Clinical trial NCT03927690
Conditions: Diabetic Macular Edema
Keywords: Macular degeneration age-related macular degeneration (ARMD) vision loss macula damage retina damage dry macular degeneration wet macular degeneration AMD diabetic macular edema DME neovascular age-related macular degeneration nAMD retinal vein occlusion RVO Diabetic Macular edema (DME) macular edema diabetic retinopathy LKA651 Lucentis
Sponsor: Novartis Pharmaceuticals
Start date: 2019-05-24; Completion date: 2022-08-31
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study were to evaluate the safety and efficacy of LKA651 in patients with macular edema from diabetic macular edema (DME),

Detailed description:
This study was a 3-arm, parallel group, randomized, patient- and investigator-masked trial planned in 90 patients with Diabetic macular edema (DME). The study consisted of a screening period of 60 days, main study (12 weeks), and an extension period (12 weeks). The study was stratified such that sentinel safety cohorts were first enrolled to test the safety of the combination of LKA651 and Lucentis before proceeding with further patient randomization. After determination of safety from Day 15 data from each sentinel cohort, patients were enrolled into 1 of 3 arms: LKA651 monotherapy, LKA651 plus Lucentis, and Lucentis monotherapy. Every patient was dosed 3 times in 4 week intervals in the treatment phase and was then followed up for an extension phase of an additional 12 weeks during which Lucentis was allowed to be administered as rescue at the discretion of the Investigator. No predefined rescue criteria were outlined as guidance.

Arms: arm 1: LKA651 Intravitreal injection arm 2: LKA651 + Lucentis Intravitreal injection arm 3: Lucentis Intravitreal injection
Interventions: intervention 1: LKA651 intervention 2: Lucentis
Intervention descriptions: intervention 1: LKA651 5 mg Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase intervention 2: Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
LKA651
Clinical Trial Protocol CLKA651X2202
ClinicalTrials.gov Identifier: NCT03927690
A randomized, active-controlled, patient and investigator-
masked, multiple dose proof-of-concept study of 
intravitreal LKA651 in patients with diabetic macular 
edema
Document type:
Amended Protocol Version
EUDRACT number:
2018-000031-28
Version number:
v06 (Clean)
Clinical Trial Phase:
II
Release date:
06-Jul-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................21
1
Introduction .......................................................................................................................24
1.1
Background............................................................................................................24
1.1.1
Non Clinical Data..................................................................................24
1.1.2
Clinical Data..........................................................................................25
1.2
Purpose ..................................................................................................................27
2
Objectives and endpoints...................................................................................................27
3
Study design ......................................................................................................................28
4
Rationale............................................................................................................................30
4.1
Rationale for study design .....................................................................................30
4.2
Rationale for dose/regimen and duration of treatment ..........................................31
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................32
4.4
Purpose and timing of interim analyses/design adaptations..................................32
4.5
Risks and benefits..................................................................................................32
4.5.1
Blood sample volume............................................................................34
5
Population..........................................................................................................................34
5.1
Inclusion criteria ....................................................................................................34
5.2
Exclusion criteria...................................................................................................35
6
Treatment...........................................................................................................................38
6.1
Study treatment......................................................................................................38
6.1.1
Investigational and control drugs..........................................................38
6.1.2
Additional study treatments ..................................................................38
6.1.3
Treatment arms/group ...........................................................................38
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6.2
Other treatment(s)..................................................................................................39
6.2.1
Concomitant therapy.............................................................................39
6.2.2
Prohibited medication ...........................................................................39
6.2.3
Rescue medication ................................................................................40
6.2.4
Restriction for study patients ................................................................40
6.3
Patient numbering, treatment assignment, randomization.....................................40
6.3.1
Patient numbering .................................................................................40
6.3.2
Treatment assignment, randomization ..................................................40
6.4
Treatment masking ................................................................................................40
6.4.1
Site staff ................................................................................................41
6.4.2
Sponsor staff..........................................................................................41
6.5
Dose escalation and dose modification..................................................................42
6.5.1
Dose escalation guidelines....................................................................42
6.6
Additional treatment guidance...............................................................................43
6.6.1
Treatment compliance...........................................................................43
6.6.2
Recommended treatment of adverse events..........................................43
6.6.3
Emergency breaking of assigned treatment code..................................43
6.7
Preparation and dispensation.................................................................................44
7
Informed consent procedures ............................................................................................44
8
Visit schedule and assessments .........................................................................................45
8.1
Screening ...............................................................................................................48
8.1.1
Eligibility Screening..............................................................................48
8.1.2
Information to be collected on screening failures.................................48
8.2
Patient demographics/other baseline characteristics .............................................48
8.3
Efficacy..................................................................................................................48
8.3.1
Efficacy assessment 1 ...........................................................................48
8.3.2
Efficacy assessment 2 ...........................................................................48
8.3.3
Appropriateness of efficacy assessments..............................................49
8.4
Safety.....................................................................................................................49
8.4.1
Vital signs..............................................................................................49
8.4.2
Height and weight .................................................................................49
8.4.3
Laboratory evaluations..........................................................................49
8.4.4
Electrocardiogram (ECG) .....................................................................50
8.4.5
Pregnancy and assessments of fertility .................................................51
8.4.6
Other safety evaluations........................................................................51
8.5
Additional assessments..........................................................................................53


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8.5.1
Pharmacokinetics, 
...............53
9
Study discontinuation and completion ..............................................................................54
9.1
Discontinuation......................................................................................................54
9.1.1
Discontinuation of study treatment .......................................................54
9.1.2
Withdrawal of informed consent...........................................................55
9.1.3
Lost to follow-up...................................................................................56
9.1.4
Study stopping rules..............................................................................56
9.1.5
Early study termination by the sponsor.................................................57
9.2
Study completion and post-study treatment ..........................................................57
10 Safety monitoring and reporting........................................................................................58
10.1
Definition of adverse events and reporting requirements......................................58
10.1.1
Adverse events (AEs)............................................................................58
10.1.2
Serious adverse events (SAEs)..............................................................59
10.1.3
SAE reporting........................................................................................60
10.1.4
Pregnancy reporting ..............................................................................61
10.1.5
Reporting of study treatment errors including misuse/abuse................61
10.2
Additional Safety Monitoring................................................................................62
11 Data Collection and Database management......................................................................62
11.1
Data collection.......................................................................................................62
11.2
Database management and quality control............................................................62
11.3
Site monitoring ......................................................................................................63
12 Data analysis and statistical methods ................................................................................64
12.1
Analysis sets ..........................................................................................................64
12.2
Patient demographics and other baseline characteristics.......................................64
12.3
Treatments .............................................................................................................64
12.4
Analysis of the primary endpoint(s) ......................................................................65
12.4.1
Definition of primary endpoint(s).........................................................65
12.4.2
Statistical model, hypothesis, and method of analysis..........................65
12.4.3
Handling of missing values/censoring/discontinuations.......................65
12.4.4
Sensitivity and Supportive analyses......................................................65
12.5
Analysis of secondary endpoints ...........................................................................66
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12.5.2
Pharmacokinetics ..................................................................................67
12.6
Analysis of exploratory endpoints.........................................................................68
12.7
Interim analyses.....................................................................................................68
12.8
Sample size calculation..........................................................................................69
13 Ethical considerations and administrative procedures ......................................................70
13.1
Regulatory and ethical compliance........................................................................70
13.2
Responsibilities of the investigator and IRB/IEC..................................................70
13.3
Publication of study protocol and results...............................................................70
13.4
Quality Control and Quality Assurance.................................................................70
14 Protocol adherence ............................................................................................................71
14.1
Protocol Amendments ...........................................................................................71
15 References .........................................................................................................................72
List of tables
Table 2-1
Objectives and related endpoints ..........................................................27
Table 6-1
Investigational drug...............................................................................38
Table 6-2
Control Drug .........................................................................................38
Table 6-3
Prohibited medication ...........................................................................39
Table 6-4
Masking levels ......................................................................................42
Table 8-1
Assessment Schedule ............................................................................46
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................61
List of figures
Figure 3-1
Study Design .........................................................................................30
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List of abbreviations
A1C
Glycated haemoglobin
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC0-28d
Area under the curve over the dosing interval
BCVA
Best Corrected Visual Acuity
BMI
Body Mass Index
BUN
blood urea nitrogen
CBC
Complete Blood Count
CDS
Core Data Sheet (for marketed drugs)
CFP
Color Fundus Photography
CFR
U.S. Code of Federal Regulations
CI
Confidence Interval
CK
creatinine kinase
Cmax
Maximum Concentration
CMO&PS
Chief Medical Office & Patient Safety
CO2
carbon dioxide
CRA
Clinical Research Associate
CRC
Central Reading Center
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
DAR
Dose Administration Record
DDE
Direct Data Entry
DME
Diabetic Macular Edema
DNA
Deoxyribonucleic Acid
DR
Diabetic Retinopathy
e.g.
For example
EC
Ethics Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA
European Medicine Agency
EPO
Erythropoietin
ETDRS
Early Treatment Diabetic Retinopathy Study
eSource
Electronic Source
FA
Fluorescein Angiography
Fc
Fragment crystallizable 
FcRn
Neonatal Fc receptor
FDA
Food and Drug Administration
FIH
First-in-Human
g/dL
Grams/deciliter
GCP
Good Clinical Practice


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GLP
Good Laboratory Practice
GGT
Gamma-glutamyl transferase
h
hour
Hb
Hemoglobin
HbA1C
Glycated haemoglobin
hCG
Human chorionic gonadotropin
IV
intravenous
IA
Interim analysis
IB
Investigators Brochure 
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IND
Investigational New Drug
IOP
Intra Ocular Pressure
IRB
Institutional Review Board
IRT
Interactive Response Technology
IVT
Intravitreal
LDH
lactate dehydrogenase
LFT
Liver function test
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
NCDS
Novartis Clinical Data Standards
NOAEL
No Observed Adverse Event Level
NOVDD
Novartis Data Dictionary
NYHA
New York Heart Association
PCI
percutaneous coronary intervention
PD
pharmacodynamic(s)
PoC
Proof of Concept
PK
pharmacokinetic(s)
PRN
Pro re nata; as needed
Q4w
Every 4 weeks
QMS
Quality Management System
QTcF
Fridericia QT corrected interval
RBC
red blood cell(s)
RDC
Remote Data Capture
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SD-OCT
Spectral domain optical coherence tomography
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SMQ
Standardized MedDRA Query
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
Tmax
Time to the first occurrence of the maximal concentration
TD
Study Treatment Discontinuation
US
United States
VEGF
Vascular Endothelial Growth Factor
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of patients fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 mg 
once a day, 5 mg once a month)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care.
Enrollment
Point/time of patient entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with 
a purpose (e.g. screening, randomization, treatment, follow-up) which applies 
across all arms of a study.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
Investigational 
drug
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug,” "Investigational Medicinal 
Product," or “test substance”
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a single 
dose part and a multiple dose part, or a part in patients with established 
disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest
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
Screen Failure
A patient who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the patient permanently stops taking study treatment prior to the defined 
study treatment completion date
Patient
A trial participant (can be a healthy volunteer or a patient)


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Patient number
A unique number assigned to each patient upon signing the informed consent. 
This number is the definitive, unique identifier for the patient and should be 
used to identify the patient throughout the study for all data collected, sample 
labels, etc.
Personal Data
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.
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 
consent (WoC)
Withdrawal of study consent: Withdrawal of consent from the study occurs 
only when a subject does not want to participate in the study any longer, and 
does not allow any further collection of personal data


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Protocol summary
Protocol number
CLKA651X2202
Full Title
A randomized, active-controlled, patient and investigator-masked, multiple 
dose proof-of-concept study of intravitreal LKA651 in patients with diabetic 
macular edema 
Brief title
A proof-of concept study of intravitreal LKA651 in patients with macular edema
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Biologic
Study type
Interventional
Purpose and 
rationale
This study will investigate whether LKA651, alone or when co-administered 
with Lucentis®, displays the clinical safety and efficacy profile to support 
further development to treat diabetic macular edema (DME)
Primary 
Objective(s) 
To evaluate the safety, tolerability, and efficacy, in reference to Lucentis®
monotherapy, of three q4w intravitreal (IVT) doses of LKA651 in treating DME
when administered as monotherapy and in combination with Lucentis®.
Secondary 
Objectives
To evaluate the serum pharmacokinetic (PK) profile of total LKA651 and 
Lucentis® following three q4w IVT doses of LKA651, or a combination of 
LKA651 and Lucentis,® in patients with DME
To evaluate duration of effect of three q4w IVT doses of LKA651 in patients 
with DME.
Study design
This study is a 3-arm, parallel group, randomized, patient and investigator-
masked trial in 90 patients with DME. The study will be stratified in that 
Sentinel Safety cohorts will first be enrolled to test the safety of the 
combination of LKA651 and Lucentis® before proceeding with further patient 
randomization. After determination of safety from Day 15 data from each 
sentinel cohort, patients will continue to be enrolled into 1 of 3 arms; LKA651 
monotherapy, LKA651 plus Lucentis®, and Lucentis® monotherapy.  Every 
patient will be dosed 3 times in 4 week intervals, and then followed for an 
extension phase of an additional 12 weeks during which PRN Lucentis® may 
be given.  
Population
Approximately 90 male or female patients between the ages of 18 and 85 with 
DME will be randomized. At least 75 patients are expected to complete the 
study.


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Key Inclusion 
criteria

Male and female patients age 18 to 85 years of age inclusive at
screening

Diagnosis of type I or type II diabetes mellitus.

The Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in
the study eye must be between 24 and 72 letters (approximate Snellen
equivalent of 20/40-20/320). The non-study eye (fellow eye) should be
≥34 letters or better (approximate Snellen equivalent of 20/200) at
screening

Presence of DME in the study eye, with decrease in vision due to foveal
thickening. Central macular thickness of ≥ 320 µm in the central subfield,
as assessed on spectral-domain ocular coherence tomography (SD-
OCT) and confirmed by the central reading center at screening
Key Exclusion 
criteria
Study treatment
LKA651
Lucentis® (ranibizumab)
Efficacy 
assessments

Best corrected visual acuity (BCVA)

Central subfield retinal thickness as determined by SD-OCT
Pharmacokinetic 
assessments
Serum levels of total LKA651
Serum levels of total ranibizumab
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Key safety 
assessments

Ocular or systemic adverse events

Vital signs

Electrocardiogram (ECG)

Safety laboratories (including reticulocyte count)

Intraocular pressure

BCVA

Central subfield retinal thickness by SD-OCT
Other 
assessments 
Data analysis
The primary objective of this study is to assess the safety and tolerability as 
well as the efficacy of LKA651 alone or in combination with Lucentis® in 
patients with DME. Descriptive statistics will be provided for all safety 
variables. Adverse events will be summarized by counts, rates and body 
system.  For efficacy evaluation, BCVA and central subfield retinal thickness 
at week 12 are the primary endpoints. A repeated measure Analysis of 
Covariance (ANCOVA) will be performed for BCVA and change from baseline 
BCVA. Independent variables will include treatment, visit, and the treatment 
by visit interaction. Baseline BCVA will be used as a covariate. Central subfield 
retinal thickness will be analyzed in a similar fashion as BCVA, except that 
central subfield retinal thickness will be log-transformed, thus results will be 
back-transformed in order to show results as a ratio to baseline and the 
difference between treatments will be expressed as a ratio of treatments.
Key words
Diabetic Macular Edema (DME)
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1
Introduction
1.1
Background
Diabetic retinopathy (DR) is the most common visual complication in patients with diabetes. 
Diabetic macular edema (DME) can occur in any stage of DR and is the main cause of vision 
loss in patients with DR. The incidence of DME after 10 years of follow-up has been reported 
to be 20.1% in Type 1 Diabetes Mellitus, 25.4% in Type 2 insulin-dependent diabetes, and 13.9% 
in Type 2 non-insulin-dependent diabetes (Klein et al 1995). The early treatment diabetic 
retinopathy (ETDRS) trial, a pioneering study in DR, demonstrated that although laser 
photocoagulation therapy reduces the risk of moderate visual loss in DME eyes by ~50% at 
3 years (ETDRS 1985), only a few eyes gain vision, and some eyes continue to experience 
vision loss even after intensive treatment (ETDRS 1985). Newer treatment options such as anti-
vascular endothelial growth factor (VEGF) therapy have helped, but even in these pivotal trials 
nearly 50% of eyes are left with visual acuities of 20/40 or worse (Mitchell et al 2011).
LKA651, an anti-erythropoietin (EPO) Fab (antibody fragment), may be an effective treatment 
for patients with DME. In DME patients, intraocular EPO concentrations are elevated in eyes 
with DME (for example Lim and Han, 2011). 
The most relevant data for the present study are summarized in the sections below. For detailed 
information, please refer to the Investigator's Brochure (IB).
1.1.1
Non Clinical Data
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1.1.2
Clinical Data
1.1.2.1
Human Safety and Tolerability Data
Safety and tolerability data from the first-in-human (FIH) trial CLKA651X2104 showed that 
all doses were safe and well tolerated. This study was a single-ascending dose study with 
28 patients who had macular edema from DME, retinal vein occlusion, or neovascular age-
related macular degeneration.  
Analyses conducted and detailed in the IB revealed no deaths, discontinuations, or serious 
adverse events (SAEs) among randomized patients. Eighteen patients had 35 treatment-
emergent AEs, all of which were mild or moderate and occurred across all dose groups and 
sham-injected patients without meaningful differences in numbers. The most common AE
related to the procedure was conjunctival hemorrhage, occurring in 4 (16.7%) patients. 
Two AEs
: anterior chamber inflammation in one patient in 
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 resolved within 24 hours of treatment with topical 
steroids, and trace vitreous cell in one patient 
seen within 
two weeks of injection of drug, that resolved without treatment, and then recurred at the end of 
study (Day 85). There were no AEs related to red blood cell production or anemia. There were 
no non-ocular AEs that were related to the study drug. 
1.1.2.2
Human pharmacokinetics, pharmacodynamics and immunogenicity
data
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1.2
Purpose
This study is being conducted to evaluate the safety/tolerability and efficacy of IVT LKA651 
for the treatment of macular edema in patients with DME.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To evaluate the safety/tolerability of 
three q4w IVT doses of LKA651 alone 
or in combination with Lucentis® in 
patients with DME.

Ocular and systemic AEs

Vital signs (blood pressure, heart rate) and ECG 
intervals.

Safety laboratory measures (including reticulocyte 
count)

Complete ophthalmic exam, including :

Intraocular Pressure (IOP)

BCVA

Macular thickness by spectral domain optical 
coherence tomography (SD-OCT) 

FA

To evaluate the efficacy, in reference 
to Lucentis® monotherapy, of three 
q4w IVT doses of LKA651 in treating 
DME when administered as 
monotherapy or in combination with 
Lucentis®.

Best Corrected Visual Acuity (BCVA) as assessed 
by ETDRS (Early Treatment Diabetic Retinopathy 
Study) visual acuity charts at week 12.

Central subfield retinal thickness as measured by 
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Objective(s)
Endpoint(s)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate duration of effect of three
q4w IVT doses of LKA651 in patients
with DME.

Time to retreatment with anti-VEGF (as
determined by PI) after week 12 during an
additional 12-week extension phase

To evaluate the serum
pharmacokinetic profile of total
LKA651 and Lucentis® following three
q4w IVT doses of LKA651 alone or in
combination with Lucentis® in patients
with DME.

Serum levels of total LKA651 (Maximum
concentration (Cmax) and Area under the curve
(AUC)0-28d in monotherapy or in combination with
Lucentis® after the first dose in a subset of patients
with sufficient quantifiable serum samples to permit
meaningful analysis.

Serum levels of ranibizumab (Cmax and AUC0-28d)
when administered in combination with LKA651
after the first dose in a subset of patients with
sufficient quantifiable serum samples to permit
meaningful analysis.
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
3
Study design
This study is a 3-arm, parallel group, randomized, patient and investigator masked trial in 
90 patients with diabetic macular edema. This study is the first that clinically tests the 
combination of 
 LKA651 and Lucentis®, therefore the study will be stratified in that 
Sentinel Safety cohorts will first be enrolled to test the safety of a patient receiving both 
LKA651 and Lucentis® as separate injections in the same eye before proceeding with further 
patient enrollment (See Section 4.5). Because the study will be run both in and ex-U.S., different 
doses of Lucentis® will be used in each region per label. Ex-U.S., the Sentinel Safety cohort 
will use the maximum dose of Lucentis® globally (0.5 mg). In the U.S., the approved dose for 
DME is 0.3 mg so this dose will be used. For each Sentinel Safety cohort, 8 patients will be 
randomized 6:1:1 to LKA651+Lucentis® (
 + 0.3 mg or 0.5 mg), LKA651 monotherapy 
(
), and Lucentis® monotherapy (0.3 or 0.5 mg). When two injections are required, as in 
the combination arm, the injections will be given 30 minutes apart. To maintain masking in the 
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monotherapy arms, a sham injection will be given as a second injection 30 minutes after the
first drug injection (A sham injection is a needle-less syringe placed against the globe with 
pressure simulating that of an injection). Safety assessments through Day 15 will be analyzed 
for all 8 patients before any other patients from the same geographical region can be randomized; 
in the FIH study, the two AEs considered related to the study drug occurred within this time 
frame.
Within each geographical region, masked analysis of Day 15 safety data of the Sentinel Safety 
cohort will be performed by a joint review by the Sponsor and Investigators who contributed 
patients to the cohorts. Data review will include the nature of adverse events, vital signs, 
electrocardiogram, safety laboratories (including reticulocyte count, intraocular pressure, 
BCVA, 
, slit lamp examination), and central subfield retinal thickness by 
SD-OCT.
After determination that there are no concerning safety signals, the study will proceed with 
randomization for the remaining 74 patients who will be randomized 9:14:14 to LKA651
+Lucentis® (
 + 0.3 or 0.5 mg), LKA651 monotherapy (
), or Lucentis® monotherapy 
(0.3 or 0.5 mg). Masking with sham injections will be performed as in the safety sentinel cohorts. 
Data from the Safety Sentinel cohorts and main study will be pooled for end-of-study safety 
and efficacy analysis.  
For all patients, a screening period of 60 days will be used to assess eligibility and to taper 
patients off disallowed medications. At Visit 1, the baseline visit, eligible patients will be 
randomized to one of the treatment arms. Randomized patients will be dosed once q4weeks for 
a total of 3 doses. The assessment to address the primary objective will be performed at the end 
of the treatment period (week 12) before the extension phase begins. After 12 weeks, efficacy 
will be determined based on BCVA criteria. Patients are then followed for an additional 
12 weeks in a maintenance/extension phase for further evaluation of secondary endpoints. 
During the extension phase, patients will be examined every 4 weeks and receive PRN anti-
VEGF treatment (Lucentis®) as determined by the Investigator for clinically significant increase 
in retinal thickness or decrease in BCVA due to DME that warrants anti-VEGF treatment. 
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Figure 3-1
Study Design
In each region, Sentinel Safety cohort is randomized 6:1:1 Combination: LKA651: Lucentis®. Main study 
is randomized 9:14:14
4
Rationale
4.1
Rationale for study design
The design of this study addresses the primary objective of improvement of BCVA in patients 
with DME and takes into account the possible additive effects of LKA651 with anti-VEGF 
treatment.

Sentinel safety cohorts: The combination of LKA651 
 and ranibizumab 0.5 mg 
was shown to be safe in a multiple dose, 13-week GLP toxicology study (see IB).  
Limiting the initial clinical exposure of the combination of LKA651+Lucentis® to 
6 patients in the U.S. and 6 patients outside the U.S., controls the risk associated with 
potential adverse events that may occur with this combination that has not yet been tested 
in humans, but has been shown safe in preclinical toxicity studies. Including one patient 
treated with LKA651 and one patient treated with Lucentis® monotherapy in the 
Sentinel Safety cohort allows for comparison and control. In addition, because the rest of 
the patient population will be screened only after Day 15 of the Sentinel Safety cohorts, 
the Sentinel Safety cohorts will remain ahead of the other patients for the duration of the 
study, and will provide alerts to potential AEs occurring after multiple doses. 
Lucentis® alone is an approved treatment for DME, and LKA651 has shown an acceptable 
safety profile in the FIH study CLKA651X2104, so overall the risk for unanticipated 
SAEs is considered to be very low. Performing the Sentinel Safety cohort both within and 
Ex-U.S. will allow the study to begin in the U.S., where the approved dose for Lucentis®
for DME is lower but where the study may begin more quickly due to operational reasons.
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
Randomization: This decreases the chance of an imbalance in patient characteristics
between groups, thereby facilitating an unbiased assessment of safety and tolerability.

Patient-masked (with selective un-masking of investigators and sponsor staff for
operational or safety reasons): Masking of patients and investigators allows for an
unbiased assessment of readouts such as adverse events. Selective un-masking of the
investigators and sponsor staff could improve the accuracy of safety-related decisions
if necessary.
4.2
Rationale for dose/regimen and duration of treatment
Two separate doses of LKA651 will be used in this study, 
 in the monotherapy arm and 
 in combination with Lucentis® in the combination arm. 
Because there are no available animal models of DME, the dose/response relationship is 
unknown for LKA651 alone or in combination with Lucentis®. Thus it is proposed to test the 
highest safe and tolerable dose of LKA651 as determined by the first-in-human study 
CLKA651X2104
 in the monotherapy arm of this proof-of-concept study. Injection of 
the maximum deliverable single dose of LKA651 
 in the monotherapy arm is supported 
by
It is possible that a synergistic pharmacological effect between LKA651 and Lucentis® could
lead to superior efficacy in the combination arm compared to the monotherapy arm; therefore 
a combination arm will be tested. The combination (two separate injections given 30 minutes 
apart)  of
 LKA651 and Lucentis® at the approved dose for DME is supported by the 
13 week intravitreal LKA651/ranibizumab combination toxicology study in cynomolgus 
monkeys. For the combination arm with ranibizumab, the proposal is to evaluate the same 
dose of LKA651 used in the 13-week IVT LKA651/ranibizumab toxicology study (
 
LKA651) and the same or lower dose of ranibizumab used (0.5 mg ranibizumab outside the 
U.S.and 0.3 mg used within the U.S. per label). 
Dosing every four weeks is an approved dosing frequency for Lucentis® in treating DME and 
will be employed in this study. Since macular edema in diseases such as DME is slowly 
progressive, several months of treatment and observation are required to detect any potential 
clinical efficacy with LKA651 as a monotherapy or in free combination with Lucentis®. 
The proposed length of treatment, 12 weeks, is supported by the length of the 13-week 
GLP-toxicology study, and is consistent with a timeframe by which a clinically significant 
change in DME can be expected. 
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4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Lucentis® will be used both as a monotherapy comparator and in combination with LKA651 
for safety and efficacy measurements. Anti-VEGF therapy is standard of care for patients with 
DME, and Lucentis® has a well established safety and efficacy profile with approved use per 
label at doses of 0.3 mg monthly within the U.S. and 0.5 mg monthly outside the U.S.  
Using Lucentis® as a monotherapy comparator will help establish if any safety or tolerability 
effects of LKA651 are attributed to the study drug as opposed to an effect of study procedures 
such as intraocular injection. In addition, because LKA651 has a different mechanism of action 
than anti-VEGF therapy, the combination of the two may provide additional efficacy benefits 
not seen with either alone. 
4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
LKA651 is an anti-EPO antibody that may be effective in treating DME (symptoms or signs), 
either alone and/or in combination with anti-VEGF therapy. Because the mechanism of 
LKA651 differs from anti-VEGF standard of care, treatment with LKA651 may offer improved 
or additional benefits to both patients who respond to anti-VEGF treatment, and those who do 
not.
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The risk to patients in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring. Potential human safety concerns 
include intraocular inflammation. 
 Further support is tendered by the 
FIH study, in which one case of anterior chamber inflammation was seen after one injection of 
 LKA651, and one case of trace vitreal cells was reported 2 weeks after injection of 
LKA651 (Section 1.1.2.1). Investigators should carefully monitor patients' eyes during the 
assessments immediately after study drug administration, and any adverse event should be 
treated according to type and local practice. Other risks not specific to LKA651 include 
hypersensitivity reactions, or side effects from intraocular injection including endophthalmitis. 
Refer to the IB for more information.
This study is the first to clinically test the combination of 
 LKA651 and Lucentis®.
The low risk to patients is supported by the GLP-compliant 13-week IVT study which found 
the combination of 
 LKA651 and 0.5 mg ranibizumab safe and well tolerated. 
Combining another ocular drug with Lucentis® has been shown to be safe in trials investigating 
other compounds.  These include intravitreally-administered anti-platelet derived growth factor
aptamer (Jaffe et al 2016), a complement factor C5 inhibitor (Mones 2010), and a topical ocular 
drug, squalamine (Wroblewski and Hu 2016). Furthermore, LKA651 
 was safe and well 
tolerated in the FIH study CLKA651X2104. In addition, the Sentinel Safety cohorts will 
mitigate risk by limiting exposure of the combination to a few patients whose safety data will 
be closely monitored, and further randomization will be gated by the review of these data after 
Day 15.
Some patients in the trial will be assigned to LKA651 without concomitant anti-VEGF therapy. 
Appropriate eligibility criteria regarding vision and concomitant retinal disease, rescue criteria, 
and stopping rules will limit disease progression in patients not receiving standard of care 
therapy. Rescue medication may be given per Section 6.2.3. Furthermore, the study period is 
only 3 months of duration, with an extension phase of an additional 3 months during which 
patients may receive PRN Lucentis® treatment.
Sodium Fluorescein: Fluorescein angiography is considered a relatively safe procedure, 
although numerous adverse reactions have been reported in the literature. These are divided 
into mild (nausea, vomiting, pruritus, sneezing, vaso-vagal disorders, inadvertent arterial 
injection), moderate (urticaria, other skin eruptions, syncope, thrombophlebitis, pyrexia, local 
tissue necrosis, muscular paralysis) and severe (bronchospasm, laryngeal edema, circulatory 
shock, myocardial infarction, tonic-clonic seizure). In a randomized trial, out of 1,500 enrolled 
patients, 69.3% underwent the test for the first time. Nausea occurred in 71 (6.83%) patients, 
vomiting in 14 (1.35%), urticaria in 11 (1.06%), bronchospasm in 4 (0.38%) and laryngeal 
edema in 1 (0.01%). Higher incidences of adverse reactions were observed in diabetic patients 
[p<0.002, RR=1.80 (CI=1.24-2.60)], patients with systemic arterial hypertension [p<0.002, 
RR=1.84 (CI=1.26-2.71)] and patients with allergy history [p<0.001, RR=3.90 (CI=2.70-5.63)]. 
A cumulative incidence of 9.72% adverse reactions was observed in patients who had 
undergone this test for the first time (Lira et al 2007).
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4.5.1
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over a period of 
6 months from each patient as part of the study. The maximum drawn at any given day is 
approximately 31 mL. Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment Schedule.
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and central laboratory manual.
5
Population
Approximately 90 patients with DME, who are either treatment naive or who have been treated
with anti-VEGF therapy >90 days before baseline, will be randomized. At least 75 patients are 
expected to complete the study.
The investigator must ensure that all patients being considered for the study meet the following 
eligibility criteria. No additional criteria should be applied by the investigator, in order that the 
study population will be representative of all eligible patients.
Patient selection is to be established by checking through all eligibility criteria at screening. 
A relevant record (e.g. checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study.
5.1
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients age 18 to 85 years of age inclusive at screening
3. Presence of type I or type II diabetes mellitus
4. The ETDRS letter score in the study eye must be between 24 and 72 letters, inclusive
(approximate Snellen equivalent of 20/40-20/320). The non-study eye (fellow eye) should
be ≥34 letters or better (approximate Snellen equivalent of 20/200) at screening
6. Sufficiently clear ocular media and adequate pupil dilation in the study eye to permit
fundus photographs of adequate clarity to measure diameters of retinal arteries and veins
at screening
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7. At screening vital signs (systolic and diastolic blood pressure and pulse rate) will be
assessed in the sitting position after the patient has rested for at least three minutes.
The Investigator should be guided by the following ranges for inclusion:

Body temperature between 35.0-37.5 °C

systolic blood pressure, 90-180 mm Hg

diastolic blood pressure, 50-100 mm Hg

pulse rate, 40 - 100 bpm
8. Able to communicate well with the investigator, to understand and comply with the
requirements of the study
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. Patient with history of treatment for DME in the study eye as defined by the following:

IVT anti-VEGF treatment
in the study eye.  
History or concurrent treatment with these medications/procedures in the non-
study eye is permitted.

Patient with history of intraocular corticosteroids in the study eye including
dexamethasone intravitreal implants during the 6 month period prior to
baseline, 
2. Concomitant conditions or ocular disorders in the study eye which may, in the opinion
of the investigator, confound the interpretation of study results, compromise visual
acuity or require medical or surgical intervention during the study period

High risk proliferative diabetic retinopathy in the study eye, as per investigator
assessment at both screening and baseline.

Patients with the following conditions in the study eye at screening or baseline
must be excluded:
, vitreous hemorrhage, retinal
detachment, vitreomacular traction, macular hole, retinal vein/arterial occlusion,
neovascularization of iris or choroidal neovascularization of any cause.
3. Laser photocoagulation (macular
) in the study eye 
4. Patients, with type 1 or type 2 diabetes who have a hemoglobin A1C ≥ 12% at
screening.
5. Any progressive disease of the retina (e.g. uveitis, rod-cone dystrophy) or optic nerve
in the study eye.
6. Area of retinal ischemia involving the macula (as measured by the foveal avascular
zone) ≥ 1000 μm in linear diameter.
7. Active intraocular inflammation (graded as trace or above) in either eye at screening.
8. Any active infection involving the study eye’s ocular adnexa including infectious
conjunctivitis, keratitis, scleritis, endophthalmitis, as well as idiopathic or
autoimmune-associated uveitis in either eye, or intraocular infection in either eye.
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14. Current diagnosis of clinically significant anemia, or hemoglobin <10 g/dL for women
and <11 g/dL for men.
22. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of
enrollment, whichever is longer; or longer if required by local regulations.
23. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a positive
hCG laboratory test.
24. Women of childbearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during duration of the study. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
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
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient.

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.

In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking investigational drug.

Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of childbearing potential.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
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6
Treatment
6.1
Study treatment
The investigational drug is LKA651 
 either alone or in free combination with Lucentis®
0.3 mg (U.S. sites) or 0.5 mg (ex-U.S. sites). Lucentis® (0.3 or 0.5 mg) will also be given in a 
control arm as monotherapy.
Detailed information regarding the materials/medications supplied to the study clinic(s) can be 
found in the SOM and pharmacy manual.
6.1.1
Investigational and control drugs
The investigational drug, LKA651 20 mg/0.2 ml (Table 6-1) will be provided by Novartis as 
open label supplies to be dispensed by the unmasked pharmacist at the investigator site 
according to the randomization schedule as described in the protocol and SOM.
Lucentis® (0.3 or 0.5 mg) is used as active control arm in a monotherapy and in combination 
with 
Table 6-1
Investigational drug
Investigational
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Sponsor 
(global or 
local)
LKA651 20 
mg/0.2ml
Liquid in Vial
Intravitreal
Open label 
bulk supply
Novartis
LKA651 (vehicle)
NA
NA
Open label 
bulk supply
Novartis
Lucentis® 10 
mg/ml solution for 
injection
(used in the 
combination arm)
Liquid in Vial
Intravitreal
Marketed 
drug
N/A
Table 6-2
Control Drug
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Sponsor 
(global or 
local)
Lucentis® 10 mg/ml
solution for injection
Liquid in Vial
Intravitreal
Marketed 
drug
N/A
6.1.2
Additional study treatments
No additional treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
For each Sentinel Safety cohort, 8 patients will be assigned at visit 1 to one of the following 
3 treatment arms/groups in a ratio of 6:1:1: LKA651+ Lucentis® free combination: LKA651: 
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Lucentis®. The remaining 74 patients will be randomized 9:14:14: LKA651 + Lucentis® free 
combination: LKA651: Lucentis®.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
If the fellow eye has DME it may be treated with local (intravitreal or topical) medications per 
the investigators discretion. The fellow eye may be treated at any time, including on the study 
day, provided its treatment does not interfere with the timing of the study procedures and 
assessments. 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after enrollment into the study. 
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant medications/Significant non-drug therapies CRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a patient 
or, if the patient is already enrolled, to determine if the patient should continue participation in 
the study.
6.2.2
Prohibited medication
Use of the treatments displayed in the below Table 6-3 are not allowed.
Table 6-3
Prohibited medication
Medication
Prohibition period
Action taken
Ozurdex® implant
Prohibited in the study eye at any time 
<6 months before or during the study
Note protocol 
deviation
Iluvien® implant
Prohibited in the study eye at any time 
before or during the study
Note protocol 
deviation
Investigational drugs
At Day 1 or any time the patient is still 
enrolled in the trial.
Discontinue from 
study treatment
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6.2.3
Rescue medication
Rescue of a patient can occur at any time post-LKA651 administration as deemed necessary by 
the study ophthalmologist.  In the case that clinically significant deterioration in a patient’s 
vision or progression of macular edema occurs as determined by the study ophthalmologist, 
laser photocoagulation can be administered in an attempt to rescue the patient’s vision if rescue 
treatment is needed within 28 days of the last treatment injection. At or after 28 days from the 
last treatment injection, the patient can be treated as needed with Lucentis® for any further 
required rescue therapy. After any rescue treatment, the patient should discontinue the 
experimental treatment.  However, unless the investigator feels it is not in the best interest of 
the patient or their condition, all patients who receive rescue medication should still participate 
in the scheduled visits and assessments as outlined in the study Assessment Schedule. 
Use 
of 
rescue 
medication/treatment 
must 
be 
recorded 
on 
the 
Concomitant 
medications/Significant non-drug therapies CRF after start of study drug.
6.2.4
Restriction for study patients
Not applicable.
6.3
Patient numbering, treatment assignment, randomization
6.3.1
Patient numbering
The patient number assigned to a patient at screening remains the unique identifier for the 
patient
throughout the study. For information on patient
numbering, please see 
‘Patient numbering’ section in the Site Operations Manual.
6.3.2
Treatment assignment, randomization
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff.  A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers.  These randomization 
numbers are linked to the different treatment arms.
6.4
Treatment masking
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
masked to the identity of study treatments according to the specifications provided in the SOM. 
Randomization data are kept strictly confidential until the time of unmasking for the respective 
person(s). Further information regarding masking (and unmasking) is presented in Table 6-4
and the SOM.
Patients will be randomized to a treatment arm to maintain the mask. Patients will remain 
masked to study treatment throughout the study, except where indicated below. 
The identity of the treatments will be concealed by the use of study drugs that are all identical 
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6.4.1
Site staff
With the exception of any unmasked site staff identified below, all site staff (including study 
investigator and study nurse) will be masked to study treatment during treatment allocation and 
patient dosing. 
Unmasking a single patient at site for safety reasons (necessary for patient management) will 
occur via an emergency system in place at the site (see Section 6.6.3) 
Drug product will be supplied in bulk, so an unmasked pharmacist or study coordinator who is 
independent of the study team will be required in order to maintain the masking. This unmasked 
pharmacist or study coordinator will randomize the patient in the IRT system. Appropriate 
measures must be taken by the unmasked pharmacist or study coordinator to ensure that the 
treatment assignments are concealed from the rest of the site staff. The injecting physician, 
different from the investigator performing the assessments, will also be unmasked.
The injecting physician will perform the injection and all assessments at 1 minute and 
30 minutes post dose. Either the unmasked (injecting) or masked physician may perform the 
dilated fundus examination on the day of injection (2-4 hours post injection). All other 
assessments will be completed by the masked investigator.
6.4.2
Sponsor staff
The following unmasked sponsor roles are required for this study:

Unmasked field monitor(s)

Unmasked clinical staff managing drug re-supply to site

Unmasked sample analyst(s) (PK blood and urine)
The unmasked field monitors are required to review drug accountability and allocation at site. 
The unmasked monitors are not provided with a randomization list directly but will be 
unmasked through review of source documentation compiled by the unmasked pharmacist, 
which details treatment allocation to individual patients. The unmasked monitors will also be 
able to review the treatment allocation cards/randomization list provided to the unmasked 
pharmacist. The names of the unmasked monitor(s) are detailed in the Monitoring Plan.
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with randomization lists directly, but may be 
unmasked through communication of drug re-supply needs via the unmasked site pharmacists. 
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under unmasked conditions unless otherwise allowed. 
The study statistician will be able to access the full randomization list from the start of the study 
and is allowed to share unmasked information with the rest of the clinical trial team as 
appropriate for internal decision purposes, as outlined in Table 6-4. For example, unmasked 
summaries and unmasked individual data can be shared with the team whenever necessary. 
Study programmers and other personnel involved in study data analysis
 are allowed to access treatment assignment 
information from the start of the study for the purpose of data analysis. 
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The clinical trial team is allowed to share unmasked results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project while 
the study is ongoing.
All unmasked personnel will otherwise keep randomization lists and data or information that 
could unmask other study team members confidential and secure except as described above. 
Following final database lock all roles may be considered unmasked.
Table 6-4
Masking levels
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single patient
unmasked)
 
dose 
escalation
Patients/Patients
M
M
UI
M
Site staff
M
M
UI
UI
Unmasked site staff (see text for 
details) 
M
UI
UI
UI
Drug Supply and Randomization 
Office
UI
UI
UI
UI
Unmasked sponsor staff (see text for 
details)
UI
UI
UI
UI
Unmasked Pharmacovigilance 
sponsor staff
UI
UI
UI
UI
Statistician/statistical 
programmer/data analysts
M
M
UI
UI
Independent committees used for 
assessing interim results
NA
NA
NA
NA
All other sponsor staff not identified 
above (trial team, project team, 
management & decision boards, 
support functions)
M
M
UI
UI
M Remains masked
NA Not applicable
UI Allowed to be unmasked on individual patient level
6.5
Dose escalation and dose modification
Study drug dose adjustments and/or interruptions are not permitted.
In case of notable adverse events or safety concerns, termination of any further doses may be 
considered as per Section 9.
These changes must be recorded on the Dosage Administration Record CRF.
6.5.1
Dose escalation guidelines
Not applicable.
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6.6
Additional treatment guidance
6.6.1
Treatment compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all patients 
treated with LKA651 and Lucentis®, as detailed in pharmacokinetics section.
6.6.2
Recommended treatment of adverse events
Ocular adverse events should be treated according to the type of adverse event. For clinically 
significant acute elevation of IOP following LKA651, anterior chamber paracentesis should be 
performed and normalization of IOP verified. For subacute or persistent elevation in IOP, 
aqueous suppressants may be indicated. 
Iritis or vitritis should be treated with steroidal or non-steroidal anti-inflammatory medications; 
other medications such as cycloplegics may be indicated; endophthalmitis should be ruled out.
Endophthalmitis should be treated with vitreous tap and culture and/or vitrectomy, as indicated, 
plus appropriate IVT antibiotics.
In case of an adverse event attributed to LKA651, such as clinically significant inflammation 
or signs of retinal toxicity not responsive to standard of care treatment, the investigator may 
wish to remove the LKA651 by pars plana vitrectomy.
Systemic hypersensitivity reactions are theoretically possible. These can manifest with itching, 
flushing, headache, nausea/vomiting, hypotension, urticaria, bronchospasm, or angioedema. 
Assess and treat for anaphylaxis if indicated, and initiate supportive care. Fluids, vasopressors, 
corticosteroids, antihistamines, bronchodilators, and oxygen should be on hand.
Patients should remain in the study even after receiving treatments for adverse events until the 
PI feels that patient discharge is warranted.
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency unmasking should only be undertaken when it is essential to treat the patient safely 
and efficaciously. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Details will be provided in the SOM.
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The unmasked treatment code should not be recorded on the eCRF.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to IRT (Interactive Response Technology) or code break cards in case of emergency. 
If appropriate, the investigator will inform the patient how to contact his/her backup in cases of 
emergency when he/she is unavailable.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
LKA651 and Lucentis® will be administered to the patient via intraocular injection at the study 
site. When administered in combination, they will be given as separate injections 30 minutes 
apart. If a patient is randomized to a monotherapy arm, a sham injection will be done 30 minutes 
after the first injection. See the SOM for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
7
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board/Independent Ethics Committee (IRB/IEC)-
approved informed consent.
If applicable, in cases where the patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
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 International Conference on Harmonization (ICH) Good Clinical 
Practice (GCP) guidelines and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be agreed 
by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB and/CDS for marketed drugs. This information will be included in the patient
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the investigational drug 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 
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Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Refer to the SOM for a complete list of ICFs included in this study.
8
Visit schedule and assessments
Assessment Schedule lists all of the assessments and indicates with an “X”, the visits when they 
are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation.
Patients should be seen for all visits/assessments as outlined in the Assessment Schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Patients who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the CRF.
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Table 8-1
Assessment Schedule
Epoch
Screening 
Baseline
Treatment
Treatment
Treatment 
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Follow-up
Follow-up
Follow-up
Study Completion2
Visit Name
Screening
Visit 1
Visit 1 2
Visit 12
Visit 4 –
Telephone 
visit
Visit 5
Visit 5 2
Visit 52
Visit 6 –
Telephone 
Visit
Visit 7
Visit 7 2
Visit 72
Visit 8
Visit 9
Visit 10
Visit 11
Visit Numbers1
10
1010
1010
1010
1040
1050
1050
1050
1060
1070
1070
1070
1080
1090
1100
1999
Days
Screen
-60 to-1
1
1
1
15
29
29
29
43
57
57
57
85
113
141
169
Visit Window (Days)
+/- 1
+/- 1
+/- 2
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
Inclusion / Exclusion 
criteria
X
X
Hematology3
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
Pulse rate
X
X
X
X
X
X
X
X
Demography
X
Physical 
Examination
X
X
Body Height
X
Body Weight
X
X
X
X
X
Study completion 
information
X
Concomitant 
therapies
X
X
X
X
X
X
X
X
X
X
Blood Pressure
X
X
X
X
X
X
X
X
Informed consent
X
Body Temperature
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG evaluation
X
X
X
Urinalysis
X
X
X
X
Medical 
history/current 
medical conditions
X
X
Ocular history
X
DME history
X
Pregnancy and 
assessments of 
fertility
X4
X4
X4
X4
X4
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Epoch
Screening 
Baseline
Treatment
Treatment
Treatment 
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Follow-up
Follow-up
Follow-up
Study Completion2
Visit Name
Screening
Visit 1
Visit 1 2
Visit 12
Visit 4 –
Telephone 
visit
Visit 5
Visit 5 2
Visit 52
Visit 6 –
Telephone 
Visit
Visit 7
Visit 7 2
Visit 72
Visit 8
Visit 9
Visit 10
Visit 11
Visit Numbers1
10
1010
1010
1010
1040
1050
1050
1050
1060
1070
1070
1070
1080
1090
1100
1999
Days
Screen
-60 to-1
1
1
1
15
29
29
29
43
57
57
57
85
113
141
169
Visit Window (Days)
+/- 1
+/- 1
+/- 2
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
Best corrected 
visual acuity (BCVA)
X
X
X6
X
X6
X
X6
X
X
X
X
Intraocular Pressure 
(IOP)
X
X
X
X
X
X
X
X
X
X
X
Slit lamp 
biomicroscopy
X
X
X
X
X
X
X
X
X
X
X
Dilated fundus exam
X
X
X7
X
X7
X
X7
X
X
X
X
Optical coherence 
tomography8
X
X
X
X
X
X
X
X
Fluorescein 
angiography
X
X
X
Color fundus photo
X
X
X
X
X
HbA1C
X
X
X
PK blood collection
X5
X5
X5
X5
X
Study drug 
administration
X
X
X
1 Visit structure given for internal programming purpose only
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8.1
Screening
8.1.1
Eligibility Screening
Rescreening is only allowed by permission of the Sponsor. 
In the case where a safety laboratory assessment at screening and/or initial baseline is outside 
of the range specified in the exclusion criteria, the assessment may be repeated once prior to 
randomization. If the repeat value remains outside of the specified ranges, the patient must be 
excluded from the study.
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the Site Operations Manual.
8.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
screening phase disposition page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure patients. No other data will 
be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a SAE during the screening phase (see SAE section for reporting details). 
8.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data as outlined in the SOM will be collected 
on all patients.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent.
8.3
Efficacy
8.3.1
Efficacy assessment 1
8.3.1.1
Best-Corrected Visual Acuity (BCVA)
ETDRS BCVA will be obtained in each eye separately. This assessment is to be performed 
prior to pupil dilation. The number of letters read correctly (for each eye) will be recorded in 
the appropriate eCRF page.
8.3.2
Efficacy assessment 2
8.3.2.1
Spectral-Domain Optical coherence tomography (SD-OCT)
SD-OCT will be performed on the designated eye(s) for each patient according to the 
Assessment Schedule (Table 8-1) and the imaging manual provided by the Central Reading 
Center (CRC). SD-OCT images will be transferred to the CRC. Certification of the equipment 
and examiners at each investigative site will occur prior to evaluation of study patients.


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8.3.3
Appropriateness of efficacy assessments
BCVA is an FDA accepted endpoint for efficacy trials in DME and will be performed using 
standardized ETDRS charts. Central subfield retinal thickness will be measured to evaluate 
changes in retinal anatomy. Although an anatomical response can correspond with 
improvements in vision, the two do not always correlate (DRCRnet 2007), and thus BCVA will 
be the primary efficacy readout. 
8.4
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment schedule (Section 8) detailing when each assessment is to be 
performed.
8.4.1
Vital signs

Body temperature

Blood pressure (BP)

Pulse 
8.4.2
Height and weight

Height

Body weight

Body mass index (BMI) will be calculated as (Body weight (kg) / [Height (m)]2)
8.4.3
Laboratory evaluations
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening and/or at the initial baseline, the assessment 
may be repeated once prior to randomization. If the repeat value remains outside of 
protocol-specified ranges, the patient is excluded from the study.
In the case where a laboratory range is not specified by the protocol, but is outside the reference 
range for the laboratory at screening and/or initial baseline, a decision regarding whether the 
result is of clinical significance or not shall be made by the Investigator and shall be based, in 
part, upon the nature and degree of the observed abnormality. The assessment may be repeated 
once prior to randomization.
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the patient to continue in the study.
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. This includes laboratory 
evaluations obtained at Baseline visit V1, if the results are not received until after study drug 
has been administered.  The results should be evaluated for criteria defining an adverse event 
and reported as such if the criteria are met. Repeated evaluations are mandatory until 
normalization of the result(s) or until the change is no longer clinically relevant. In case of doubt, 
Novartis personnel should again be contacted.


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8.4.3.1
Hematology
CBC (Hemoglobin, hematocrit, red blood cell count, white blood count, platelet count) white 
blood cell differential (e.g. neutrophils, basophils, eosinophils, monocytes, lymphocytes) and 
reticulocyte count will be measured.
Additional measurements of hemoglobin A1c, CBC, and reticulocytes will be measured as 
outlined in the Assessment Schedules. Sample handling will be as outlined in the laboratory 
manual. 
8.4.3.2
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, chloride, 
creatinine, creatinine kinase (CK), gamma-glutamyl transferase (g-GT), glucose, lactate 
dehydrogenase (LDH), inorganic phosphorus, lipase, amylase, magnesium, potassium, total 
protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), sodium, 
triglycerides, urea/ blood urea nitrogen (BUN) and uric acid will be measured.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reacting bilirubin should be differentiated.
Sample handling will be outlined in the laboratory manual.
8.4.3.3
Urinalysis
A midstream urine sample (approximately 30 mL) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments.
A semi-quantitative "dipstick" evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leukocytes and blood.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts.
8.4.4
Electrocardiogram (ECG)
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Single 12 lead ECGs are collected. The original ECGs and copy on non-heat sensitive paper, 
appropriately signed, should be collected and archived at the study site.
Each ECG tracing should be labeled with study number, patient initials, patient number, date 
and time, be appropriately signed and dated to confirm review and filed in the study site source 
documents. For any ECGs with patient safety concerns, two additional ECGs should be 
performed to confirm the safety finding. Clinically significant ECG findings prior to dosing 
with investigational treatment must be discussed with the sponsor.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF / e(CRF) page as appropriate.


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8.4.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. See the 
Assessment schedule, Table 8-1, for timing of the protocol required pregnancy testing; 
additional pregnancy testing may be performed to meet local requirements*. A positive urine 
pregnancy test requires immediate interruption of study treatment until serum beta-human 
chorionic gonadotropin β-hCG is performed and found to be negative. 
*If additional pregnancy testing is needed per local requirements, those additional results will 
be kept as source documentation only. 
8.4.6
Other safety evaluations
8.4.6.1
Best-Corrected Visual Acuity (BCVA)
ETDRS BCVA will be obtained in each eye separately. This assessment is to be performed 
prior to pupil dilation. The number of letters read correctly (for each eye) will be recorded in 
the appropriate eCRF page.
8.4.6.2
Intraocular Pressure (IOP)
Intraocular pressures will be measured per the study site’s regular practice.
8.4.6.3
Fluorescein angiography (FA)
FA using a standardized technique (with transit views of the study eye) will be performed on 
the designated eye(s) for each patient according to the Assessment schedule (Table 8-1) and the 
imaging manual.
8.4.6.4
Slit lamp biomicroscopy
Slit lamp exam of the adnexae, conjunctiva/sclera, cornea, anterior chamber, iris, and lens will 
be obtained on both eye(s) for each patient according to the Assessment Schedule (Table 8-1). 
Results from the slit lamp biomicroscopy exam for both eyes will be recorded in the appropriate 
eCRF page.
8.4.6.5
Dilated fundus exam
Dilated exam of the vitreous, optic nerve, choroid, macula, peripheral retina will be obtained 
on the designated eye(s) for each patient according to the Assessment schedule (Table 8-1). 
The process will be outlined in the SOM. 
8.4.6.5.1 Vitreous haze and hemorrhage
During the above examination, additional attention should be directed to scoring the evaluation 
for retinal tear/detachment, retinal hemorrhage, vitreous hemorrhage, density and vitreous haze. 
Results from the dilated fundus exam (for each eye) will be recorded on the appropriate eCRF 
page. Vitreous Haze grade will be outlined in the SOM.


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8.4.6.6
Spectral-Domain Optical coherence tomography (SD-OCT)
SD-OCT will be performed on the designated eye(s) for each patient according to the 
Assessment Schedule (Table 8-1) and the imaging manual provided by the Central Reading 
Center (CRC). SD-OCT images will be transferred to the CRC. Certification of the equipment 
and examiners at each investigative site will occur prior to evaluation of study patients.
8.4.6.7
Color Fundus Photo
Color fundus photography will be performed on the designated eye(s) for each patient according 
to the Assessment schedule (Table 8-1) and the imaging manual. Fundus photograph will be 
performed according to a standardized procedure for the collection of fundus photographic 
images as outlined in a separate manual provided by the CRC. Training of examiners at each 
investigative site will occur prior to evaluation of study patients.
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8.5
Additional assessments
8.5.1
Pharmacokinetics, 
Quantitation of 
total 
LKA651, free 
ranibizumab,
 will be performed. 
For a detailed PK,
 sampling schedule, please refer to the Assessment 
schedule (Table 8-1), SOM, and the lab manual. All samples will be given a unique sample 
number and a collection number as outlined in the SOM. Additional collection, processing and 
shipping details for samples collected for the quantitation of serum total LKA651 and 
ranibizumab are available in the SOM.  Additional collection, processing and shipping details 
for samples collected for analysis for anti-LKA651 antibodies and anti-ranibizumab antibodies 
are available in the SOM.
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8.5.5
Other Assessments
Not applicable.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation of study treatment can be decided by either 
the patient or the investigator.
Study treatment must be discontinued under the following circumstances:

An SAE or severe AE that in the opinion of the Investigator is related to the study
treatment.

Patient/guardian decision - patients may choose to discontinue study treatment for any
reason at any time.

The investigator believes that continuation would negatively impact the safety of the
patient or the risk/benefit ratio of trial participation.

Any protocol deviation that results in a significant risk to the patient’s safety.

Pregnancy (see Section 8.4 (Safety) and Section 10.1.4 (Pregnancy reporting))

Use of prohibited treatment as outlined in Table 6-3.

Any laboratory abnormalities that in the judgment of the investigator, taking into
consideration the patient’s overall status, prevents the patient from continuing
participation in the study.

Emergence of the following adverse events:

Acute, marked, reduction in visual acuity, defined as either of the following: At least
a 3-line (15-letter) decrease within the first 8 days that persists until day 15, or at least
a 5-line (25-letter) decrease as assessed on any post injection day through Day 15.

Presence of persistent grade 2 or more anterior chamber inflammation (cells ± flare)
for 14 days or more following IVT injection of study drug.

An increase in vitreous inflammation of 2 units on a Vitreous Haze Scale sustained
over 14 days or more following IVT injection of study drug.
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
Sustained elevation of intraocular pressure characterized by an increase of 15 mmHg 
over pre-dose value for >60 minutes, or an intraocular pressure >30 mmHg 
maintained for an hour after the injection.

The following deviations from the protocol treatment: 

Treatment with LKA651 and/or Lucentis® within less than 28 days from the previous 
treatment.
The appropriate personnel from the site and Novartis will assess whether investigational drug 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason.
If discontinuation of study treatment occurs, investigator must determine the primary reason for 
the patient’s premature discontinuation of study treatment and record this information on the 
Dosage Administration CRF.
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2, Withdraw of Informed Consent). Where possible, they should 
return for the assessments indicated by an asterisk (*) in the Assessment table. If they fail to 
return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) 
should be made to contact the patient/pre-designated contact as specified in Section 9.1.3
(Lost to follow-up). This contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
9.1.1.1
Replacement policy
Not applicable.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

Does not want 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 subject’s decision to withdraw his/her consent 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. 


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Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
Assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting from 
the analysis of a subject’s samples until their time of withdrawal) according to applicable law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
Assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.4
Study stopping rules
Enrollment in the study will be placed on hold if any of the following occurs during any part of 
the study:

One (1) or more patients presenting with acute or delayed hypersensitivity of study drug 
administration.

One (1) or more patients presenting with a serious adverse event (SAE) that, in the 
opinion of the investigator, is related to the study drug, at any time during the trial.

Patient(s) presenting with dose-limiting toxicity defined as any one of the following 
suspected to be related to study drug administration: 

Two (2) or more patients presenting with:  

Acute, marked, reduction in visual acuity, defined as either of the following:
At least a 3-line (15-letter) decrease within the first 8 days that persists until 


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day 15, or at least a 5-line (25-letter) decrease as assessed on any post injection day 
through Day 15.

Presence of persistent grade 2 anterior chamber inflammation (cells ± flare) for 
14 days or more following IVT injection of study drug.

An increase in vitreous inflammation of 2 units on a Vitreous Haze Scale for 
14 days or more following IVT injection of study drug.

Sustained elevation of intraocular pressure characterized by an increase of 
15 mmHg over pre-dose value for >60 minutes, or an intraocular 
pressure >30 mmHg maintained for an hour after the injection.

The aggregate severity, frequency, and/or drug relatedness of adverse events, in the 
opinion of the investigator, merit placing the study on hold; or

Other clinically significant changes or effects that, in the opinion of the Investigator or 
Sponsor, are deemed unsafe to continue dosing
The study may resume following the safety review, if the Investigators and Sponsor agree it is 
safe to proceed.
9.1.5
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 (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the patient welfare and safety. Should early termination be 
necessary, patients must be seen as soon as possible (provide instruction for contacting the 
patient, when the patient should stop taking drug, when the patient should come for a final visit) 
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 or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Each patient will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them. There are approved medications for the disease under 
study, and the patient can continue treatment with these medications as per his or her physician’s 
recommendation.
Study completion is defined as when the last patient completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.


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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events (AEs)
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a patient or clinical 
investigation patient after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual patient and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. AEs also may be detected when they are volunteered by the patient during or 
between visits or through physical examination findings, laboratory test findings, or other 
assessments.
AEs must be recorded in the AE CRF under the signs, symptoms or diagnosis associated with 
them, accompanied by the following information (as far as possible) (if the event is serious 
refer to Section 10.1.2):
1. The severity grade
mild: usually transient in nature and generally not interfering with normal activities
moderate: sufficiently discomforting to interfere with normal activities
severe: prevents normal activities
2. Its relationship to the study treatment If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single patient
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All AEs must be treated appropriately. Treatment may include one or more of the following:

Dose not changed

Dose Reduced/increased


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
Drug interrupted/withdrawn
6. its outcome  
a. not recovered/not resolved;
b. recovered/resolved;
c. recovering/resolving,
d. recovered/resolved with sequelae; 
e. fatal; or unknown
Information about adverse drug reactions for the investigational drug can be found in the IB.
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 patients with 
the underlying disease.
Follow the instructions found in the SOM for data capture methodology regarding AE collection 
for patients that fail screening.
10.1.2
Serious adverse events (SAEs)
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:

fatal

life-threatening
Life-threatening in the context of a 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 (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or 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

social reasons and respite care in the absence of any deterioration in the patient’s 
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
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

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above
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. Such events should be 
considered as “medically significant”. 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.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has
provided informed consent and until 30 days after study exit must be reported to Novartis safety 
within 24 hours of learning of its occurrence. Detailed instructions regarding the submission 
process and requirements are to be found in the investigator folder provided to each site.
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.
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 Novartis Chief Medical 
Office and Patient Safety (CMO & PS) 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.
Any SAEs experienced after the 30 day period should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment.


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10.1.4
Pregnancy reporting
Pregnancies
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational study treatment any pregnancy outcome. 
Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
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. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness. Please see Table 10-1 for details.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
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
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a 
SAE
For more information on AE and SAE definition and reporting requirements, please see the
respective sections.


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10.2
Additional Safety Monitoring
Not applicable.
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Designated investigator staff will enter the data required by the protocol into the eCRFs. 
The eCRFs have been built using fully validated secure web-enabled software that conforms to 
21 CFR Part 11 requirements, Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) 
(entered into eCRF) is complete, accurate, and that entry and updates are performed in a timely 
manner. The Investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site.
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
vendor working on behalf of Novartis.
Remote monitoring of the original electronic source records will take place, however on-site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
adherence, to assess site operational capabilities, and to perform other monitoring activities that 
cannot be performed remotely.
The investigator must certify that the data entered into eCRF are complete and accurate. 
After database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.


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Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Randomization codes and data about all study treatment (s) dispensed to the patient and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unmasked and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eSource DDE or eCRFs) 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 data capture / data entry, 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/delegated CRO/CRA organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis clinical teams to assist with trial 
oversight.
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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 on 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 (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. 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.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.  Descriptive analyses will be defined as number of 
observations, mean, standard deviation, median, first quartile and third quartile, minimum and 
maximum.
12.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The safety analysis set will include all patients that received any study drug.
The PD and efficacy analysis set will include all patients with available PD and efficacy data 
and no protocol deviations with relevant impact on PD or efficacy data.
12.2
Patient demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and patient. 
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and patient.
12.3
Treatments
Data for study drug administration and concomitant therapies will be listed by treatment group 
and patient.


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12.4
Analysis of the primary endpoint(s)
12.4.1
Definition of primary endpoint(s)
Primary efficacy endpoints for this study are BCVA as assessed by ETDRS visual acuity charts 
at week 12 and central retinal thickness as measured by SD-OCT at week 12. Primary safety 
endpoints include adverse events, vital signs, ECG intervals, safety laboratory measures, and 
complete ophthalmic exam, including: intraocular pressure, BCVA, dilated fundus exam, slit 
lamp examination, macular thickness by SD-OCT, and FA.
12.4.2
Statistical model, hypothesis, and method of analysis
BCVA will be analyzed with the change from baseline and a repeated measures model. 
Independent variables will include treatment, visit, and the treatment by visit interaction. 
Baseline BCVA and treatment naive and treatment experienced variable will be used as a 
covariate. An unstructured covariance matrix will be used. The mixed model repeated measures 
technique will be used to account for missing values. The Kenward-Rodger estimate of 
denominator degrees of freedom will be used. Least-square means for each treatment by time 
combination will be presented. Additionally at each time, the difference between the 
combination treatment and Lucentis® alone, as well as the difference between LKA651 and 
Lucentis® alone will be presented along with the resulting p-value and 90% confidence interval. 
The primary inference will be based on the null hypothesis on no treatment difference for Day 
85. A one-sided, alpha=0.05 test will be used for this purpose.
Central subfield retinal thickness will be analyzed in a similar fashion as BCVA, except that 
central subfield retinal thickness will be log-transformed, thus results will be back-transformed 
in order to show results as a ratio to baseline and the difference between treatments will be 
expressed as a ratio of treatments. Similarly the covariates will be the log-transformed baseline 
central subfield retinal thickness and treatment naive and treatment experienced variable. 
Although there appears to be a slight skewness in the distribution of central retinal thickness, 
making the inferential results of a log-transformed analysis more reliable, it is uncommon for 
this parameter to be analyzed this way. Thus, analysis will also be done with untransformed 
data, but with deference given to the inferential results (p-values and confidence intervals) of 
the log-transformed analysis.
Safety analysis is described in Section 12.5.1.
12.4.3
Handling of missing values/censoring/discontinuations
Missing values will be accounted for my using mixed methods repeated measures.
12.4.4
Sensitivity and Supportive analyses
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12.5
Analysis of secondary endpoints
Time to retreatment with anti-VEGF (as determined by PI) after week 12 may be examined 
with a Kaplan-Meier plot; however, this may be abandoned if the time data are too sparse for 
accurate model fitting. 
12.5.1
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to the end 
of the extension phase. 
Adverse events
All information obtained on adverse events will be displayed by treatment group and patient.
The number (and percentage) of patients with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind treatment 
but increased in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment.
A patient with multiple AEs within a primary system organ class is only counted once towards 
the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment, patient, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time.
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12-lead ECG
All ECG data will be listed by treatment, patient and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.
12.5.2
Pharmacokinetics
Due to the reduced number of visits for remaining patients to enroll into the study, there will be 
fewer overall blood draws for PK sampling. Accordingly, the PK analysis will only be 
performed in a subset of patients where sufficient serum samples have been collected to permit 
meaningful analysis. The following systemic serum PK parameters for LKA651 and 
ranibizumab will be determined after the first dose, if feasible, using non-compartmental 
method(s): area under the curve AUC last, AUC 0-28d, Maximal concentration (Cmax), and time to 
the first occurrence of the maximal concentration (Tmax). PK parameters will be determined 
using non-compartmental methods using the most recent version of WinNonlin Phoenix 
(Version 8.2).
Descriptive summaries including mean, coefficient of variation, median, minimum and 
maximum 
 be presented by 
treatment and study day/sampling point.
The derivation of PK parameters at the patient level will be based on observed concentrations 
only,
. A plot of mean concentration-time profile will be constructed. Plots of 
mean-time concentration profile of total LKA651 concentrations and ranibizumab will also be 
constructed.
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12.5.5
Patient reported outcomes
Not applicable.
12.6
Analysis of exploratory endpoints
12.7
Interim analyses
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12.8
Sample size calculation
Twenty five patients per arm provide 80% power to detect a 5 letter improvement in BCVA 
compared to Lucentis®, p=0.05 (one-sided) for the single comparison (after 12 weeks of 
treatment), assuming a standard deviation (SD) of 7 letters, the SD observed in the Lucentis® DME 
trials. The software nQuery 7.0 was used to evaluate the power estimation and the sample size.


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13
Ethical considerations and administrative procedures
13.1
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 with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
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, patient recruitment procedures 
(e.g., advertisements) and any other written information to be provided to patients. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial results 
website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.) .
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.


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14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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Amended Protocol Version v06 (Clean)
Protocol No. CLKA651X2202
15
References
References are available upon request
DRCRnet (2007) Relationship between optical coherence tomography-measured central 
retinal thickness and visual acuity in diabetic macular edema. Ophthalmology; 114(3):525-
536
ETDRS (1985) Photocoagulation for Diabetic Macular Edema - Early Treatment Diabetic-
Retinopathy Study Report,  Archives of Ophthalmology; 103:1796-1806.
Jaffe GJ, Eliott D, Wells JA, et al (2016) A Phase 1 Study of Intravitreous E10030 in 
Combination with Ranibizumab in Neovascular Age-Related Macular Degeneration. 
Ophthalmology; 123(1):78-85.
Klein R, Klein BEK, Moss SE, et al (1995) The Wisconsin Epidemiologic-Study of Diabetic-
Retinopathy the Long-Term Incidence of Macular Edema. Ophthalmology; 102:7-16.
Lin CS, Lim SK, D’Agati V, et al (1996). Differential effects of an erythropoietin receptor 
gene dis- ruption on primitive and definitive erythropoiesis. Genes Dev; 10:154-164.
Lira RP, Oliveira CL, Marques MV, et al (2007) Adverse reactions of fluorescein 
angiography: a prospective study. Arq Bras Oftalmol; 70(4):615-618.
Mitchell P, Bandello F, Schmidt-Erfurth U, et al (2011) The RESTORE study: ranibizumab 
monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. 
Ophthalmology; 118:615-625.
Mones J (2010) Complement Factor 5 Inhibition in Age-related Macular Degeneration. Retina 
Today. October 2010:52-55
Wroblewski JJ, Hu AY (2016) Topical Squalamine 0.2% and Intravitreal Ranibizumab 0.5 
mg as Combination Therapy for Macular Edema Due to Branch and Central Retinal Vein 
Occlusion: An Open-Label, Randomized Study. OSLIRetina; 47(10):914-923.
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SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LKA651
CLKA651X2202
Clinical Trials.gov Identifier: NCT03927690
A randomized, active-controlled, patient and investigator-
masked, multiple dose proof-of-concept study of 
intravitreal LKA651 in patients with diabetic macular edema
Statistical Analysis Plan (SAP)
Author(s):
 
Document type:
SAP Documentation – NIBR 
Document status:
Amendment v03
Release date:
03-Aug-2022
Number of pages:
19
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


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Table of contents
Table of contents .................................................................................................................4
List of tables ........................................................................................................................4
List of Figures......................................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Scope of document ..................................................................................................6
1.2
Study reference documentation ...............................................................................6
1.3
Study objectives.......................................................................................................6
1.4
Study design and treatment......................................................................................8
2
First interpretable results (FIR) ...........................................................................................9
3
Interim analyses.................................................................................................................11
4
Statistical methods: Analysis sets......................................................................................11
5
Statistical methods for Pharmacokinetic (PK) parameters................................................13
5.1
Variables................................................................................................................13
5.2
Descriptive analyses ..............................................................................................13
6
Statistical methods for Efficacy/Pharmacodynamic (PD) parameters ..............................13
6.1
Primary objective...................................................................................................14
6.1.1
Variables ...............................................................................................14
6.1.2
Descriptive analyses..............................................................................14
6.1.3
Statistical model, assumptions and hypotheses.....................................14
6.1.4
Supportive and sensitivity analysis .......................................................15
6.2
Secondary objective...............................................................................................15
6.2.1
Variables ...............................................................................................15
6.2.2
Descriptive analyses..............................................................................16
6.2.3
Statistical model, assumptions and hypotheses.....................................16
6.3
Exploratory objectives...........................................................................................16
6.3.1
Descriptive analyses..............................................................................16
7
Statistical methods for safety and tolerability data............................................................16
7.1
Variables................................................................................................................17
7.2
Descriptive analyses ..............................................................................................17
9
Reference list.....................................................................................................................19
List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................12
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List of Figures
Figure 1.1: Study Design............................................................................................................8


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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLKA651X2202”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol for the final analysis, as well as the outputs planned for the interim 
analyses.
1.2
Study reference documentation
Final study protocol amendment (v05) is available at the time of finalization of the Statistical 
Analysis Plan.
1.3
Study objectives
1.3.1
Primary Objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To evaluate the safety/tolerability of 
three q4w IVT doses of LKA651 alone 
or in combination with Lucentis® in 
patients with DME.

Ocular and systemic AEs

Vital signs (blood pressure, heart rate) and 
ECG intervals.

Safety laboratory measures (including 
reticulocyte count)

Complete ophthalmic exam, including:

Intraocular Pressure (IOP)

BCVA

Macular 
thickness 
by 
spectral 
domain
optical 
coherence 
tomography (SD-OCT)

FA

To evaluate the efficacy, in reference to 
Lucentis® monotherapy, of three q4w 
IVT doses of LKA651 in treating DME 
when administered as monotherapy or 
in combination with Lucentis®.

Best Corrected Visual Acuity (BCVA) as 
assessed by ETDRS (Early Treatment 
Diabetic Retinopathy Study) visual acuity 
charts at week 12.

Central subfield retinal thickness as 
measured by SD-OCT at week 12
1.3.2
Secondary Objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)


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
To evaluate duration of effect of three
q4w IVT doses of LKA651 in patients
with DME.

Time to retreatment with anti-VEGF (as
determined by PI) after week 12 during an
additional 12-week extension phase

To evaluate the serum pharmacokinetic
profile of total LKA651 and Lucentis®
following three q4w IVT doses of
LKA651 alone or in combination with
Lucentis® in patients with DME.

Serum levels of total LKA651 (Maximum
concentration (Cmax) and Area under the
curve (AUC)0-28d in monotherapy or in
combination with Lucentis® after the first dose
in a subset of patients with sufficient
quantifiable 
serum 
samples 
to 
permit
meaningful analysis.

Serum levels of ranibizumab (Cmax and
AUC0-28d) when administered in combination
with LKA651 after the first dose in a subset of
patients with sufficient quantifiable serum
samples to permit meaningful analysis.
1.3.3
Exploratory Objective(s)
Exploratory objective(s)
Endpoints related to exploratory objective(s)
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1.4
Study design and treatment
This study is a 3-arm, parallel group, randomized, patient and investigator-masked phase II trial 
in 90 patients with DME who are either treatment naïve or who have been treated with anti-
VEGF therapy >90 days before baseline. The study will be first stratified in two Sentinel Safety 
cohorts (n=16; 8 in each geographical region). The Sentinel Safety patients will be randomized 
6:1:1 to LKA651 plus Lucentis® (
 + 0.3 or 0.5 mg), LKA651 monotherapy (
) or 
Lucentis® (0.3 or 0.5 mg). Sentinel Safety cohorts will first be enrolled to test the safety of the 
combination of LKA651 and Lucentis® by Day 15 before proceeding with further patient 
randomization. After determination that there are no concerning safety signals, the study will 
proceed with randomization for the remaining 74 patients who will be randomized 9:14:14 to 
LKA651 plus Lucentis® (
 + 0.3 or 0.5 mg), LKA651 monotherapy or Lucentis®. Data 
from the Safety Sentinel cohorts and main study will be pooled for end of study safety and 
efficacy analysis.
Figure 1.1: Study Design depicts the design of the study, starting from a screening epoch (60 
days) of the Sentinel safety cohort, a treatment period from Visit 1 (Baseline visit) to Day 15. 
If safety will be determined for the first 8 patients in a region at Day 15, that region can continue. 
After determination of safety from the two Sentinel Safety cohorts the remaining 74 patients 
will be randomized. Every patient will be dosed 3 times in 4-week intervals, and then followed 
for an extension phase of an additional 12 weeks during which PRN Lucentis® may be given.
Figure 1.1: Study Design
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2
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
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3
Interim analyses 
4
Statistical methods: Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) they received.
The safety analysis set will include all patients who received any study drug.
The PD and efficacy analysis set will include all patients with available PD and efficacy data 
and no protocol deviations with relevant impact on PD or efficacy data.
Dose sensitivity analysis set will include patients in the efficacy analysis set who received all 3 
doses with 6 injections and dosed correctly.
The PK analysis set will include all patients with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The analysis sets and protocol deviation codes are related as follows:
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Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation 
code
Text description of deviation
Data exclusion
Subjects are excluded from safety analysis in case of 
these PDs: 
Exclude subject from safety analysis set 
INCL01
Deviation from inclusion criterion 1
Yes
Subjects are excluded from PK analysis in case of 
these PDs: 
Exclude subject from PK analysis set 
EXCL01
Deviation from exclusion criterion 1
(anti-VEGF at baseline)
Yes
EXCL22
Deviation from exclusion criterion 22 
(investigational drugs at Screening or 
during the trial)
Yes
Subjects are excluded from PD analysis in case of 
these PDs:
Exclude subject from PD analysis set
INCL01
Deviation from inclusion criterion 1
Yes
INCL03
Deviation from inclusion criterion 3
Yes
EXCL01
Deviation from exclusion criterion 1
Yes
EXCL02
Deviation from exclusion criterion 2
Yes
EXCL03
Deviation from exclusion criterion 3
Yes
EXCL04
Deviation from exclusion criterion 4
Yes
EXCL05
Deviation from exclusion criterion 5
Yes
EXCL08
Deviation from exclusion criterion 8
Yes
EXCL09
Deviation from exclusion criterion 9
Yes
EXCL10
Deviation from exclusion criterion 10
Yes
EXCL11
Deviation from exclusion criterion 11
Yes
EXCL13
Deviation from exclusion criterion 13
Yes
EXCL15
Deviation from exclusion criterion 15
Yes
EXCL22
Deviation from exclusion criterion 22
Yes
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Category
Deviation 
code
Text description of deviation
Data exclusion
COMD01
Use of prohibited medication during 
the study 
Yes (from this date onwards)
TRT01
Wrong injection/treatment 
administered during the study
From dose sensitivity analysis
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
PK analysis will only be performed in a subset of patients where sufficient serum samples have 
been collected to permit meaningful analysis.
5.1
Variables 
The following systemic serum PK parameters for LKA651 and ranibizumab will be determined 
after the first dose, if feasible, using non-compartmental method(s): 

Area under the curve AUClast, AUC0-28d, maximum concentration (Cmax), and time to the
first occurrence of the maximal concentration (Tmax).
PK parameters will be determined using non-compartmental methods using the most recent 
version of WinNonlin Phoenix (Version 8.2). 
5.2
Descriptive analyses
Descriptive summaries including mean, coefficient of variation, median, minimum and 
maximum and including frequency of concentrations below LLOQ, will be presented by 
treatment and study day/sampling point. Concentrations below LLOQ will be treated as ½ LLOQ 
in the summary statistics.
A plot of Geometric mean (SE) concentration-time profile of LKA651 from Day 1 0 hour (visit 
1) to Day 29 (visit 5) following first LKA651dose will be constructed. Similarly, plot of
Geometric mean (SE) concentration-time profile of ranibizumab from Day 1 0 hour (visit 1) to
Day 29 (visit 5) following first ranibizumab dose will be constructed. Those Geometric mean
concentration by time profile will be plotted on linear-linear and log-linear scale.
6
Statistical methods for Efficacy/Pharmacodynamic (PD) 
parameters
All patients within the PD analysis set will be included in the PD data analysis.


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6.1
Primary objective
The primary objective of this study is to evaluate the efficacy, in reference to Lucentis®
monotherapy, of three q4w IVT doses of LKA651 in treating DME when administered as 
monotherapy or in combination with Lucentis®. 
6.1.1
Variables 
Best Corrected Visual Acuity (BCVA) at week 12 and central subfield retinal thickness as 
determined by Spectral Domain-Optical coherence tomography (SD-OCT) at week 12.
6.1.2
Descriptive analyses
The absolute and change from baseline as well as percent change from baseline BCVA and 
central subfield retinal thickness measurements will be listed by treatment, patient and visit/time 
and descriptive statistics will be provided by treatment and visit/time. Summary statistics will 
include number of observations, mean, standard deviation, median, minimum and maximum. 
6.1.3
Statistical model, assumptions and hypotheses
BCVA
BCVA for study eye will be analyzed using two repeated measures models. A first model where 
BCVA will be the dependent variable and a second one where change from baseline of BCVA 
will be the dependent variable. Independent variables will include treatment, visit, and the 
treatment by visit interaction. Baseline BCVA for study eye and treatment naïve and treatment 
experienced variable will be used as covariates. An unstructured residual covariance structure 
will be used, if possible. If not possible, simpler covariance structures will be considered and 
the best will be selected using information criteria.
The Kenward-Rodger estimate of denominator degrees of freedom will be used. Least-square
means for each treatment by time combination will be presented. Additionally at each time, the
difference between the combination treatment and Lucentis® alone, as well as the difference
between LKA651 and Lucentis® alone will be presented along with the resulting p-value and
90% confidence interval.
The 
primary 
inference
will 
be 
based 
on 
the 
null 
hypothesis 
on 
no
treatment difference for Day 85. A one-sided, alpha=0.05 test will be used for this purpose, with 
an increase considered as beneficial.
Central subfield retinal thickness
Central subfield retinal thickness will be analyzed in a similar fashion as BCVA, except that
central subfield retinal thickness will be log-transformed, thus results will be back-transformed
in order to show results as a ratio to baseline and the difference between treatments will be
expressed as a ratio of treatments. Similarly, the covariates will be the log-transformed baseline
central subfield retinal thickness and treatment naïve and treatment experienced variable. 


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6.1.4
Supportive and sensitivity analysis
Dose sensitivity analysis will be performed to exclude patients who did not receive all 3 doses
(6 injections) or dosed improperly, including both BCVA (absolute value and change from 
baseline) and CSFT (change from baseline and ratio to baseline). Analysis will consist of 
repeating MMRM models and reporting corresponding model estimated means (90% CI) and 
estimated treatment differences (90% CI). Model estimated mean plots with 90% CI error bars 
over time may be provided to support the analysis.
6.2
Secondary objective
The secondary objectives are: 

To evaluate duration of effect of three q4w IVT doses of LKA651 in patients with DME.
6.2.1
Variables 
The variables related to the secondary objectives are: 
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
Time to retreatment with anti-VEGF after week 12 during an additional 12 week
extension phase
6.2.2
Descriptive analyses
Time to retreatment with anti-VEGF after week 12 and number of patients with 2 and ≥3 step 
improvement in the diabetic retinopathy severity scale by color fundus photos at week 12 and 
week 24 will be listed by treatment group, patient and visit/time, and descriptive statistics will 
be provided, for raw data, by treatment group (i.e. LKA651 vs Lucentis®, LKA651/Lucentis®
combination vs Lucentis®, and LKA/Lucentis® vs LKA651) and visit/time. Summary statistics 
will include number of observations, mean, standard deviation, median, minimum and
maximum.
6.2.3
Statistical model, assumptions and hypotheses
Time to retreatment with anti-VEGF (as determined by PI) after week 12 may be examined 
with a Kaplan-Meier plot; however, this may be abandoned if the time data are too sparse for 
accurate model fitting. 
6.3
Exploratory objectives
6.3.1
Descriptive analyses
7
Statistical methods for safety and tolerability data
The safety analysis set will include all patients that received any study drug.
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7.1
Variables
Adverse events, vital signs (blood pressure, heart rate) and ECG intervals, laboratory 
measurements (including reticulocyte count), complete ophthalmic exam, 
 in patients with DME as well as patient demographics, baseline characteristics, and 
treatment information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and patient. 
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and patient.
Treatment
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by treatment group and patient.
Vital signs
Vital sign data such as body temperature, blood pressure and heart rate will be listed by 
treatment, patient, and visit/time and if ranges are available abnormalities (and relevant 
orthostatic changes) will be flagged. Summary statistics will be provided by treatment and 
visit/time.
12-lead ECG
All ECG data will be listed by treatment, patient and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory evaluations will be listed by treatment, patient, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing will be provided presenting 
all parameters in a patient with any abnormal values. Summary statistics will be provided by 
treatment and visit/time.
Reticulocyte count
Reticulocyte count will be listed by treatment, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing will be provided presenting all 
parameters in a patient with any abnormal values. Summary statistics including mean, standard 
deviation, median, minimum and maximum will be provided by treatment and visit/time.
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Intraocular pressure (IOP)
Intraocular pressure (IOP) will be listed for each eye by treatment, patient, and visit/time and if 
normal ranges are available abnormalities will be flagged. Summary statistics including mean, 
standard deviation, median, minimum and maximum will be provided by treatment and 
visit/time.
Dilated fundus exam
Dilated fundus exam results will be summarized using descriptive statistics. Descriptive 
statistics including frequency and proportion will be provided. These will be presented by 
treatment and visit/time.
Slit lamp examination
Slit lamp examination findings will be listed for each eye by treatment, patient, and visit/time 
and if normal ranges are available abnormalities will be flagged. Summary statistics will be 
provided by treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group and patient.
The number (and percentage) of patients with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind treatment 
but increased in severity based on preferred term) will be summarized in the following ways:
by treatment, primary system organ class and preferred term.
by treatment, primary system organ class, preferred term and maximum severity.
by treatment, Standardized MedDRA Query (SMQ) and preferred term
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment.
A patient with multiple adverse events within a body system is only counted once towards the 
total of this body system and treatment.
Separate tables will be provided for ocular events and non-ocular events.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
1.
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE
2.
more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.


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For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
9
Reference list
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