

new / concomitant treatments

Adverse Events/Serious Adverse Events
5.6.3
Premature patient withdrawal from the study
The patient must be withdrawn from the study if, on balance, the investigator believes that 
continuation would negatively impact the risk/benefit of the patient's participation in the trial. 
A final evaluation at the time of the patient’s study withdrawal should be made as detailed in 
Table 6-1. The investigator must also contact the IRT to register the patient’s withdrawal from 
the study if it occurs before the patient has completed the last visit in Epoch 1 and document 
the decision to withdraw the patient in the Study Completion CRF and patient's source 
documents.


Novartis
Confidential
Page 36
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
5.6.3.1
Withdrawal of informed consent
Patient’s parent(s) or legal guardian(s) may voluntarily withdraw consent for the patient to 
participate in the study for any reason at any time. Withdrawal of consent occurs only when 
patient’s parent(s) or legal guardian(s):

Does not want the patient to participate in the study anymore and
Does not allow further collection of personal data In this situation, the investigator should make 
a reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for the 
patient's parent(s) or legal guardian decision to withdraw his/ her consent to the patient's 
participation and record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient’s parent(s) or legal guardian(s) are not allowed unless 
safety findings require communicating or follow-up.
A final evaluation at the time of the patient’s study withdrawal should be made as detailed in 
Table 6-1. 
Novartis will continue to keep and use collected study information according to applicable law.
The investigator must also contact the IRT to register the patient’s withdrawal from the study 
if it occurs before the patient has completed the last visit in Epoch 1 and document the patient's 
parent(s) or legal guardian(s) decision to withdraw consent in the Study Completion CRF and 
patient's source documents.
5.6.4
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 stated an intention to discontinue or withdraw their child, the 
investigator should show "due diligence" by documenting in the source documents steps taken 
to contact the patient’s parent(s) or legal guardian(s), e.g. dates of telephone calls, registered 
letters, etc.
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as 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 
(IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 and Table 6-2 list all study related assessments and indicate with an “x” when the 
visits are performed. When a visit as per the additional assessment schedule coincides with a 


Novartis
Confidential
Page 37
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
visit as per the main assessment schedule, assessments have to be performed as per the main 
assessment schedule. Non study-related assessments and follow-ups which are performed 
according to local medical practice should not be considered as unscheduled study visits.
Patients/subjects should be seen for all visits on the designated day, or as close to it as possible 
(visit window as indicated on the relevant assessment schedule tables should be considered). 
Alternatively, Visit 304 may be conducted remotely by phone, at the investigator’s discretion. 
Study visit assessments should be carried out on the same day. If required, assessments may be
conducted on two consecutive days, in order to decrease patient burden. Missed visits should 
be re-scheduled as soon as possible. Missed or rescheduled visits should not lead to automatic 
discontinuation. Patients/subjects who prematurely discontinue the study for any reason should 
be scheduled for a visit as soon as possible, at which time the assessments listed for Visit 399
(final visit) will be performed unless otherwise specified. 
Patient’s parent(s) or legal guardian(s) will be contacted for safety evaluations during the 30 
days following the last study visit (see Section 7.2).


Novartis
Confidential
Page 38
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Table 6-1
Main Assessment Schedule
Epoch 1
(Post-treatment follow-up 1)
Epoch 2
(Post-treatment follow-up 2)
Visit
201a
(baseline)
202
203
301
302
303
304
399 incl. 
premature 
withdrawal
Supplemental 
visit n
Timepoint 
(referring to the 
Day 1 in the study 
CRFB002H2301)
Day of the 
patient’s last visit 
in core 
CRFB002H2301a
Week 32
(+/- 1 
week)
Week 40
(+/- 1 week)
Week 52
(+/- 2 weeks)
Child’s 2 years’ 
corrected agei
(+/- 4 weeks)
Child’s 3 years’ 
corrected agei
(+/- 4 weeks)
Child’s 4th
birthdayj
(+/- 4 weeks)
Child’s 5th
birthdayj
(+/- 12 weeks)
Obtain informed 
consent
X
Inclusion/Exclusion X
Demography
X
Relevant medical 
conditions
Xc
Adverse events
Xb
X
X
X
X
X
X
X
X
Concomitant 
medication use
Xd
X
X
X
X
X
X
X
X
Health status 
(respiratory and 
hearing function)
X
X
Hospital 
dischargeh
X
X
X
X
X
X
X
X
X
Blood pressure
X
Height, weight
X
X
Head 
circumference
X
Laboratory tests
X


Novartis
Confidential
Page 39
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Epoch 1
(Post-treatment follow-up 1)
Epoch 2
(Post-treatment follow-up 2)
Visit
201a
(baseline)
202
203
301
302
303
304
399 incl. 
premature 
withdrawal
Supplemental 
visit n
Timepoint 
(referring to the 
Day 1 in the study 
CRFB002H2301)
Day of the 
patient’s last visit 
in core 
CRFB002H2301a
Week 32
(+/- 1 
week)
Week 40
(+/- 1 week)
Week 52
(+/- 2 weeks)
Child’s 2 years’ 
corrected agei
(+/- 4 weeks)
Child’s 3 years’ 
corrected agei
(+/- 4 weeks)
Child’s 4th
birthdayj
(+/- 4 weeks)
Child’s 5th
birthdayj
(+/- 12 weeks)
Ocular 
examinatione
X
X
X
X
X
Fundus 
examination by 
ophthalmoscopy
X
X
X
X
X
Ocular and visual 
function 
Xm
Xm
Xg,q
Xo
Epoch 1 
dispositionf
X
Study disposition
X
a – Visit 201 (baseline) of CRFB002H2301E1 can occur on the same day as the patient’s last visit in CRFB002H2301 (i.e. on Day 169 / Visit 112 of 
CRFB002H2301 or at the last of the additional assessments visit as per protocol in CRFB002H2301). b - Adverse Events which are ongoing at the 
patient’s last visit in CRF002H2301 and at the baseline visit in the extension study must be recorded and entries in the extension study database 
should match those in the core study database as appropriate.


Novartis
Confidential
Page 40
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Epoch 1
(Post-treatment follow-up 1)
Epoch 2
(Post-treatment follow-up 2)
Visit
201a
(baseline)
202
203
301
302
303
304
399 incl. 
premature 
withdrawal
Supplemental 
visit n
Timepoint 
(referring to the 
Day 1 in the study 
CRFB002H2301)
Day of the 
patient’s last visit 
in core 
CRFB002H2301a
Week 32
(+/- 1 
week)
Week 40
(+/- 1 week)
Week 52
(+/- 2 weeks)
Child’s 2 years’ 
corrected agei
(+/- 4 weeks)
Child’s 3 years’ 
corrected agei
(+/- 4 weeks)
Child’s 4th
birthdayj
(+/- 4 weeks)
Child’s 5th
birthdayj
(+/- 12 weeks)
c - When baseline visit of the extension study does not occur on the same day as the last visit in the core study, relevant medical conditions which 
started and/or ended after the last visit in the core and before the baseline visit in the extension study will be recorded (see Section 6.2).
d – Concomitant medications which are ongoing at the patient’s last visit in CRF002H2301 must be recorded and entries in the extension study 
database should match those in the core study database as appropriate. For patients whose baseline visit of the extension study does not occur on 
the same day as the last visit in the CRFB002H2301 core study, relevant medications and procedures which started after the last visit in the core 
study and before the baseline visit in the extension study will also be recorded (see Section 5.5.7).
e - Including examination of the anterior segment and lens
f - To be recorded once upon Epoch 1 completion
g - Will not be performed in case of patient’s premature withdrawal
h - To be recorded once upon first hospital discharge home
i – Visit should be scheduled as close as possible when child reaches this corrected age
j – Visit should be scheduled as close as possible to the child’s appropriate birthday
m - Assessment of presence/ absence of 
 refraction. See 
Section 6.4.2.
n – The supplemental visit should take place as early as possible after the protocol amendment is implemented. If the date of this visit is within 2 
months prior the next scheduled visit, then this supplemental visit may be delayed and performed with the next scheduled visit
p – ETDRS visual acuity test (using Lea symbols) to be performed by a masked VA assessor: See Section 6.4.3.
q – Includes assessments (m) and vision function form (peripheral vision).


Novartis
Confidential
Page 41
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Table 6-2
Additional Assessment Schedule – Treatment with Ranibizumab
Visit
29y1f
29y2f
29y3f
29y4f
Days after ranibizumab treatmenta
(visit window)
0
3
(-2 day/+1 day)
7
(±2 day)
14b
(±4 days)
Adverse events
X
X
X
X
Concomitant medication use /Surgical and 
medical procedures
X
X
X
X
Ocular examinationc
Xd
X
X
X
Fundus examination
Xd
X
X
X
Administer ranibizumabe
X
a – Up to 2 re-treatments (including treatments administered in the Core Study) are allowed for each eye if required
b – After this visit, the patient resumes the next visit according to their original Main Assessment Schedule
c – Includes examination of the anterior chamber and lens
d – Assessments to be conducted before administration of ranibizumab treatment
e – The ranibizumab treatment dose will be as per Table 5-1
f – y is the number corresponding to the ranking of the post-baseline treatment, continuing from the core (e.g. 1 corresponds to the 1st treatment after 
the core study baseline treatment)


Novartis
Confidential
Page 42
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
6.1
Information to be collected on screening failures
Not applicable. There is no screening Epoch.
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). Entries in the extension 
study database should match those in the core study database.
For patients whose baseline visit of the extension study does not occur on the same day as the 
last visit in the CRFB002H2301 core study, relevant medical condition which started and/or 
ended after the last visit in the core study and before the baseline visit in the extension study 
will be recorded in the extension study database.
6.3
Treatment exposure and compliance
Every time that ranibizumab treatment is to be administered, IRT needs to be contacted for the 
medication (kit) number. 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 until completion of 
Epoch 1 using vial counts and information provided by the pharmacist or by the investigator.
6.4
Efficacy
6.4.1
Ophthalmic fundus features
The presence of the following fundus features will be assessed by indirect ophthalmoscopy in 
both eyes by the investigator at study visits specified in Table 6-1 and Table 6-2:

Features of active ROP disease:

ROP disease – zone, stage, extent by clock hours, and characteristics of vascular 
changes of plus disease (extent by quadrants and severity) (up to Visit 301 included)

Extra-retinal vessels extending from the retina into the vitreous and judged to be a 
sign of active ROP disease (up to Visit 301 included)

Features of late sequelae of ROP /ocular structural abnormalities:

Retrolental membrane obscuring the view of the posterior pole

Substantial temporal retinal vessel dragging causing abnormal structural features

Posterior retinal fold involving the macula

Retinal detachment involving the macula

Retinal detachment not involving the macula

Pre-retinal fibrosis

Optic disc pallor (from Visit 301 included onwards)




Novartis
Confidential
Page 44
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
6.4.4
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).
Ocular and visual function assessments and VA assessment are standard visual function 
assessments (Kvarnström 2005, Becker 2002).
6.5
Safety
6.5.1
Ocular examination
The presence of fundus features abnormalities will be assessed in both eyes at study visits 
described in Section 6.4.1).
Ocular examination of structures in addition to that of the fundus will be performed in both eyes, 
including assessment of anterior ocular structures and the lens, described in Table 6-1.
Clinically significant abnormal findings will be reported as AEs in the CRF except for specific 
events as defined in Section 7.1.
6.5.2
Vital signs
6.5.2.1
Blood pressure
No Blood Pressure measurement is required to be performed 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 Table 6-1.
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 CRF.
6.5.2.2
Standing height, sitting height, weight and head circumference
For the assessment of standing/sitting heights, weight and head circumference, the patient 
should be wearing minimal clothing (e.g., a clean diaper if applicable and undershirt). Study 
staff trained in the assessment of infants or children will perform these assessments as 
applicable.
Standing and sitting height in centimeters will be measured using a stadiometer or according to 
local clinical practice. Leg length will be derived from the difference between standing height 
and sitting height.
Body weight will be measured using an electronic scale or according to local clinical practice.
The maximum occipitofrontal head circumference in centimeters will be measured using a tape 
measure.


Novartis
Confidential
Page 45
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
6.5.3
Health status
6.5.3.1
Respiratory function status
Patients’ respiratory function status will be assessed at visits specified in Table 6-1 by recording 
the use of any oxygen supplementation and the presence, frequency and severity of wheezing 
symptoms in the last 12 months.
6.5.3.2
Hearing function status
Patient’s hearing function status assessment will include the presence of hearing impairment 
and the use of hearing aids. Usual hearing (normal or near normal; hearing loss corrected with 
aids (moderate or severe); hearing loss not corrected with aids (profound); no useful hearing 
even with aids) will be assessed.
6.5.3.3
Hospitalization
Duration of hospitalization (from birth to first hospital discharge home) and weight at the first 
discharge from hospital home will be collected, only if not already recorded during the core 
study.
6.5.4
Laboratory evaluations
No laboratory evaluations are required per protocol (e.g., hematology, clinical chemistry or 
urinalysis). However, data from tests which were performed as part of routine clinical practice 
will be collected. At visits specified in Table 6-1, the most recent laboratory values for the tests 
below will be collected on the eCRF, where such data are available.
6.5.4.1
Hematology
Hematology will include hemoglobin (Hb), white cell count (WCC) and platelet count (PLT).
6.5.4.2
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)).
6.5.4.3
Urinalysis
Urinalysis will include urine protein.
6.5.5
Appropriateness of safety measurements 
The safety assessments selected are standard for this patient population.


Novartis
Confidential
Page 46
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after parent(s)/ legal guardian(s) provided written informed 
consent for their child’s participation in the study until the end of study visit. Therefore, an AE 


Novartis
Confidential
Page 47
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
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 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:

Substantial temporal retinal vessel dragging causing abnormal structural features/ macular 
ectopia

Retrolental membrane obscuring the view of the posterior pole

Posterior retinal fold involving the macula

Retinal detachment

Pre-retinal fibrosis

Optic disc pallor (from Visit 301 included onwards)

Optic disc swelling (from Visit 301 included onwards)

Pigmentary disturbance in the macula (from Visit 301 included onwards)

Atrophic changes in macula (from Visit 301 included onwards)
In this study, from Visit 301, common childhood infections and accidents/ injuries are not 
required to be reported as AEs, unless the AE meets one of the serious criteria (SAEs) (Section 
7.2.1).
All other AEs and SAEs, whether or not considered related to ranibizumab by the investigator, 
must be reported.
The occurrence of adverse events must 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 findings, laboratory test findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one 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 must 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 non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

Severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities


Novartis
Confidential
Page 48
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1

severe: prevents normal activities

Site (non-ocular/ocular) and laterality (bilateral/left eye/right eye), if an ocular AE

Relationship to the study treatment 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 must be reported

Whether it constitutes a serious adverse event (SAE - see Section 7.2 for definition of 
SAE)

If it constitutes an SAE (see Section 7.2 for definition of SAE), seriousness criteria (e.g. 
death, requires or prolongs hospitalization)

Action taken with investigational treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: no action taken (e.g.,
further observation only)/temporarily interrupted/permanently discontinued due to this 
adverse event/unknown/not applicable

Medications or therapies taken (no concomitant medication or non-drug therapy/ 
concomitant medication or non-drug therapy)

Outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, 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 Investigator Brochure (IB). This information will be included in the informed 
consent and should be discussed with the patient’s parent(s) or legal guardian(s) during the 
study as needed. Any new information regarding the safety profile of the medicinal product that 
is identified between IB updates will be communicated as appropriate, for example, via an 
Investigator Notification or an Aggregate Safety Finding. New information might require an 
update to the informed consent and has then to be discussed with the patient’s parent(s) or legal 
guardian(s).
The investigator must also instruct each patient’s parent(s) or legal guardian(s) to report any 
new adverse event (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 study 
treatment. This information must 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 SAE
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

is fatal or life-threatening 


Novartis
Confidential
Page 49
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1

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 (specify what this includes)

elective or pre-planned 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 a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. 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 it were more severe (see Annex IV, 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 listed above. 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 safety events listed in Section 7.1 will be collected as study endpoints only 
and are not to be additionally 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.
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 study 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.


Novartis
Confidential
Page 50
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment (if study treatment consists of several components), complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study 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 (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
In this study, safety events that are collected as study endpoints will not be recorded 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.
7.3
Reporting of study treatment errors
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/ parent(s)/ 
legal guardian(s) or consumer (EMA definition).
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE.
Treatment error 
type
Document in Dose 
Administration 
(DAR) eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE


Novartis
Confidential
Page 51
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
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 GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to 
Good Clinical Practice, 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, 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 


Novartis
Confidential
Page 52
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
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.
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical (ATC) classification system. Concomitant procedures, non-drug therapies and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Randomization codes and data about all study drug(s) dispensed to the patient will be tracked 
using an Interactive Response Technology (IRT) during Epoch 1. 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. 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 (e.g. DMC involved in the core study CRFB002H2301) 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. The 
DMC will operate until the last patient has completed visit 301 (i.e. week 52 after the 1st study
treatment in the core study) or discontinued the study whichever is the earliest.
8.5
Adjudication Committee
Not required.
9
Data analysis
The statistical analysis will be performed or directed by the Analytics Cluster of Novartis.
Three planned analyses will be performed in this study; two interim analyses (see Section 9.7) 
and one final analysis at the completion of the study. Additional interim analyses may be 
conducted on safety or efficacy data as required. Further technical details and discussions of the 
statistical considerations for each will be provided in the appropriate Statistical Analysis Plan 
(SAP), which will be finalized prior to first patient first visit (FPFV).
Descriptive statistics (mean, median, standard deviation, lower quartile (Q1), upper quartile 
(Q3), minimum, and maximum) will be presented for continuous variables. The number and 
percentage of patients in each category will be presented for categorical variables.


Novartis
Confidential
Page 53
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
There are three treatment groups defined by the original treatment received at baseline in the 
core study:

0.2 mg Ranibizumab group 

0.1 mg Ranibizumab group 

Laser treatment group 
All results will be displayed by the above three treatment groups. If appropriate, within each of 
these three treatment groups, analyses may also be conducted separately for patients who 
received monotherapy or who switched treatment (by eye or by patient as applicable).
Two baselines are defined; the core baseline and the extension baseline. The core baseline will 
be the baseline of the core study. For statistical purposes, the last available non-missing values 
collected in study CRFB002H2301 or CRFB002H2301E1 prior to or on visit 201 will be 
considered to be extension baseline values. Core baseline will be used as baseline for both 
efficacy and safety analyses. The extension baseline will be used for demographic summary of
the extension study.
9.1
Analysis sets
The Extension Safety Set for this study is defined as the subset of the Safety Set of the study 
CRFB002H2301 who enters this study.
All analyses will be carried out on the Extension Safety Set and displayed by the original study 
treatment received at baseline in the core study unless otherwise specified.
9.2
Patient demographics and other baseline characteristics
Demographic information will be summarized for each treatment group and for all patients 
(total).
Relevant medical history and current medical conditions using the core baseline will be 
tabulated by system organ class (arranged alphabetically) and preferred term (arranged by 
decreasing frequency in the ranibizumab 0.2 mg treatment arm) according to the latest version 
of MedDRA. Separate tables will be presented for ocular and non-ocular histories and 
conditions.
The same approach will be used for such data collected after the last visit in the core study 
CRFB002H2301 and before the baseline visit in this extension study (Section 6.2).
ROP disease status will be defined as the value derived in the study CRFB002H2301.
9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Exposure to investigational treatment will be presented by treatment group. 
Patient disposition and reasons for discontinuation of study medication and discontinuation of 
study will be summarized by treatment group and total.


Novartis
Confidential
Page 54
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Concomitant therapies recorded during the core study (CRFB002H2301) and the extension 
study will be summarized by preferred term according to the latest version of the WHO Drug 
Reference List dictionary and ATC codes. 
9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)
The primary efficacy variable is the visual acuity (VA) in the better-seeing eye at the patient’s 
fifth birthday as recorded by the investigator.
9.4.2
Statistical model, hypothesis, and method of analysis
If the primary hypothesis testing in the core study shows statistical significance, the primary 
objective of the extension study will be assessed by testing the superiority of ranibizumab 0.2 
mg to laser as follows: 
H01: µ0.2 mg Ranibizumab - µLaser = 0 versus HA1: µ0.2 mg Ranibizumab - µLaser ≠ 0
where μTreatment Group is the unknown mean VA in the better-seeing eye at the fifth birthday of 
patients in the relevant treatment group.
The hypothesis will be tested by using stratified analysis of variance (ANOVA) using the 
Cochran-Mantel-Haenszel (CMH) test with the observed VA values as scores as the response 
variable and the treatment group as the factor (with levels 0.2 mg ranibizumab and laser). 
Stratification will be based on the ROP zone at the core study baseline. Superiority of 
ranibizumab 0.2 mg over laser will be concluded if the hypothesis H01 is rejected at the two-
sided 5% significance level and μRanibizumab 0.2 mg > μLaser. 
If the primary hypothesis testing in the core study does not show statistical significance, only 
descriptive statistics (i.e., point estimate, and the 95% confidence interval) will be provided for 
the comparison between ranibizumab 0.2 mg and laser.
In addition, an unstratified two-way ANOVA using VA as the response variable and treatment 
group and zone as factors will be performed. Two-sided 95% confidence intervals, assuming 
normality, will be produced for the VA within each treatment arm and the difference in VA 
between a pair of treatment arms will be calculated from least squares means. No p-values will 
be displayed for this analysis.
Note that µ0.2 mg Ranibizumab is estimated using those patients that received 0.2 mg ranibizumab at 
baseline in the core study CRFB002H2301. This includes patients that received laser treatment 
at a later date in either the core or extension study. Patients that permanently discontinue 
treatment with 0.2 mg ranibizumab are also included. However, patients for which the value of 
the primary variable is missing are excluded (see Section 9.4.3). A similar approach is taken for 
the 0.1 mg ranibizumab arm.
Similarly, µLaser is estimated using those patients that received laser at baseline in the core study 
CRFB002H2301. This includes patients that received 0.2 mg ranibizumab treatment at a later 
date in either the core or extension study. Patients that permanently discontinue treatment with 
laser are also included. However, patients for which the value of the primary variable is missing
are excluded (see Section 9.4.3).


Novartis
Confidential
Page 55
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
9.4.3
Handling of missing values/censoring/discontinuations
Missing data will not be imputed for the primary efficacy analysis. Hence, as stated in Section 
9.4.2, the analysis of the primary variable is only conducted for patients with a non-missing 
value for VA.
9.4.4
Sensitivity analyses
The primary variable will also be assessed by using the randomized rather than the original 
treatment received in core study.
Additional analyses may be conducted for patients who switch treatment and patients who do
not switch treatment. 
Additional analyses may be conducted for patients who receive a medication which prohibits 
further use of ranibizumab or study laser. These analyses will be specified in the SAP.
9.5
Analysis of secondary variables
The analyses for objectives which are assessed up to a particular time (e.g. up to the patient’s 
fifth birthday) will include data collected in both the core and extension studies.
No multiplicity adjustment will be used for the analysis of secondary variables. 
No imputation of missing data will be used for the analysis of secondary variables unless 
specified in a scoring manual or similar.
Hence the analysis of all secondary variables will be based on the non-missing observations of 
patients that have not received a medication which prohibits further use of ranibizumab or study 
laser but may have permanently discontinued study treatment for another reason. 
9.5.1
Efficacy variables
Continuous variables:
If the primary hypothesis testing of the core study shows statistical significance, the following 
objectives will be tested for the continuous variables below by using the same CMH test 
approach as the primary analysis. 
The superiority of ranibizumab 0.1 mg to laser with regard to the VA of the better- seeing eye 
at the patient’s fifth birthday 

The superiority of ranibizumab 0.2 mg to ranibizumab 0.1 mg with regard to the VA of 
the better-seeing eye at the patient’s fifth birthday 

The three superiority tests comparing pairs of treatment arms will be repeated with regard 
to the VA of the worse-seeing eye at the patient’s fifth birthday
Binary variables:

The absence of all ocular structural abnormalities (see Section 3.5.2 for the definitions) at 
or before the patient’s 2 years corrected age and fifth birthday.

The recurrence of ROP up to 52 weeks post baseline visit in the core study

The absence of active ROP at 52 weeks post baseline visit in the core study


Novartis
Confidential
Page 56
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
The CMH test with ROP Zone as assessed at the baseline of the core study as stratification 
factor will be used for inference concerning binary secondary efficacy variables. However, the 
test will be based on proportions rather than a stratified ANOVA using the VA as a score. 
Mantel-Haenszel odds ratios and their two-sided 95% confidence intervals will be presented. 
Superiority will be defined as a rejection of the null hypothesis (equality of proportions) and 
the Mantel-Haenszel odds ratio is in favor of the hypothesized superior treatment.
Other efficacy variables:
Descriptive statistics will be provided for these efficacy variables by treatment arm:

The absence of all ocular structural abnormalities (see Section 3.5.1 for the definitions) at
or before 40 weeks post baseline visit in the core study

The recurrence of ROP up to 40 weeks post baseline visit in the core study

The absence of active ROP at 40 weeks post baseline visit in the core study

The absence of each ocular structural abnormality considered individually (see Section 
3.5.2 for the definitions) at or before the patient’s 2 years’ corrected age and at or before 
the patient’s fifth birthday

The number of ranibizumab injections received in the treatment of patients with ROP up to 
and including 40 weeks post baseline visit in the core study by eye and overall 

At the patient’s 2 years corrected age and fifth birthday 

The refraction in each eye: Refractive error will be categorized into myopia (spherical 
equivalent of 0.25 diopters or more of myopia) and high myopia (spherical equivalent 
of 5.00 diopters or more of myopia). The percentage of patients without myopia, with 
myopia, and with high myopia will be displayed. 
9.5.2
Safety variables
Safety analyses will be assessed by using treatment-emergent AEs by treatment group and 
overall. Adverse events (overall AE, ocular AE, non-ocular AE) will be presented by primary 
system organ class (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 study
treatment, leading to permanent study/study treatment discontinuation, and deaths) will be 
tabulated and listed as appropriate.
The number of hospitalizations/ prolongations of hospitalization due to an SAE will be 
summarized.
Deaths, SAEs, and AEs leading to permanent discontinuation of study treatment will be listed 
separately and, if appropriate, summarized by primary system organ class and preferred term.
Unless otherwise specified, AE data from the first study treatment in the core study will be 
included in all AE analyses. Vital signs, requirement for respiratory support and laboratory 
evaluations will be summarized by presenting descriptive statistics of raw values and change 
from baseline (if appropriate) by visit and treatment group. 


Novartis
Confidential
Page 57
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Other safety data will be summarized and listed as appropriate.
9.7
Interim analyses
Two interim analyses will be performed by the Novartis CTT (see Section 3.5 for more details).




Novartis
Confidential
Page 59
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
9.8
Sample size calculation
The sample size calculation is not based on a power calculation. The number of patients enrolled 
in this study depends on the number of patients in the core study fulfilling the eligibility criteria 
of the extension study (see Section 4).
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, 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
Eligible patients may only be included in the study after their parent(s) or legal guardian(s) have 
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 
(e.g. all of the procedures described in the protocol). The process of obtaining informed consent 
must 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 Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to the patient’s parent(s) or 
legal guardian(s). 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
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 




Novartis
Confidential
Page 61
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Connolly BP, Ng EY, McNamara JA, et al [2002] A comparison of laser photocoagulation with 
cryotherapy for threshold retinopathy of prematurity at 10 years: Part 2. Refractive outcome. 
Ophthalmology; 109(5):936-41.
Cryotherapy for Retinopathy of Prematurity Cooperative Group [1988] Multicenter trial of 
cryotherapy for retinopathy of prematurity. Preliminary results. Arch Ophthalmol; 106(4):471-
9.
Darlow BA, Ells AL, Gilbert CE, et al [2013] Are we there yet? Bevacizumab therapy for 
retinopathy of prematurity. Arch Dis Child Fetal Neonatal Ed; 98(2):F170-4.
De Pasquale MD, Pessolano R, Boldrini R, et al [2011] Continuing response to subsequent 
treatment lines with tyrosine kinase inhibitors in an adolescent with metastatic renal cell 
carcinoma. J Pediatr Hematol Oncol; 33(5):e176-9.
Edward DP, Kaufman LM [2003] Anatomy, development, and physiology of visual system. 
Pediatr. Clin North Am; 50(1):1-23.
Eremina V, Cui S, Gerber H, et al [2006] Vascular endothelial growth factor a signaling in the 
podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am 
Soc Nephrol; 17(3):724-35.
Eremina V, Jefferson JA, Kowalewska J, et al [2008] VEGF inhibition and renal thrombotic 
microangiopathy. N Engl J Med; 358(11):1129-36.
European Medicines Agency (EMEA) [2006] Avastin: EPAR - scientific discussion. 
24 Jan 2006. Available from:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR 
_Scientific_Discussion/human/000582/WC500029262.pdf (Accessed 17 Sep 2014)
European Medicines Agency (EMEA) [2013] Eylea: EPAR - public assessment report. 
21 Feb 2013. Available from:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR 
_Public_assessment_report/human/002392/WC500135744.pdf (Accessed 17 Sep 2014)
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)
Gerber HP, Hillan KJ, Ryan AM, et al [1999] VEGF is required for growth and survival in 
neonatal mice. Development; 126(6):1149-59.
Gilbert C [2008] Retinopathy of prematurity: a global perspective of the epidemics, 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.
Good WV, Early Treatment for Retinopathy of Prematurity Cooperative Group [2004] Final 
results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial. Trans 
Am Ophthalmol Soc; 102:233-48.


Novartis
Confidential
Page 62
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
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.
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.
Kvarnström G, Jakobsson P [2005] Is vision screening in 3-year-old children feasible? 
Comparison between Lea Symbol chart and the HVOT (LM) chart Acta Ophthalmol. Scand. 
83; 76-80
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 SY, 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:
https://iovs.arvojournals.org/article.aspx?articleid=2360939


Novartis
Confidential
Page 63
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
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.
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;148:536 –543
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.
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.
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.
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 
retinopathy of prematurity. Pediatr Int; 55(5):599-603.
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 Ophthalmol; 
153(2):327-33.
Smith AR, Hennessy JM, Kurth MA, et al [2008] Reversible skeletal changes after treatment 
with bevacizumab in a child with cutaneovisceral angiomatosis with thrombocytopenia 
syndrome. Pediatr Blood Cancer; 51(3):418-20.
Smith LE [2008] Through the eyes of a child: understanding retinopathy through ROP the 
Friedenwald lecture. Invest Ophthalmol Vis Sci; 49(12):5177-82.
Sonmez K, Drenser KA, Capone A Jr, et al [2008] Vitreous levels of stromal cell-derived factor 
1 and vascular endothelial growth factor in patients with retinopathy of prematurity. 
Ophthalmology; 115(6):1065-70.
Wu WC, Kuo HK, Yeh PT, et al [2013] An updated study of the use of bevacizumab in the 
treatment of patients with prethreshold retinopathy of prematurity in Taiwan. Am J Ophthalmol; 
155(1):150-8.


Novartis
Confidential
Page 64
Amended Protocol Version v02 (Clean)
Protocol No. CRFB002H2301E1
Wu WC, Yeh PT, Chen SN, et al [2011] Effects and complications of bevacizumab use in 
patients with retinopathy of prematurity: a multicenter study in Taiwan. Ophthalmology; 
118(1):176-83.
Zepeda-Romero LC, Liera-Garcia JA, Gutierrez-Padilla JA, et al [2010] Paradoxical vascular‑
fibrotic reaction after intravitreal bevacizumab for retinopathy of prematurity. Eye (Lond); 
24(5):931-3.
Zhou Y, Jiang Y, Bai Y, et al [2015] Vascular endothelial growth factor plasma levels before 
and after treatment of retinopathy of prematurity with ranibizumab. Graefes Arch Clin Exp 
Ophthalmol (DOI 10.1007/s00417-015-2996-0)

SAP_001.pdf: 


Novartis
For business use only
Page 2
SAP
CRFB002H2301E1
Document History – Changes compared to previous final version of SAP
Version
Date
Changes
Amendment 1
June 14, 2016
1.
Combined (ocular and non-ocular) AE tables are excluded 
as these are redundant
2.
RMP safety risk tables/listing included
3.
Study day for Extension baseline modified
4.
Rules of data mapping/reporting of last study visit and 
additional assessment visits updated
5.
Definitions updated on: prior/concomitant medications, 
Extension safety set,
6.
Section of baseline and demographic characteristics added
7.
Data entry/reporting rules included for prior/concomitant 
medications, medical history, AEs, etc.
8.
Text added in Section 1.2, as suggested by DMC member to 
emphasize that the study is not intended or powered for 
hypothesis testing.
9.
Definitions of absence of active ROP, absence of structural 
abnormalities, etc. included in Section 2.7
10. Objectives of efficacy analyses of hypotheses tesing 
changed, as requested by DMC member
12. SAS codes of inferential analyses included
13. Safety observation period and AE presentation updated
14. Japan specific outputs adeed to interim analysis I
15. Disposition and demographics added to interim analysis I
Amendment 2
Mar 13, 2018
1.
Definitions of absence of ocular structural abnormalities and 
active ROP clarified in Section 2.8.1
2.
Data cut-off date added
Amendment 3
Sept 6, 2018
1.
Primary analysis changed to descriptive statistics, as 
defined in the protocol.
2.
Imputation rule changed for primary, secondary 
 
analyses by not exluding data after the use of 
the treatments prohibiting further use of investigational 
ranibizumab (protocol Table 5-2).
3.
AEs presented by switch/no switch removed following the 
amendment of the protocol.
4.
Additional analyses added to the interim analyses II in 
Sections 2.14 and 2.15.
5.
Analysis of recurrence of ROP up to Week 52 removed, as 
it’s not applicable.
6.
Output of demographics and baseline characteristics at core 
baseline included in IA2 in Section 2.15
7.
Definition of absence of ocular structural abnormalities 
updated in Section 2.8.1
8.
Interim analysis II updated in Section 2.15


Novartis
For business use only
Page 3
SAP
CRFB002H2301E1
Version
Date
Changes
Amendment 4
December 16,
2019
1.
Definition on the composite and individual components of 
ocular structural abnormality updated in Section 2.8.1, to 
align with the protocol.
Amendment 5
May 24, 2022
1.
Align section numbers in Table 1.1
2.
Update definition of study day relative to Core/Extension 
baseline.
3.
Update mapping rules for end of study visit
4.
Update definitions of better-seeing eye, worse-seeing eye, 
best eye, worst eye, best vision of the Low Visual Acuity 
Testing
5.
Added several sensitivity analyses for the primary endpoint
6.
Added analyses for the Low Visual Acuity Testing
7.
Added outputs for AEs that start prior to / on or after the 
Extension baseline
8.
Added reference SAS code for unstratified ANOVA


Novartis
For business use only
Page 4
SAP
CRFB002H2301E1
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
1.3
Cut-off dates ..........................................................................................................12
2
Statistical methods.............................................................................................................12
2.1
Changes to the planned analyses in the protocol...................................................12
2.2
Data analysis general information .........................................................................13
2.2.1
General definitions................................................................................13
2.2.2
Data for permanent study treatment discontinuation ............................17
2.3
Analysis sets ..........................................................................................................17
2.4
Patient disposition, demographics and other baseline characteristics ...................17
2.4.1
Patient disposition.................................................................................19
2.4.2
Baseline and demographic characteristics ............................................19
2.5
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................21
2.5.1
Study treatment / compliance................................................................21
2.5.2
Prior and concomitant medications.......................................................21
2.5.3
Surgical and medical procedure............................................................23
2.6
Analysis of the primary objective..........................................................................23
2.6.1
Primary endpoint...................................................................................23
2.6.2
Statistical hypothesis, model, and method of analysis..........................24
2.6.3
Handling of missing values/censoring/discontinuations.......................24
2.6.4
Supportive analyses...............................................................................24
2.7
Analysis of the key secondary objective ...............................................................25
2.8
Analysis of secondary efficacy objective(s)..........................................................25
2.8.1
Secondary endpoints .............................................................................25
2.9
Safety analyses.......................................................................................................27
2.9.1
Risk Management Plan (RMP) adverse events.....................................28
2.9.2
Adverse events (AEs)............................................................................28
2.9.3
Laboratory data .....................................................................................30
2.9.4
Other safety data ...................................................................................30
2.10
Pharmacokinetic endpoints....................................................................................31
2.11
PD and PK/PD analyses.........................................................................................31
2.12
Patient-reported outcomes .....................................................................................32


Novartis
For business use only
Page 5
SAP
CRFB002H2301E1
2.13
Biomarkers.............................................................................................................32
32
2.15
Interim analysis......................................................................................................33
3
Sample size calculation .....................................................................................................35
4
Appendix ...........................................................................................................................35
4.1
Imputation rules.....................................................................................................35
4.1.1
Study drug.............................................................................................36
4.1.2
Adverse event date imputation..............................................................36
4.1.3
Medical history date of diagnosis imputation.......................................38
4.1.4
Concomitant treatment date imputation................................................39
4.2
Laboratory parameters derivations ........................................................................41
4.3
Statistical models and SAS codes..........................................................................41
4.4
Rule of exclusion criteria of the analysis setset.....................................................43
43
5
Reference...........................................................................................................................46


Novartis
For business use only
Page 6
SAP
CRFB002H2301E1
List of abbreviations
AE
Adverse Event
ATC
Anatomical Therapeutic Classification
ANOVA
Analysis of Variance 
CMH
Cochran-Mantel-Haenszel 
CSR
Clinical Study Report
CRF
Case Report Form 
 
DMC 
Data Monitoring Committee 
DAR
Drug Administration Record 
eCRF
Electronic Case Report Form
EMA
European Medicins Agency 
 
IRT
Interactive Response Technology
MedDRA
Medical Dictionary for Drug Regulatory Affairs
PD
Pharmacodynamics 
PK
Pharmacokinetics
PT
Preferred Term 
PIP
Pediatric Investigational Plan
Q1
Lower Quartile 
Q3
Upper Quartile 
RMP
Risk Management Plan
ROP
Retinopathy of Prematurity
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software 
SOC
System Organ Class
SOP
Standard Operating Standard 
VA
Visual Acuity 
WHO
World Health Organization


Novartis
For business use only
Page 7
SAP
CRFB002H2301E1
1
Introduction
This Statistical Analysis Plan (SAP) 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.
1.1
Study design
This is a multicenter open-label Extension study (Figure 1-1). Patients who have successfully 
completed the 24-week Core study (CRFB002H2301) are eligible for entry into the study. 
Visit 201/ baseline visit of the Extension study can occur on the same day as the last visit in 
the CRFB002H2301 study.
At Visit 201 (Extension baseline), the investigator or his/her delegate will contact the IRT after 
confirming the patient fulfills all the inclusion/exclusion criteria. Sample size estimation or 
formal power calculation was not done for this study. The number of patients is the actual 
enrollment in the Extension study (Section 4 of study protocol). 
Treatment with study ranibizumab (either as re-treatment after ranibizumab has already been 
injected or as switch ranibizumab treatment from study laser therapy administered in the Core
study) will be permitted for eligible eyes up to and including the study visit V203 (week 40 
from the baseline visit in the Core study (CRFB002H2301) (equal to week 16 from the 
baseline visit in Extension study, when the baseline visit in Extension study coincides with the 
week 24 visit in the Core study) [Epoch 1]). During Epoch 1, the investigator or his/her 
delegate will contact the IRT upon decision to administer study treatment. IRT will specify a 
unique medication number for the package of study drug to be dispensed to the patient. The 
remainder of the Extension study (from the study visit V203, to patients’ 5th birthday visit) 
[Epoch 2] is observational.
Assessment visits will be performed regularly throughout Epoch 1 and Epoch 2, with the last 
study visit to be as close as possible to the patient’s fifth birthday. The assessments related to 
the primary objective will be performed at the study visit V399, corresponding to the 
approximate time of the patient’s fifth birthday. 
Two interim analyses are planned for the study. Additional interim analyses may be 
conducted on safety or efficacy data as required.
The first interim analysis will be conducted to comply with the plan for specific follow-up set 
out in the Pediatric Investigational Plan (PIP) with the EMA and to support the inclusion of 
information related to the treatment of ROP in the Lucentis product information. This will be 
performed when the last patient has completed the last visit in the Core study or when at least 
half of the patients who were enrolled in the Core study have completed the visit which 
corresponds to the visit occurring 40 weeks after the first study treatment (in the Core study), 
whichever is the latest.  
The second interim analysis will be performed when the last patient has completed the visit 
which corresponds to the patient’s 2 years’ corrected age. A patient’s corrected age is its 
chronological age corrected for its prematurity, i.e. calculated by subtracting the number of 
weeks of prematurity from the chronological age. 


Novartis
For business use only
Page 8
SAP
CRFB002H2301E1
Figure 1-1
Study design 
1.2
Study objectives and endpoints
All study objectives will be assessed by initial study treatment received at baseline of the Core
study CRFB002H2301. The objectives, along with its endpoints and time point for analyses are 
presented in Table 1-1.
Table 1-1
Study objectives and endpoints 
OBJECTIVE
Endpoint Title, Description and Reporting Time frame for 
analysis and Unit of measure
Primary
To evaluate the visual 
function of patients, by 
assessing the visual 
acuity in the better-seeing 
eye at the patient’s fifth 
birthdaya,e
Title: visual acuity in the better-seeing eye at the patient’s 
fifth birthday
Unit of measure: visual acuity score (Lea symbols 
optotypes)
Time frame: at the patient’s fifth birthdaye
Secondary
To evaluate the safety 
outcomes by analyzing 
the type, frequency and 
severity of ocular and 
non-ocular Adverse 
Eventsb
Title: ocular and non-ocular Adverse Events
Unit of measure: number and percentage of patients having 
e.g. any AE; number of hospitalization/ prolongation of 
hospitalization due to SAE
Time frame: from the first study treatment in the Core
study up to V203 (Week 40), V302 (the patient’s 2 years’ 
corrected age) and V399 (the patient’s fifth birthday) in the 
Extension study


Novartis
For business use only
Page 9
SAP
CRFB002H2301E1
OBJECTIVE
Endpoint Title, Description and Reporting Time frame for 
analysis and Unit of measure
To evaluate the visual 
function by assessing the 
visual acuity in the 
worse-seeing eye at the 
patient’s fifth birthdaya
Title: visual acuity in the worse-seeing eye at the patient’s 
fifth birthday
Unit of measure: visual acuity score (Lea symbols 
optotypes) 
Time frame: at the patient’s fifth birthday
To evaluate the absence 
of active ROP at 40 
weeks and 52 weeks post 
baseline visit in the Core
study
Title: absence of active ROP
Unit of measure: number and percentage of patients
Time frame: at V203 and V301 (40 weeks and 52 weeks 
post baseline visit in the Core study)
To evaluate the absence 
of ocular structural 
abnormalities at or before 
40 weeks post baseline 
visit in the Core study, at 
the patient’s 2 years’ 
corrected age and fifth 
birthday
Title: absence of all ocular structural abnormalities as listed 
in Section 2.8.1
Unit of measure: number and percentage of patients
Time frame: at or before V203 (Week 40) in the Core/ 
Extension study, at or before V302 (the patient’s 2 years’ 
corrected age), at or before V399 (the patient’s fifth 
birthday)
Title: absence of each ocular structural abnormality as 
listed in Section 2.8.1considered individually
Unit of measure: number and percentage of patients 
Time frame: at or before week 40, at or before patient’s 2 
years’ corrected age, at or before patient’s fifth birthday
To evaluate the 
recurrence of ROP up to 
40 weeks post baseline 
visit in the Core study
Title: recurrence of ROP
Unit of measure: number and percentage of patients with 
recurrence of ROP
Description: Recurrence of ROP is defined as ROP 
receiving any intervention after the 1st study treatment in 
the Core studyd.
Time frame: up to 40 weeks postbaseline visit in the Core
study
To assess the number of 
ranibizumab injections 
received in the treatment 
of patients with ROP up 
to and including 40 
weeks post baseline visit 
in the Core study
Title: number of ranibizumab injections
Unit of measure: number of ranibizumab injections
Description: as per title
Time frame: up to and including 40 weeks post baseline 
visit in the Core study


Novartis
For business use only
Page 10
SAP
CRFB002H2301E1
OBJECTIVE
Endpoint Title, Description and Reporting Time frame for 
analysis and Unit of measure
To evaluate the refraction 
in each eye at the 
patient’s 2 years’ 
corrected age and fifth 
birthdaya
Title: refraction in each eye
Unit of measure: diopters
Time frame: at patient’s 2 years’ corrected age, patient’s 
fifth birthday
To evaluate the physical 
development at the 
patient’s 2 years’ 
corrected age and fifth 
birthdayb
Title: standing/sitting height, leg length, weight
Unit of measure: centimeter, gram (as appropriate)
leg length will be derived from standing/sitting height 
difference
Time frame: at the patient’s 2 years’ corrected age, at the 
patient’s fifth birthday
Title: head circumference
Unit of measure: centimeter
Time frame: at the patient’s 2 years’ corrected age
To evaluate the health 
status at the patient’s 2 
years’ corrected age and 
fifth birthdayb,c
Title: respiratory functionb
Unit of measure: number and percentage of patients with 
oxygen supplementation; with presence of wheezing 
symptoms
Title: hearing functionc
Unit of measure: number and percentage of patients with 
presence of hearing impairment
Title: duration of hospitalization after first hospital 
discharge home; weight at first hospital discharge home
Unit of measure: days/months as appropriate; gram
Time frame: at the patient’s 2 years’ corrected age, at the 
patient’s fifth birthday


Novartis
For business use only
Page 11
SAP
CRFB002H2301E1
OBJECTIVE
Endpoint Title, Description and Reporting Time frame for 
analysis and Unit of measure


Novartis
For business use only
Page 12
SAP
CRFB002H2301E1
a - Variable corresponding to “ocular effects” in the plan for specific follow-up in the 
Pediatric Investigation Plan (EMA)
b - Variable corresponding to “clinical outcomes” in the plan for specific follow-up in the 
Pediatric Investigation Plan (EMA)
c - Variable corresponding to “neurodevelopmental outcomes” in the plan for specific follow-
up in the Pediatric Investigation Plan (EMA)
d - Supplementary laser treatments (as per CRFB002H2301 study protocol) are considered 
part of the complete laser treatment
e - At the visit as close as possible to the patient’s fifth birthday 
1.3
Cut-off dates
Interim Analysis I: only subjects who have completed Week 40 visit prior to or on December 
31, 2017 will be included in Interim Analysis I. For all domains with visit numbers (e.g., DM, 
DS, ZX, EX), Week 40 visit number will be used for cut-off. For event data without visit 
number (e.g., AE), December 31, 2017 will be used as the cut-off date. 
Interim Analysis II：all subjects from the extension safety set will be included in Interim 
Analysis II, with a cut-off date defined as the date when the last patient has completed the 2 
years’ corrected age visit. For all domains with visit numbers (e.g., DM, DS, ZX, EX), the 2 
years’ corrected age visit number will be used for cut-off. For event data without visit number 
(e.g., AE), all data up to the cut-off date will be reported.
2
Statistical methods
2.1
Changes to the planned analyses in the protocol
The Extension study is conducted to fulfill regulatory requirements independent of whether  
the Core study succeeds on its primary objective or not. As such, Type I error and power 
control is not a feature of the Extension study design, and the results cannot be viewed within 
a valid inferential context. Thus, statistical significance cannot be inferred from any analyses 
based upon reaching specific significance thresholds. As a result, all hypotheses testing is not 
aimed to claim statistical significance or superiority of one treatment group against another, 
but needs to be interpreted with caution.
Patients may receive study treatment up to Week 40 only, while the study is purely 
observational beyond this time point. Therefore, results from the analysis of “recurrence of 
ROP up to 52 weeks post baseline visit in the Core study” (stated in protocol Section 9.5.1) 
would be identical to the results performed for “recurrence of ROP up to week 40 post 
baseline visit in the Core study”, since recurrence (defined as intervention, i.e. study 
treatment, received after baseline of the Core study”) remains unchanged and such analysis at 
week 52 is considered not meaningful.


Novartis
For business use only
Page 13
SAP
CRFB002H2301E1
2.2
Data analysis general information
Three planned analyses will be performed in this study: two interim analyses and one final 
analysis at the completion of the study. The statistical analysis will be performed or directed by 
the Biostatistics & Pharmacometrics of Novartis. 
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) will be presented for continuous variables. The number and 
percentage of patients in each category will be presented for categorical variables. If a 
confidence interval is presented for a categorical variable, then the exact Clopper-Pearson 
method (Newcombe, R.G., 1998) will be used to calculate the 2-sided 95% confidence interval.
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. 
2.2.1
General definitions 
Study treatment refers to study ranibizumab in both Core and Extension studies, and laser 
therapy in the  Core study. (Please note that laser is a study treatment in the Core study but not 
a study treatment in the Extension study.) In this document, patient and subject are used 
interchangeably throughout the document.
A patient randomized to ranibizumab in the Core study can receive switch/rescue laser therapy 
in either eye; a patient randomized to laser therapy in the Core study can receive switch/rescue 
ranibizumab 0.2 mg in either eye. The change of treatment modality from laser to ranibizumab 
can occur at any time in the Core study and only in Epoch 1 of the Extension study, while the 
change of treatment modality from ranibizumab to laser can only occur in the Core study as 
only ranibizumab is available as study treatment in the Extension study. No further ranibizumab 
treatment can be administered to the eye after it has been switched to laser. The switch of study 
treatment occurs when the patient first receives a treatment modality other than the modality of 
the first study treatment in either eye, which can occur in the Core or Extension study period.
There are three treatment arms defined by the initial treatment received at baseline of the Core
study:

0.2 mg Ranibizumab arm (same as Ranibizumab 0.2 mg arm)

0.1 mg Ranibizumab arm (same as Ranibizumab 0.1 mg arm)

Laser treatment arm (same as Laser arm)


Novartis
For business use only
Page 14
SAP
CRFB002H2301E1
All results will be displayed by the initial treatment received at Core study baseline. If 
appropriate, within each of these three treatment arms, analyses may also be conducted 
separately for patients who received monotherapy or who switched treatment (by eye or by 
patient as applicable) during the Core study.
Two baselines are defined; Core baseline and Extension baseline. For statistical purposes, the 
last available non-missing values collected in study CRFB002H2301 or CRFB002H2301E1 
prior to or on visit 201 will be considered to be the Extension baseline values. Core baseline 
will be used as baseline for both efficacy and safety analyses. The Extension baseline will be 
used for the demographic summary of the Extension study. 
2.2.1.1
Baseline definition and post-baseline definitions 
All data collected after Day 1 of the Core study are defined as post-Core baseline.
All data collected after the Extension baseline visit are defined as post-Extension baseline. The 
study day relative to Core baseline for a scheduled or unscheduled visit which is on or after the 
date of first study treatment (of the Core study) in either eye is defined as
Study day = (Date of visit) – (date of first study treatment in either eye in Core study) + 1
The study day relative to Core baseline for a scheduled or unscheduled visit which is before 
the date of first study treatment (of the Core study) in either eye is defined as
Study day = (Date of visit) – (date of first study treatment in either eye in Core study)
The study day relative to Extension baseline for a scheduled or unscheduled visit on or after
Extension baseline is defined as
Study day = (Date of visit) – (date of Visit 201 in Extension study) + 1
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 2-1, will be 
used to classify the eye at Core 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 2-1 will be derived from the eCRF.
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, then the
left eye will be assigned as the worst eye. 
The better-seeing eye and the worse-seeing eye at the 5th birthday visit are defined as the eye 
with a higher and lower ETDRS letter score, respectively. If both eyes have the same ETDRS 
letter score, then the left eye will be assigned as the worse-seeing eye.
The best vision of the Low Visual Acuity Testing is defined as the best assessment with an 
answer 'YES', in the order of 'Count fingers' > 'Hand movement' > 'Light perception'. If all 
assessments have answers 'No', the best vision of the Low Visual Acuity Testing is defined as 
'None of the above'. If the eye had a Low Visual Acuity Testing and all assessments have 
missing answers, the best vision of the Low Visual Acuity Testing is defined as 'Missing'.


Novartis
For business use only
Page 15
SAP
CRFB002H2301E1
Table 2-1
Ranking of Retinopathy of Prematurity Disease
Zone 
Stage
Any
5
Any
4
I
AP-ROP
II
AP-ROP
I
3+
I
3
I
2+
I
1+
II
3+
II
2+
I
2
I
1
II
3
II
2
II
1+
II
1
III
3+
III
3
III
2+
III
2
III
1+
III
1
Abbreviations: AP-ROP - aggressive posterior retinopathy of prematurity; ROP - retinopathy of
prematurity
2.2.1.2
The last study visit 
The last study visit is Visit 399 (including premature withdrawal). If the patient does not 
discontinue the study, Visit 399 will occur close to the patient’s fifth birthday.
For the visual acuity at Visit 399, the study day will be allocated to the 5th birthday visit if the 
study day is before the 5th birthday and within 3 months of the 5th birthday, or if the study day 
is after the 5th birthday.
For all other variables except for the visual acuity, the study day for the premature withdrawal 
Visit 399 will be allocated to the nearest planned main visit if data for the nearest planned main 
visit does not already exist and if the study day is within the allocation windows of the planned 
main visit.
All applicable assessments will be captured by scheduled visit. Table 2-2 shows the allocation 
windows of premature withdrawal visit to a scheduled main visit of H2301E1.




Novartis
For business use only
Page 17
SAP
CRFB002H2301E1
2.2.1.5
Missing baseline data
Missing baseline data (both Core baseline and Extension baseline) will not be imputed. This 
includes variables which are not allowed to be collected according to local regulations (e.g. race 
in France).
2.2.1.6
Missing post-baseline data 
Observations with values ‘not done’, ‘not evaluable’, ‘not applicable’ will be treated as
missing values.
Missing efficacy data will not be imputed. 
Apart from AE and concomitant medication dates, missing post-baseline safety data will not be 
imputed.
Missing data for other variables will not be imputed unless otherwise specified.
2.2.2
Data for permanent study treatment discontinuation 
Patients that permanently discontinue study treatment will remain in the study and all planned 
assessments should be conducted (Section 5.6.2 of Protocol). 
2.3
Analysis sets
The Extension Safety Set for this study is defined as the subset of the patients from the Safety 
Set of the Core study who enter this Extension study and comprises data from both the Core
and Extension studies.
All analyses will be carried out on the Extension Safety Set and displayed by the initial study 
treatment received at the baseline of the Core study unless otherwise specified.
Table 4-1 shows the protocol deviations leading to data exclusion from the analysis data set. 
2.4
Patient disposition, demographics and other baseline 
characteristics
Outputs for subject disposition, and demographic characteristics will be reported for each 
treatment arm and all patients (total). Demographic and baseline characteristics will be 
summarized for both Core baseline and Extension baseline. 
No tests for differences in demographic characteristics among treatment arms will be performed.
Relevant medical history and current medical conditions using the Core baseline will be 
tabulated by system organ class (arranged alphabetically) and preferred term (arranged by 
decreasing frequency sequentially in the ranibizumab 0.2 mg treatment arm) according to the 
latest MedDRA version . Separate tables will be presented for ocular and non-ocular histories 
and conditions. The reporting will be by patient (not eye). 
The same approach will be used for the relevant medical history and current medical conditions 
using the Extension baseline, which will include medical history/condition collected after the 
last visit in Core study and before the baseline visit in this Extension study, corresponding to 
segment b of Figure 2-1.


Novartis
For business use only
Page 18
SAP
CRFB002H2301E1
Partial dates of diagnosis will be imputed using imputation rules as stated in Section 4.1.3.
Guidance of Data Entry rules in the Extension study eCRF which provides details on handling 
of Medical History in the Extension study.

Core Medical History which is still ongoing at the time of enrollment (Baseline Visit)
into the Extension study will not be reported again as Extension Medical History.

Core Medical History which resolved before enrollment into the Extension will not be
reported as Extension Medical History.

Core Medical History which resolved before the Core End of Study visit and which 
reoccurred after the Core End of Study visit but before enrollment into the Extension
study, will be entered as Extension Medical History. For such cases, multiple episodes
of the same Medical History will appear across the Core and Extension study but with
different start dates.

Adverse Events (AEs) and Serious Adverse Events (SAEs) continuing at the end of Core
study which resolved prior to Extension informed consent form date will be reported as 
Extension medical history with medical history ongoing status as “No”, further medical 
history term, preferred term (start date) should be an exact match to adverse event term, 
preferred term and adverse event start date. No plausible entries are accepted. 

Adverse Events (AEs) and Serious Adverse Events (SAEs) which started after end of 
Core study and resolved before the time of Extension study enrollment (Baseline Visit) 
will be reported as Extension medical history with medical history ongoing status as 
“No”.

Adverse Events (AEs) and Serious Adverse Events (SAEs) which started after end of 
Core study and are ongoing at the time of Extension study enrollment (Baseline Visit) 
will be reported as Extension medical history with medical history ongoing status as 
“Yes”.. 
Tabular format for Data Entry rules in the Extension study eCRF for Medical History
Item
Started 
Ended 
Action for ECRF
Med Hx
before 
Core
Ongoing end of Core and at 
beginning of Ext
Don't record as MHx in Ext (MHx 
of Core)
Med Hx
before 
Core
Ongoing end of Core and finished in 
Gap
Don't record as MHx in Ext (MHx 
of Core)
Med Hx
Gap
Gap
Record as MHx in Extension (not 
ongoing)
Med Hx
Gap
Ongoing at beginning of Ext
Record as MHx in Extension
(ongoing)
(S)AEs
Core
ongoing end of Core and finish in gap 
(before Ext)
Record as MHx in Extension (not 
ongoing)
condition
Gap
Ongoing at beginning of Ext
Record as MHx in Extension
(ongoing)
condition
Gap
Gap
Record as MHx in Extension (not 
ongoing)


Novartis
For business use only
Page 19
SAP
CRFB002H2301E1
2.4.1
Patient disposition
All disposition tables will be based on the Extension safety set. Subject disposition data is 
collected in specific eCRF disposition pages based on the epochs (time intervals in the course 
of the study) as defined in the protocol; reporting of disposition data will be presented by epoch. 
The Extension study period starts from Extension baseline and includes 2 epochs: post-
treatment follow-up 1 and post-treatment follow-up 2. 
The number and proportion of patients who completed each epoch and who discontinued the 
study prior to completion of the epoch will be presented. Also the number and proportion of the 
primary reason for not completing each epoch will be presented. 
The primary reason for premature study discontinuation and permanent study treatment 
discontinuation will be displayed by actual treatment and overall for this Extension study. 
Baseline-Failure Subjects are patients with informed consent obtained from their parent(s) or 
legal guardian(s) but who were discontinued at the baseline visit because they did not meet all 
inclusion/exclusion criteria.
The number of these patients and their reasons
for 
inclusion/exclusion failure will be summarized.
The number of patients with CSR reportable PDs according to the applicable SOP will be 
presented for this Extension study. The results will be grouped using the broad categories 
defined in the applicable SOP, which currently are:

Eligibility: Patients who entered the trial even though they did not satisfy the entry criteria 

Withdrawal: Patients who developed withdrawal criteria during the trial, but were not 
withdrawn 

Study Drug: Patients who received the wrong treatment or incorrect dose  

Concomitant Medication: Patients who received an prohibited concomitant medication 

Other reportable protocol deviation 
The reasons for exclusion from efficacy or safety analysis will be listed.
2.4.2
Baseline 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 2-3 shows the allocation of baseline parameters into groups and which are displayed as 
continuous and/or categorical variables.
Table 2-3
Display of baseline parameters:
Demographic
ROP characteristics 
and relevant medical 
history
Continuous
Categorical
Race
x
x


Novartis
For business use only
Page 20
SAP
CRFB002H2301E1
Ethnicity (based on that of 
mother)
x
x
Sex
x
x
Gestational age at birth (by 
completed weeks)
x
x
x
Chronological age at Core
baseline (by weeks)
x
x
Chronological age at Extension
baseline (by weeks)
x
x
Post-menstrual age at Core
baseline (by weeks)
x
x
Post-menstrual age at Extension
baseline (by weeks)
x
x
Corrected age at Extension
baseline (by weeks)
x
x
Birth weight (g)
x
x
x
Body length at birth (cm)
x
x
x
Head circumference at birth 
(cm)
x
x
x
Lower leg length
x
x
x
ROP zone by patient
x
x
ROP zone by eye
x
x
AP-ROP status by patient
x
x
AP-ROP status by eye
x
x
ROP disease status by patient
x
x
ROP disease status by eye 
(worst/best)
x
x
APGAR sCore at 1 minute
x
x
APGAR sCore at 5 minutes
x
x
Intubation requirement before 
enrollment (y/n)
x
x
Multiple pregnancy (y/n)
x
x
Number in multiple infants born 
of a multiple pregnancy
x
x
Born in study hospital (y/n)
x
x
Time from first diagnosis of 
ROP to screening visit (weeks)
x
x
x
Time from ROP fulfilling 
treatment criteria to screening 
visit (weeks)
x
x
x


Novartis
For business use only
Page 21
SAP
CRFB002H2301E1
Chronological age and Post-menstrual age will be calculated from Core study baseline as below: 
Chronological age at Core/Extension baseline (weeks) = [Core/Extension baseline visit date -
(start date of the mother's last normal menstrual period + gestational age at birth*7)+1]/7
Post menstrual age at baseline (weeks) = (Core/Extension baseline visit date - start date of the 
mother's last normal menstrual period+1)/7
Corrected age at Extension baseline (weeks) = [Extension baseline visit date - (start date of 
the mother's last normal menstrual period + 40*7)+1]/7
The time from a pre-screening event (e.g. diagnosis of a condition or taking a medication) in 
days will be derived using the formula:
        Time since <event> [days] = date of screening– date of event  
2.5
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.5.1
Study treatment / compliance
Exposure will be calculated for patients in the Extension safety set from Core baseline. Note 
that only study ranibizumab 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. Laser treatment is not a study treatment in the Extension study and 
therefore will not be collected in the DAR eCRF and will not be summarized here. 
Exposure to ranibizumab is defined as the number of injections of ranibizumab received by 
worst/best eye (as defined in the Core study) and by patient. 
The total number of ranibizumab injections will be summarized by worst/best eye and by 
patient by treatment arm. Summaries will be provided for the entire study period from Core
baseline, and for Extension study period. (Note: summary will be summarized by initial 
treatment received at the baseline ofofof the Core.
The duration of the observation period will be displayed for each treatment arm, and in the 
Extension study, and overall from Core study baseline.
2.5.2
Prior and concomitant medications
Separate listings and summaries will be produced for ocular and non-ocular, for both prior and 
concomitant medication, in both Core baseline and Extension baseline based on the Extension
safey set.   
For Core baseline: 
Prior medications are defined as those taken and stopped prior to the date of first study treatment 
in the Core study. Any medication given at least once on or after the first study treatment date 
of the Core study will be defined as a concomitant medication.  Concomitant therapies taken 
after the first study treatment in the Core study, which prohibits further use of study treatment 


Novartis
For business use only
Page 22
SAP
CRFB002H2301E1
(refers to ranibizumab or study laser in the Core study period and only refers to ranibizumab in 
the Extension study period) may be summarized separately.
For Extension baseline: 
Prior medications are defined as those with an end date prior to the Extension baseline visit. 
Any medication given at least once on or after the Extension baseline visit will be defined as 
concomitant medication. Concomitant therapies taken after the extension baseline visit, which 
prohibits further use of ranibizumab  (in the Extension study) may be summarized separately.
Guidance of Data Entry rules in the Extension study eCRF which provides details on handling 
of Concomitant Medication in Extension study.

Concomitant Medications continuing at the Core End of Study visit which are ongoing at 
the time of enrollment into the Extension need to be reported as Extension Concomitant 
Medication with the same Medication term, Category, Location, Laterality, Is med used for 
ocular condition, Location of treated condition, Reason and Start date.

Concomitant Medications continuing at the Core End of Study visit which stopped before  
enrollment into the Extension, need to be reported again as Extension Concomitant 
Medication with the same Medication term, Category, Location, Laterality, Is medication 
used for ocular condition, Location of treated condition, Reason and Start date. Note, that 
in such a case the Extension Concomitant record must have an end date.

For subjects where the Core End of Study and Extension baseline visit are occurring on the 
same date; any ongoing concomitant medication with a start date at this combined Core End 
of Study and Extension baseline visit, should be recorded in both, the Core and Extension 
“Prior and Concomitant Medications” CRF pages.

With regards to vaccinations, if the initial administration was performed in the Core study, 
this should not be again recorded in the Extension. Only booster doses administered during 
the Extension study, if any, should be recorded.
Tabular format for Data Entry rules in the Extension study eCRF for Concomitant Medication
Item
Started 
Ended 
Action for ECRF
Con 
Meds
Core
Ongoing at beginning of Ext
Record as Con Med in Extension
Con 
Meds
Core
Gap
Record as Con Med in Extension
(=reported as prior medication)
Con 
Meds
Gap
Gap
Record as Con Med in Extension
*(Only if this conmed is of 
relevance and in the context of a 
recorded medical history record or 
(S) AE. Not as a 
standalone.=reported as prior 
medication)
Con 
Meds
Gap
Ongoing beginning of Ext
Record as Con Med in Extension
Con 
Meds
Ext
Record as Con Med in Extension


Novartis
For business use only
Page 23
SAP
CRFB002H2301E1
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. 
For missing medication date, please refer to Appendix 4 for imputation rule. 
2.5.3
Surgical and medical procedure
Surgical and medical procedures will be displayed separately for Core and Extension studies, 
and separate from concomitant medications.
Guidance of Data Entry rules in the Extension study eCRF which provides details on handling 
of Surgeries and procedures in Extension study:

It is not expected that records for surgery and procedures in the Core study must be re-
entered in the Extension study, as they are usually not continuing over a long period of 
time. However, if any, records are expected to match (with the exceptions of end dates).

Procedures which occurred after end of Core study and ended prior to enrollment in to 
the Extension study should be entered in Extension medical history.  
The same approach will be taken to display surgeries and procedures as specified for 
concomitant medications in Section 2.5.2. Surgical and medical procedures will be identified 
by primary system organ class and preferred team according to the WHO Drug Reference List 
dictionary.  
2.6
Analysis of the primary objective
2.6.1
Primary endpoint
The primary efficacy variable is the visual acuity (VA) in the better-seeing eye at the patient’s 
fifth birthday as recorded by the investigator. 
The primary efficacy analysis will be based on the Extension safety set. 
Note that the ranibizumab 0.2 mg arm includes those patients that received ranibizumab 0.2 mg
at baseline in the Core study. This includes patients that received laser treatment at a later date 
in either the Core or Extension study. Patients that permanently discontinue treatment with 
ranibizumab 0.2 mg are also included in primary efficacy analysis. However, patients for which 
the value of the primary variable is missing are excluded. A similar approach is taken for the 
ranibizumab 0.1 mg arm.
Similarly, the laser arm includes those patients that received laser at baseline in the Core study 
CRFB002H2301. This includes patients that received ranibizumab 0.2 mg treatment at a later 
date in either the Core or Extension study. Patients that permanently discontinue treatment with 
laser are also included in the primary efficacy analysis. However, patients for which the value 
of the primary variable is missing are excluded.


Novartis
For business use only
Page 24
SAP
CRFB002H2301E1
2.6.2
Statistical hypothesis, model, and method of analysis
If the primary hypothesis testing in the Core study shows statistical significance, the primary 
objective is to compare ranibizumab 0.2 mg versus laser with an informal testing as follows: 
H01: µranibizumab 0.2 mg - µLaser = 0 versus HA1: µranibizumab 0.2 mg - µLaser ≠0
where μTreatment arm is the unknown mean VA in the better-seeing eye at the fifth birthday of 
patients in the relevant treatment arm. 
The hypothesis will be tested by using stratified analysis of variance (ANOVA) using the 
Cochran-Mantel-Haenszel (CMH) test with the observed VA values (letters) as the ordinal 
response variable and the treatment arm as the factor (with levels ranibizumab 0.2 mg and laser). 
The effect of ROP zone at the baseline of the Core study is expected to have an effect at 5 years 
of age. Hence this variable is used as stratification factor in the analysis.
If the primary hypothesis testing in the Core study does not show statistical significance, only 
descriptive statistics (i.e., point estimate, and the 95% confidence interval) will be provided for 
the comparison between ranibizumab 0.2 mg and laser.
In addition, an unstratified two-way ANOVA using VA as the response variable and treatment 
arm and ROP zone as factors will be performed. This is essentially a one-way ANOVA using 
VA as the response variable and treatment arm as the factor, without ROP zone as the 
stratification factor. Two-sided 95% confidence intervals, assuming normality, will be produced 
for the VA within each treatment arm and the difference in VA between a pair of treatment 
arms will be calculated from least squares means. No p-values will be displayed for this analysis. 
2.6.3
Handling of missing values/censoring/discontinuations
Missing data will not be imputed for the primary efficacy analysis. Hence, the analysis of the 
primary variable is only conducted for patients with a non-missing value of VA at the patient’s 
fifth birthday visit.
2.6.4
Supportive analyses
The primary variable will also be assessed by using the randomized rather than the initial
treatment received at baseline of Core study.
If a sufficient number of patients switch treatment during either the Core or Extension studies 
then additional analyses may be considered. This includes providing summary statistics for 
patients that receive monotherapy and on those that switch treatment separately. 
If a sufficient number of patients receive a medication which prohibits further use of 
ranibizumab or study laser then an additional analysis will be conducted by performing the 
primary analysis (CMH test of Section 2.6.2) on the total Extension safety set including patients 
who received prohibited medications. 
As a sensitivity analysis, the primary variable was also assessed separately for patients who had 
positive visual acuity letter score (excluding patients who have a 0 or missing visual acuity 
letter score).
As a sensitivity analysis, the primary variable was also assessed separately by best/worst eye.


Novartis
For business use only
Page 25
SAP
CRFB002H2301E1
The primary endpoint was also summarized by frequency of its value falling into several 
categories: 0 letter, >= 1 letter to <= 34 letters, >=35 letters to <= 70 letters, and >= 71 letters.
2.7
Analysis of the key secondary objective
There is no key secondary objective. 
2.8
Analysis of secondary efficacy objective(s)
The analyses for objectives which are assessed up to a particular time (e.g. up to the patient’s 
fifth birthday) will include data collected in both the Core and Extension studies. The secondary 
efficacy analysis will be based on Extension safety set. 
No multiplicity adjustment will be used for the analysis of secondary variables. 
2.8.1
Secondary endpoints
Continuous variables:
The following objectives will be assessed for the continuous variables below by using the same 
CMH test approach as the primary analysis with ROP zone at Core baseline as stratification 
factor. 

The comparison between ranibizumab 0.1 mg and laser with regard to the VA of the 
better- seeing eye at the patient’s fifth birthday 

The comparison of  ranibizumab 0.2 mg versus ranibizumab 0.1 mg with regard to the VA 
of the better-seeing eye at the patient’s fifth birthday 

The three pairwise comparisons of treatment arms will be repeated with regard to the VA 
of the worse-seeing eye at the patient’s fifth birthday
Again, one needs to be cautious interpreting the p-values when they show statistical 
significance and the point estimates indicate ranibizumab treatment is better than laser.
Recurrence of ROP is defined as ROP receiving any study intervention after the first study 
treatment of the Core study.
Binary variables:

The absence of all ocular structural abnormalities (see below for the definitions) at or 
before the patient’s 2 years’ corrected age and fifth birthday.

The absence of active ROP at 52 weeks post Core baseline 
The CMH test with ROP Zone as assessed at the baseline of the Core study as stratification 
factor will be used for inference concerning binary secondary efficacy variables. Mantel-
Haenszel odds ratios and their two-sided 95% confidence intervals will be presented. The
rejection of the null hypothesis (equality of proportions) and the Mantel-Haenszel odds ratio
being in favor of the hypothesized superior treatment should be interpreted with caution. 
The absence of active ROP in both eyes is defined by the absence of all of the following features: 

Vessel dilatation of plus disease in at least 2 quardrants (some persisting tortuosity is 
allowed)


Novartis
For business use only
Page 26
SAP
CRFB002H2301E1

Extra-retinal vessels extending from the retina into the vitreous and judged to be a sign 
of active ROP disease. 
The absence is defined as the absence of both of the above individual components at a particular 
time point, e.g., at week 40. 
The absence of all ocular structural abnormalities is defined by the absence of all of the 
following fundus features in both eyes at or before a particular time point, e.g., week 40 after 
the first study treatment in the Core study:

Substantial temporal retinal vessel dragging causing abnormal structural features/ 
macular ectopia

Retrolental membrane obscuring the view of the posterior pole

Posterior retinal fold involving the macula

Retinal detachment involving the macula
The absence is defined as the absence of the above individual components at all visits prior to 
and at a particular time point. Therefore, at least one presence of the above individual 
components at any visit prior to or at that time point is considered presence of ocular structural 
abnormalities. If at all visits up to that time point, the entry of at least one of the individual 
components is missing and none of the others indicates the presence of the disease feature, the 
subject will be considered as having missing record for this outcome.
The absence of each ocular structural abnormality considered individually in both eyes at or 
before a particular time point:

Substantial temporal retinal vessel dragging causing abnormal structural features/ 
macular ectopia

Retrolental membrane obscuring the view of the posterior pole

Posterior retinal fold involving the macula

Retinal detachment involving the macula

Retinal detachment not involving the macula

Pre-retinal fibrosis

Optic disc pallor (from Visit 301/week 52 included onwards)

Optic disc swelling (from Visit 301/week 52 included onwards)

Pigmentary disturbance in the macula (from Visit 301/week 52 included onwards)

Atrophic changes in the macula (from Visit 301/week 52 included onwards)

Low visual acuity testing:
Descriptive statistics will be provided for the best vision of the Low Visual Acuity Testing
by treatment arm for subjects who have 0 or missing ETDRS letter scores at the 5th birthday 
visit by best/worst eye.
Other efficacy variables:
Descriptive statistics with 95% Clopper-Pearson exact confidence interval will be provided for 
these efficacy variables by treatment arm:


Novartis
For business use only
Page 27
SAP
CRFB002H2301E1

The absence of all ocular structural abnormalities (see Section 2.15 for the definitions) at 
or before 40 weeks post baseline visit in the Core study

The recurrence of ROP up to 40 weeks post Core baseline

The absence of active ROP at 40 weeks post Core baseline

The absence of each ocular structural abnormality considered individually (see Section 
2.14 for the definitions) at or before the patient’s 2 years’ corrected age and at or before the 
patient’s fifth birthday

At the patient’s 2 years’ corrected age and fifth birthday 

The refraction in each eye: Refractive error will be categorized into myopia (spherical 
equivalent of equal to or less than -0.25 dioptres) and high myopia (spherical 
equivalent of equal to or less than -5.00 dioptres). The percentage of patients with and 
without myopia, and with high myopia will be displayed. 
If the entry of one of the above individual components is missing and the other indicates 
absence of the disease feature, the subject will be considered as having missing record for this 
outcome.Handling of missing values/censoring/discontinuations
No imputation of missing data will be used for the analysis of secondary variables unless 
specified in a scoring manual or similar.
2.9
Safety analyses
Safety analyses will be conducted on data from the Extension Safety Set by initial treatment 
received in the Core study. Adverse events, vital signs, health status and laboratory evaluations 
will be summarized and listed.
The safety observation period (days) for treated patients comprises two segments: 
(1) the first segment starts from first study treatment in the Core study and ends at the last 
visit in the Core study. This corresponds to period “a” in Figure 2-1. 
(2) the second segment starts from the Extension baseline visit to the last visit in the 
Extension study. This corresponds to period “c” in Figure 2-1. 
This safety observation period for a patient can be seamless (when the last visit of Core study 
occurs on the same day as the Extension baseline visit) or non-seamless (when the last visit of 
Core study does not occur on the same day as the Extension baseline visit). Any safety signs 
occurring in the gap, segment “b”, will be reported as medical history of Extension baseline as 
in Section 2.3. The resulted safety observation period (days) for the Extension study is defined 
as below:
-
For seamless roll-over:
o
Safety observation period for the Extension: date of last visit in Extension study –
date of baseline visit of Extension study
o
Safety observation period from Core baseline: date of last visit in Extension study –
date of first study treatment in Core study + 1
-
For non-seamless roll-over:


Novartis
For business use only
Page 28
SAP
CRFB002H2301E1
o
Safety observation period for the Extension: date of last visit in Extension study (or 
cut-off date) – date of baseline visit of Extension study +1
o
Safety observation period from Core baseline: (date of last visit in Extension study 
– date of baseline visit of Extension study +1) + (date of last visit in Core study –
date of first study treatment in Core study +1)
Figure 2-1
Safety observation period 
2.9.1
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 for the entire study period. 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 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.
2.9.2
Adverse events (AEs)
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 in Core study will be 
listed for patients. 
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 in the Core study. When an AE’s start date is equal to the 
date of first study treatment and either the start time of the AE or the first treatment time is 
missing, AEs are defined as treatment emergent. As stated in Appendix 4, adverse events with 
completely missing start date will be defined as treatment emergent.
The AE incidence rates will be tabulated using the latest MedDRA SOCs and PTs by initial 
study treatment received at Core baseline. 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 (with/without laser).)). Patients who experienced multiple AEs for a preferred 


Novartis
For business use only
Page 29
SAP
CRFB002H2301E1
term will be counted once, similarly for patients with multiple AEs per system organ class. In-
text tables will display the frequency of AEs at the PT level. 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 on the AE CRF form).
Guidance of Data Entry rules in the Extension study eCRF which provides details on handling 
of Adverse Events (AEs) and Serious Adverse Events (SAEs) in Extension study.

Adverse Events (AEs) and Serious Adverse Events (SAEs) ongoing at the end of Core
study visit which are ongoing at the Extension study informed consent form date needs 
to be reported as Adverse Event (AEs) or Serious Adverse Events (SAEs) for Extension
study. Adverse event term, preferred term, category, does Adverse event meet definition 
of Serious Adverse events, Serios adverse event date, severity, location, laterality, 
Adverse Event start date and time must match between Core and Extension study. 
Note: there can be differences across seriousness criteria, action taken with study 
treatment, medication or therapies taken etc. 

AEs which resolved in the Core study should not be re-entered (duplicated) in the
Extension.

An Extension adverse event or serious adverse events with a start date prior to end of 
Core study must have a corresponding Core adverse event record. 

Any serious adverse events, regardless of causality, newly occurring or recurring after 
Informed Consent Form was obtained for the Extension study needs to be reported to 
Novartis Safety as part of the Extension study.

Serious adverse events should never be reported to Novartis Safety in duplicate, i.e. 
for the Core and the Extension study. Any serious adverse events follow-ups sent to 
Novartis Safety should be sent as part of the study where the original SAE was 
reported.
Item
Started 
Ended 
Action for ECRF
(S)AEs
Core
Ongoing end of Core and ongoing at 
beginning of Ext (Signed ICF)
Record as (S)AE in Extension
(S)AEs
Ext
Record as (S)AE in Extension
All AE tables will show the frequency and crude incidence rate by initial study treatment 
received 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 

Adverse events with start dates prior to the extension baseline

Adverse events with start dates on or after the extension baseline

Serious adverse event, regardless of study treatment or procedure relationship 

All adverse events suspected to be related to study treatment or procedure

Serious adverse event suspected to be related to study treatment or procedure 


Novartis
For business use only
Page 30
SAP
CRFB002H2301E1

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.

Deaths, SAE, or AE leading to permanent study treatment discontinuation 
All deaths, SAEs, and AEs leading to permanent study drug discontinuation will be listed 
separately. 
For missing dates for medication or AE, please refer to Appendix 4 for imputation rule. 
2.9.2.1
Adverse events of special interest / grouping of AEs
The number of hospitalizations/prolongations of hospitalization due to an SAE will be 
summarized. 
2.9.3
Laboratory data
Laboratory evaluations (hematology, chemistry, urinalysis) will be summarized by presenting 
summary statistics of values and change from Core baseline at applicable visits by treatment 
arm.
2.9.4
Other safety data
2.9.4.1
ECG and cardiac imaging data
Not applicable. 
2.9.4.2
Vital signs
Vital signs (weight, head circumference, body length, standing height, knee to heel length, 
sitting height, 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) for available visits by treatment group. Their changes from Core baseline values will also be 
summarized if applicable by treatment arm.
Leg length= standing height – sitting height
Table 2-2
Vital signs collection in Core and Extension study 
Vital signs
Core study
Extension study
Weight
x
Day 1, 85, 169
x
Year 2, 5th birthday
Head 
circumference
x
Day 1, 85, 169
x
Year 2
Body length*
x
Day 1, 85, 169
Standing 
height*
x
Year 2, 5th birthday


Novartis
For business use only
Page 31
SAP
CRFB002H2301E1
Sitting height
x
Year 2, 5th birthday
Knee to heel 
length
x
Day 1, 85, 169
Leg length*
Blood pressure
x
Day 1, 85, 169
x
Year 2
Note: * body length is collected in the Core study while standing height is collected in the 
Extension study. These two variable are assessing whole body growth but are not fully 
comparable. Leg length will be derived from the standing/sitting height difference.
2.9.4.3
Health status 
Respiratory function status:  
The patient’s respiratory function status will be summarized and listed for applicable visits by 
treatment arm. 
For the Core study period, the requirement for respiratory support (other than oxygen therapy) 
and the requirement for oxygen therapy will be summarized. Positive end-expiratory pressure, 
fraction of inspired oxygen and percentage of oxygen saturation will be summarized by 
presenting summary statistics of values and change from Core baseline to day 169 by treatment 
arm.
For the Extension study period, the respiratory function status (wheezing/whistling status, 
number of attacks of wheezing, frequency of sleep disturbance, presence of wheezing limiting 
patient’s speech ability, dry cough status and presence of smoker at home) will be summarized 
for the patients’ 2 years’ corrected age visit and 5th birthday visit. 
Hearing function status:  
The patient’s hearing function status will be summarized and listed for the patients’ 2 years’ 
corrected age visit and 5th birthday visit. 
Hospitalization: 
Duration of hospitalization (from birth to first hospital discharge home) from the Core study 
and weight at the first discharge from hospital home will be summarized. 
2.10
Pharmacokinetic endpoints  
Not applicable. 
2.11
PD and PK/PD analyses
Not applicable. 


Novartis
For business use only
Page 32
SAP
CRFB002H2301E1
2.12
Patient-reported outcomes
Not reported. 
2.13
Biomarkers
Not applicable. 


Novartis
For business use only
Page 33
SAP
CRFB002H2301E1
2.15
Interim analysis
Two interim analyses will be performed by the Novartis CTT. 
Interim Analysis I: 
The first interim analysis will be performed when the last patient has completed the last visit in 
Core study or when at least half of the patients enrolled in the Core study have completed the 
visit corresponding to 40 weeks after the first study treatment (in the Core study), whichever is 
later.
The purpose of the first interim analysis is to provide some longer term data on ocular structural 
abnormalities. This is to comply with the plan for specific follow-up in the Pediatric 
Investigation Plan (EMA). At the first interim analysis, descriptive statistics will be produced 
as appropriate and no inferential analyses will be conducted. The variables below will be 
summarized.

Epoch 1 phase subject disposition

Subject demographics

The absence of all ocular structural abnormalities as defined in Section 2.8.1.

The recurrence of ROP up to 40 weeks post baseline visit from the Core study

The absence of active ROP at 40 weeks as defined in Section 2.8.1

The number of ranibizumab injections received in the treatment of patients with ROP up 
to 40 weeks post baseline visit of the Core study by eye and overall

The type, frequency, and severity of ocular and non-ocular adverse events
The above outputs will be repeated for the subgroup of Japan, to support the submission to the 
PMDA.
Interim analysis II: 
The interim analysis II will be performed when the last patient has completed the visit which 
corresponds to the patient’s 2 years’ corrected age. 
The purpose of the second interim analysis is to evaluate the absence of all ocular structural 
abnormalities as defined in Interim Analysis I at the patient’s 2 years’ corrected age.




Novartis
For business use only
Page 35
SAP
CRFB002H2301E1

Summary of body height, body weight, and head circumference at Core study baseline, at 
the year 2 visit of the Extension study, and their change from Core study baseline to the 
year 2 visit

Subject disposition

Summary of reasons for permanent discontinuation from study treatment

Deaths by preferred term

Number (%) of subjects with deaths, SAEs or AEs leading to permanent discontinuation 
of study treatment

Analysis sets by treatment

Pre-retinal fibrosis and its relationship to laser therapy, ocular injection therapy, and study 
drug by eye
The safety follow up period (in months) is defined as: (The earlier date of the extension EOS 
data and snapshot date of the interim analysis – Core study baseline date +1)/30.
In addition, a selection of the above outputs will be repeated for the subgroup of Japan, to 
support the submission to the PMDA.
3
Sample size calculation
The sample size calculation is not based on a power calculation. The number of patients enrolled 
in this study depends on the number of patients that were enrolled and completed the Core
study, are willing to participate in the Extension study and fulfill the eligibility criteria of the 
Extension study (Section 4 of Protocol).
4
Appendix
4.1
Imputation rules
The general approach to handling missing dates is shown below for dates of AEs, medical 
history diagnosis, and concomitant treatment. The imputation of missing dates for surgery or 
procedures will use the same rules as for concomitant treatment.
Imputation rules described here only apply to events, conditions and treatments 
(1) That are ongoing at the end of the Core study and at the time the patient enters the 
Extension study 
(2) That are not ongoing at the end of the Core study (start after last visit of Core study and 
are recorded in the Extension study for the first time). 
For events, conditions and treatments that ended before/on last visit of the Core study, the 
imputation rules defined in the Core study are applicable.
The detailed algorithms will be described in the Programming Dataset Specifications. 
For the purpose of date imputation, the treatment follow up period date is defined as the last 
available visit date.


Novartis
For business use only
Page 36
SAP
CRFB002H2301E1
4.1.1
Study drug
Missing date and time of study treatment will not be imputed for this study. 
4.1.2
Adverse event date imputation
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.
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.
Partial AE start dates are imputed with reference to the two reference dates depending on 
whether the AE is ongoing or not ongoing at the end of the Core study. If the AE is ongoing at 
the last visit of the Core study, treatment start date (TRTSTD) will be used as reference date for 
imputation, otherwise, if the AE is not ongoing at the last visit of the Core study, the Extension
baseline visit date (EXTBL) will be used as the reference date for imputation. The reference 
dates are 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 AE is ongoing at the the end of Core study , 
AE start reference date = treatment start date  
2. If the (imputed) AE end date is complete and AE is not ongoing at the the end of Core
study 
(a) The (imputed) AE end date < Extension baseline visit date then AE start reference date 
= min (informed consent date of Extension study, earliest visit date).
(b) Else AE start reference date = Extension baseline visit 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
Extension Baseline Visit Date (EXTBL)
Not used
EXTBLEXTBLEXTBL
EXTYEXEXTY
The following matrix explains the logic behind the imputation.


Novartis
For business use only
Page 37
SAP
CRFB002H2301E1
If the AE is ongoing at the end of the Core study: 
Comparison 
of Month 
section
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY 
MISSING
NC
NC
NC
NC
YYYY < 
TRTY
01JULYYYY
Before Treatment 
Start
15MONYYYY
Before 
Treatment Start
15MONYYYY
Before 
Treatment Start
15MONYYYY
Before 
Treatment Start
YYYY = 
TRTY
AE start reference 
date + 1 day
Uncertain
15MONYYYY
Before 
Treatment Start
TRTSTD +1
Uncertain
01MONYYYY
After Treatment 
Start
YYYY > 
TRTY
01JANYYYY
After Treatment 
Start
01MONYYYY
After Treatment 
Start
01MONYYYY
After Treatment 
Start
01MONYYYY
After Treatment 
Start
If the AE is not ongoing at the end of the Core study:
Comparison 
of Month 
section
MON MISSING
MON < EXTBL
MON = EXTBL
MON > EXTBL
YYYY 
MISSING
Uncertain 
Uncertain
Uncertain
Uncertain
YYYY < 
EXTBLY
Later of 
(01JULYYYY, 
date of last visit of 
Core study+1)
Before Extension
baseline visit
Later of 
(15MONYYYY, 
date of last visit 
of Core study+1)
Before 
Extension
baseline visit
Later of 
(15MONYYYY, 
date of last visit 
of Core study+1)
Before 
Extension
baseline visit
Later of 
(15MONYYYY, 
date of last visit 
of Core study+1)
Before 
Extension
baseline visit
YYYY = 
EXTBLY
EXTBL + 1 day
Uncertain
Later of 
(15MONYYYY, 
date of last visit 
of Core study+1)
Before 
Extension
baseline visit
EXTBL +1
Uncertain
01MONYYYY
After  Extension
baseline visit 
YYYY > 
EXTBLY
01JANYYYY
After  Extension
baseline visit 
01MONYYYY
After  Extension
baseline visit 
01MONYYYY
After  Extension
baseline visit 
01MONYYYY
After  Extension
baseline visit 
The following table is the legend to the logic matrix.
Relationship


Novartis
For business use only
Page 38
SAP
CRFB002H2301E1
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
Before Extension Baseline Visit
Partial date indicates AE start date prior to Extension Baseline 
Visit  Date
After Extension Baseline Visit
Partial date indicates AE start date after Extension Baseline Visit 
Date
Uncertain
Partial date insufficient to determine relationship of AE start date 
to Extension Baseline Visit Date
If a complete (imputed) AE end date is available and the imputed AE start date is greater than 
the (imputed) AE end date, then the imputed AE start date should be set to the (imputed) AE 
end date.
4.1.3
Medical history date of diagnosis imputation
Medical history date of diagnosis imputation for the Core study
Completely missing dates and partially missing diagnosis dates will not be imputed. 
Partial dates of diagnosis will be compared to the treatment start date.

If DIAG year <= Core study 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 = Core study treatment start date year 

and (DIAG month is missing OR DIAG month is equal to Core study 
treatment start month), the imputed DIAG date is set to one day before Core
study treatment start date

else if DIAG month <= Core study treatment start month, the imputed DIAG 
date is set to the mid-month point (15MON YYYY)

else if DIAG month > Core study treatment start month => data error

If DIAG year > Core study treatment start date year => data error
Medical history diagnose year imputation for the Extension study
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the end of Core study date (if medical conditions is ongoing at 
the end of Core study but not onoing at Extension baseline) , the ExtensionICF signsignsign
date (if medical conditions is ongoing at Extension baseline), .
If medical condition is ongoing at the end of Core study but not ongoing at Extension baseline: 
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to end of Core study date.


Novartis
For business use only
Page 39
SAP
CRFB002H2301E1

If diagnosis year <= end of Core study date year and diagnosis month is missing, the 
imputed diagnosis date is set to the mid-year point (01JULYYYY)

else if diagnosis month is not missing, the imputed diagnosis date is set to the mid-
month point (15MONYYYY)

If diagnosis year = end of Core study date year 

and (diagnosis month is missing OR diagnosis month is equal to end of Core study 
date month), the imputed diagnosis date is set to one day before end of Core study
date

else if diagnosis month < end of Core study date month, the imputed diagnosis date is 
set to the mid-month point (15MON YYYY)

else if diagnosis month > end of Core study date month => data error

If diagnosis year > end of Core study date year => data error
If medical condition is ongoing at Extension baseline (CIF sign date): 

If diagnosis year <= Extension ICF sign  date year and diagnosis month is missing, the 
imputed diagnosis date is set to the earlier of (mid-year point (01JULYYYY), Extension
ICF sign date ---1)

else if diagnosis month is not missing and not equal to ICF sign date month, the 
imputed diagnosis date is set to the earlier of (mid-month point (15MONYYYY), 
Extension ICF sign date---1)

else ifdiagnosisififdiagnosis month equal to ExtensionICF sign date month,, the 
imputed diagnosis date is set to one day before Extension ICF sign  date

ICF> Extension ICF sign date month => data error

If diagnosis year > Extension ICF sign date year => data error
4.1.4
Concomitant treatment date imputation
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.
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.
If medication is ongoing at the last visit of Core study: 


Novartis
For business use only
Page 40
SAP
CRFB002H2301E1
Completely missing start dates will be set to one day prior to start treatment date.... Concomitant 
treatments with partial start dates will have the date or dates imputed. Partial concomitant 
treatment start dates are imputed with reference to the treatment start date (TRTM) in 
accordance with the rules outlined below: 
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date (TRTM)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY MISSING
Uncertain
Uncertain
Uncertain
Uncertain
YYYY < TRTY
01JULYYYY
Before treatment 
start
15MONYYYY
Before treatment 
start
15MONYYYY
Before 
treatment start
15MONYYYY
Before treatment 
start
YYYY = TRTY
Uncertain
15MONYYYY
Before treatment 
start
Uncertain
01MONYYYY
After treatment 
start
YYYY > TRTY
01JANYYYY
After treatment 
start
01MONYYYY
After treatment 
start
01MONYYYY
After treatment 
start
01MONYYYY
After treatment 
start
If medication is not ongoing at the last visit of Core study: 
Completely missing start dates will be set to one day prior to Extension baseline visit date. 
Concomitant treatments with partial start dates will have the date or dates imputed. Partial 
concomitant treatment start dates are imputed with reference to the Extension baseline visit date 
(EXTBL) in accordance with the rules outlined below: 
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Extension Baseline Visit Date 
(EXTBL)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON MISSING
MON < EXTBL
MON = EXTBL
MON > EXTBL
YYYY MISSING
Uncertain
Uncertain
Uncertain
Uncertain
YYYY < EXTBL
Later of 
(01JULYYYY, 
date of last visit of 
Core study +1)
Before Extension
baseline visit
Later of 
(15MONYYYY, 
date of last visit of 
Core study +1)
Before Extension
baseline visit
Later of 
(15MONYYYY, 
date of last visit 
of Core study 
+1)
Before 
Extension
baseline visit
Later of 
(15MONYYYY, 
date of last visit of 
Core study +1)
Before Extension
baseline visit


Novartis
For business use only
Page 41
SAP
CRFB002H2301E1
YYYY = EXTBL
Uncertain
Later of 
(15MONYYYY, 
date of last visit of 
Core study +1)
Before Extension
baseline visit
Uncertain
01MONYYYY
After Extension
baseline visit
YYYY > EXTBL
01JANYYYY
After Extension
baseline visit
01MONYYYY
After Extension
baseline visit
01MONYYYY
After Extension
baseline visit
01MONYYYY
After Extension
baseline visit
The following table is the legend to the logic matrix.
Relationship
Before Extension baseline 
visit
Partial date indicates CMD start date prior to Extension baseline 
visit Date
After Extension baseline visit
Partial date indicates CMD start date after Extension baseline 
visit date
Uncertain
Partial date insufficient to determine relationship of CMD start 
date to Extension baseline visit date
If a complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then the imputed CM start date should be set to the (imputed) CM 
end date.
4.2
Laboratory parameters derivations
Not applicable. 
4.3
Statistical models and SAS codes
CMH test:
The primary efficacy variable is the visual acuity (VA) in the better-seeing eye at the patient’s 
fifth birthday as recorded by the investigator. 
The following primary hypothesis will be used to test the comparison of ranibizumab 0.2 mg 
versus laser as follows: 
H01: µranibizumab 0.2 mg - µLaser = 0 versus HA1: µranibizumab 0.2 mg - µLaser ≠0
where μTreatment arm is the unknown mean VA in the better-seeing eye at the fifth birthday of 
patients in the relevant treatment arm.
The hypothesis will be tested by using stratified analysis of varaiance (ANOVA) using the 
Cochran-Mantel-Haenszel (CMH) test with the observed VA values as the response variable 
and the treatment arm as the factor (with levels 0.2 mg and laser). Stratification will be based 
on the ROP zone at the Core study baseline. 
The test statsitics can be written in the form (Lehmann, E. L. (1975) and Van Elteren, P.H. 
(1960)):


Novartis
For business use only
Page 42
SAP
CRFB002H2301E1
                                   
where
ijk
R
is the VA sCore of subjectkwithin strata j of treatment i, i=0,1 denotes the treatment 
arm,  j=1, 2 denotes the ROP zone, k=1,.., nij denotes the subjects within the ith treatment arm
in the jth ROP zone and 

j
R
is the average VA sCore of all subjects in Zone  j.
For large sample sizes (within each strata) the test statistic has a standard normal distribution; 
therefore the two-sided test would reject the null hypothesis if 
, where Z is the 
N(0, 1) distribution. 
The option CMH with SCORESSCORES=TABLE in the OUTPUT statement requests the 
CMH row means sCore statistics and the corresponding two-sided p-value:
proc freq data = <input_dataset sorted> noprint;
tables <stratavar> * <treatmentvar> * <responsevar> / CMH
SCORESSCORES=TABLE ;
output out = <output_dataset> (keep =_CMHRMS_ P_CMHRMS) CMH;
run;
The two-sided p-value will then be converted to a one-sided p-value: For each comparison, if 
the direction of the observed difference supports the superiority outcome (e.g. mean ifference 
> 0), the two-sided p-value will be converted to a one-sided p-value by dividing by two. If 
mean difference < 0, the one-sided p-value will be calculated as 1 - (the two-sided p-value 
divided by two).
ANOVA model:
The ANOVA analysis will be performed using SAS procedure PROC MIXED.
Stratified ANOVA:
proc mixed data = <input_dataset sorted> noprint;
class <treatmentvar> <stratavar>;
model <responsevar> = <stratavar> <treatmentvar> ;
lsmeans <treatmentvar> / om;
estimate “”<treatmentvar>;
run;
Unstratified ANOVA:
proc mixed data = <input_dataset sorted> noprint;
class <treatmentvar>;
model <responsevar> = <treatmentvar> ;
lsmeans <treatmentvar> / om;
estimate “”<treatmentvar>;
run;
Calculating 95% confidence intervals for proportions using Clopper-Pearson method:

























1
0
2
1
1
0
1
2
1
1
1
1
0
0
1
0
1
0
1
)
(
1
1
1
1
*
1
i
j
ijk
n
k
j
j
J
j
j
n
k
jk
j
n
k
jk
j
j
j
j
j
J
j
j
R
R
n
n
a
R
n
R
n
n
n
n
n
a
W
ij
j
oj
2
/
*

Z
W



Novartis
For business use only
Page 43
SAP
CRFB002H2301E1
The confidence intervals for the proportions will be calculated using the Clopper-Pearson
method. It will be performed using SAS procedure PROC FREQ with the BINOMIAL option
in the TABLES and EXACT statements:
proc freq data = <input_dataset sorted> noprint;
by <treatmentvar>;
tables <responsevar> / binomial (cl=exact );
exact binomial;
run;
4.4
Rule of exclusion criteria of the analysis setset 
Table 4-1
Protocol deviations that cause subjects to be excluded
Deviation 
ID
Description of Deviation
Exclusion in Analyses
INCL01
Informed consent was not obtained 
before study related assessment 
performed
Excluded
from
extension
safety set: both safety and 
efficacy analysis
WITH02
Patient was not withdrawn from the 
study despite withdrawal of consent
Excluded 
from 
extension 
safety set: both safety and 
efficacy analysis


Novartis
For business use only
Page 44
SAP
CRFB002H2301E1


Novartis
For business use only
Page 45
SAP
CRFB002H2301E1


Novartis
For business use only
Page 46
SAP
CRFB002H2301E1
5
Reference
1. Lehmann, E. L. (1975). Nonparametrics: Statistical Methods Based on Ranks, San 
Francisco: Holden-Day, pp 132-137, 145.
2. Van Elteren, P. H. (1960). "On the combination of independent two-sample tests of 
Wilcoxon, Bulletin of the International Statistical Institute", 37, 351-361.
3. Newcombe R.G., Two-sided CIs for the single proportion: comparison of seven 
methods, Statistics in Medicine, (1998) 17, 857-872
4. Newcombe R.G., Interval Estimation for the Difference between Independent 
Proportions: Comparison of Eleven Methods. Statistics in Medicine 1998; 17: 873-890