Conditions: Geographic Atrophy
Keywords: Geographic atrophy (GA) Macular degeneration Dry age-related macular degeneration (AMD) Intravitreal (IVT) Retinal diseases Fundus auto fluorescence (FAF)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 114
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of 12 (every 28 days) intravitreal (IVT) injections of CLG561 as a monotherapy and in combination with LFG316 as compared to sham in subjects with geographic atrophy.

Detailed description:
This study consists of an up-to 30-day screening period, an approximately 336-day treatment period, and a follow-up period consisting of two visits occurring 4 and 16 weeks after the last administered injection.

Arms:
arm 1: CLG561 10 mg, one IVT injection every 28 days for a total of 12 injections arm 2: CLG561 5mg + LFG316 5 mg, one IVT injection every 28 days for a total of 12 injections arm 3: One sham injection every 28 days for total of 12 sham injections

Interventions: intervention 1: CLG561 intervention 2: LFG316 intervention 3: Sham injection
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: Empty syringe (without a needle) placed against the eye

Protocol document:
Prot_001.pdf: 
 
 
 
a Novartis company 
Short Title 
Proof-of-concept study of intravitreal CLG561 and LFG316 in subjects 
with geographic atrophy 
 
Long Title 
A
 randomized, multi-center
, single masked, sham controlled, proof-of-
concept study of intravitreal CLG561 as a monotherapy and in 
combination with LFG316 in subjects with geographic atrophy 
 
Protocol Number:  
CLG561-2201 (CCLG561X2201A) 
Study Phase: 
Phase 2 
Sponsor Name and 
Address: 
Alcon Research, Ltd. 
Investigational Product:  CLG561, LFG316 
Indication Studied:  
Ophthalmology  
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Amended Protocol VersionNo. 01 (Clean)
Protocol No. CCLG561X2201A
Manual of Operations (MOP)
A Manual of Procedures (MOP) accompanies this protocol, providing the operational details 
for study conduct.
Notification of serious adverse events
Refer to Section 9.2of the protocol for definitions and reporting requirements for SAEs 
(within 24 hours after awarenessof the SAEdocument the event on the SAE eCRF).
Contact information is listed in the MOP.
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Amended Protocol VersionNo. 01 (Clean)
Protocol No. CCLG561X2201A
Table of contents
Manual of Operations (MOP)..............................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................3
List of tables........................................................................................................................6
List of figures......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols.........................................................................11
Amendment 1 (January 2016)...........................................................................................12
Protocol synopsis...............................................................................................................18
1 Introduction.......................................................................................................................25
1.2
Study purpose........................................................................................................40
2 Study objectives.................................................................................................................40
2.1
Primary objective(s)...............................................................................................40
2.2
Secondary objective(s)...........................................................................................41
3 Investigational plan...........................................................................................................44
3.1
Study design...........................................................................................................44
3.2
Rationale of study design.......................................................................................45
3.3 
Rationale of dose/regimen and duration of treatment............................................46
3 4 
Rationale for choice of comparator
46
3.6
Risks and benefits..................................................................................................47
4 Population..........................................................................................................................51
4.1
Inclusion criteria....................................................................................................51
4.2
Exclusion criteria...................................................................................................52
5 Restrictions for study subjects...........................................................................................53
5.1
Contraception requirements...................................................................................53
5.2
Prohibited treatment...............................................................................................53
6 Treatment...........................................................................................................................54
6.1
Study treatment......................................................................................................54
6.1.1
Investigational treatment.......................................................................54
6.2
Treatment arms......................................................................................................54
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Protocol No. CCLG561X2201A
6.4
Treatment assignment............................................................................................55
6.5
Treatment masking................................................................................................55
6.6
Emergency breaking of assigned treatment code..................................................55
6.7
Treatment exposure and compliance.....................................................................55
6.8
Recommended treatment of adverse events..........................................................55
6.9
Rescuemedication.................................................................................................55
6.10 Concomitant treatment...........................................................................................55
7 Discontinuation and study completion..............................................................................56
7.1
Discontinuation of study treatment........................................................................56
7.2
Study completion and post-study treatment..........................................................56
7.2.1
Lost to follow-up...................................................................................57
7.3
Withdrawal of consent...........................................................................................57
7.4
Study stopping rules..............................................................................................58
7.5
Early study termination..........................................................................................58
8 Procedures and assessments ..............................................................................................58
8.1
Informed consent procedures.................................................................................66
8.2 
Subject demographics/other baseline characteristics.............................................66
8.3
Efficacy / pharmacodynamics................................................................................67
8.3.1
Pharmacodynamic sample collection....................................................67
8.3.2
Pharmacodynamic analytical methods..................................................67
8.3.3
Ocular pharmacodynamic assessments.................................................68
8.4
Safety.....................................................................................................................69
8.4.1
Vital signs and body measurements......................................................69
8.4.2
Laboratory evaluations..........................................................................69
8.4.3
Post-injection safety assessments..........................................................69
8.4.4
Pregnancy..............................................................................................70
8.5
Other assessments..................................................................................................70
8.5.1
Immunogenicity ....................................................................................70
8.5.2
Pharmacokinetics..................................................................................70
8.5.3
Drug administration..............................................................................70
8.5.4
Ocular examination...............................................................................71
8.5.8
General comments.................................................................................71
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9 Safety monitoring..............................................................................................................73
9.1
Adverse events -general information....................................................................73
9.2 
Monitoring for adverse events 
...............................................................................73
9.3
Procedures for recording and reporting AEs and SAEs........................................73
9.4
Intensity and causalityassessments.......................................................................76
9.5
Unmasking of study treatment...............................................................................77
9.6
Follow-up of subjects with adverse events............................................................77
10 Data review and database management.............................................................................78
10.1 Site monitoring......................................................................................................78
10.2 Data collection 
.......................................................................................................79
10.3 Data monitoring committee 
...................................................................................80
10.4 Adjudication committee.........................................................................................80
10.5 Safety committee...................................................................................................80
10.6 Regulatory documentation and records retention..................................................80
11 Data analysis......................................................................................................................80
11.1 Analysis sets..........................................................................................................80
11.2 Subject demographics and other baseline characteristics......................................81
11.3 Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................81
11.4 Analysis of the primary variable(s).......................................................................81
11.4.1
Variable(s).............................................................................................81
11.4.2
Statistical model, hypothesis, and method of analysis..........................81
11.4.3
Handling of missing values/censoring/discontinuations.......................82
11.4.4
Supportive analyses...............................................................................82
11.4.5
Subgroup analyses.................................................................................82
11.5 Analysis of secondary and exploratory variables 
..................................................83
11.5.1
Efficacy endpoints.................................................................................83
11.5.2
Pharmacodynamic endpoints................................................................83
11.5.3
Immunogenicity endpoints....................................................................84
11.5.4 
Pharmacokinetic endpoints ...................................................................84
11.5.6 
Safety.....................................................................................................85
11.5.7
Other assessments.................................................................................86
11.6 Sample size calculation..........................................................................................87
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Protocol No. CCLG561X2201A
12 Ethical considerations........................................................................................................88
12.1 Regulatory and ethical compliance........................................................................88
12.2 Responsibilities of the Investigator and IRB/IEC.................................................88
12.3 Publication of study protocol and results...............................................................89
13 Protocol adherence............................................................................................................90
14 References.........................................................................................................................91
Table 8-1
Non-ocular assessment schedule...........................................................60
Table 8-2
Ocular assessments................................................................................63
Table 8-3
Post-injection exams at injection visits 
.................................................65
List of figures
Figure 3-1
Study design..........................................................................................45
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List of abbreviations
µL
microliter
ADA
anti-drug antibodies
AE
adverse event
AEF
adverse event form
ALT
alanine aminotransferase
AMD
age-related macular degeneration
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AREDS
age-related eye disease study
ARMS2
Age-related maculopathy susceptibility 2
AST
aspartate aminotransferase
BCVA
best corrected visual acuity
BMI
body mass index
BP
blood pressure
bpm
beats per minute
C3GN 
C3 glomerulonephropathy
CFH
Complement Factor H 
CFP
color fundus photography
CFR
code of federal regulation
CK
creatinine kinase
CNV
choroidal neovascularization
CRC
central reading center
CSM
clinical site manager
CSR
clinical study report
CV
coefficient of variation
DDD
dense deposit disease
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
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ELISA
enzyme-linked immunosorbent assay
EOS
end of study
ESI
event of special interest
ETDRS
early treatment diabetic retinopathy study
Fab
fully-human antibody
FA
fluorescein angiography
FAF
fundus autofluorescence
FU
follow up
GA
geographic atrophy
GCP
good clinical practice
GGT
gamma-glutamyl transferase
GLP
good laboratory practice
HIV
human immunodeficiency virus
HTRA1
high temperature requirement A serine peptidase 1
IAG 
image acquisition guidelines 
IB
Investigator
's brochure
IC50
inhibitor concentration 50%
ICH
international conference on harmonization
IEC
independent ethics committee
Ig
immunoglobulin
IOP
intraocular pressure
IRB 
Institutional Review Board
IRC
independent review charter
IRT
interactive response technology
IVT
Intravitreal
IV           
Intravenous
kg
kilogram
LASIK
laser-assisted in situ keratomileusis
LDH
lactate dehydrogenase
LLN
lower limit of normal
LLOQ
lower limit of quantification
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MedDRA
medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
mmHG
millimeters of mercury
MMRM
mixed-effect model repeated measure
MOP 
manual of procedures
MPGN II
membranoproliferative glomerulonephritis type II
N or n
sample size
NEI VFQ-25 National Eye Institute Visual Functioning Questionnaire – 25
nM
nanometer
No.
number
NOAEL
no observed adverse effect level
OD
Right eye
OS
left eye
PD
pharmacodynamic(s)
pH
negative log of the activity of the hydrogen ion in an aqueous solution
PK
pharmacokinetic(s)
pM
picometer
POC
proof of concept
PP
per-protocol
PRK
photorefractive keratectomy
PT/INR
prothrombin time/international normalized ratio
q2w
biweekly
q4w
every 4 weeks
RBC
red blood cell(s)
RPE
retinal pigment epithelium
SAD
single-ascending dose
SAE
serious adverse event
SD
standard deviation
SD-OCT
spectral domain optical coherence tomography
SNP
single nucleotide polymorphism
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ULOQ
upper limit of quantification
VEGF
vascular endothelial growth factor
WBC
white blood cell(s)
WHO
world health organization
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Pharmacokinetic definitions and symbols
AUC
The area under the plasma (or serum or blood) concentration-time curve
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Tmax
The time to reach the maximum concentration after drug administration 
[time]
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Amended Protocol VersionNo. 01 (Clean)
Protocol No. CCLG561X2201A
Protocol synopsis
Protocol 
number
CCLG561X2201A(CLG561-2201)
Title
A randomized, multi-center, single masked, sham controlled, proof-of-concept 
study of intravitreal CLG561 as a monotherapy and in combination with LFG316 
in subjects with geographic atrophy
Brief title
CLG561 (anti-properdin) proof-of-concept study as a monotherapy and in 
combination with LFG316 (anti-C5) for subjects with geographic atrophy (GA).
Sponsorand
clinical phase
Alcon Research, Ltd., a Novartis company
Phase II
Intervention 
type
Biologic
Study type
Interventional
Purpose and 
rationale
To identify whether CLG561 as a monotherapy and in combination with LFG316 
has the desired clinical profile in treatment of GA to warrant further development.
Primary 
Objectives
To evaluate the safety of 12(every 28 days) IVT injections of CLG561 as a 
monotherapy and in combination with LFG316 as compared to sham
To evaluate in the study eye the efficacy of 12 (every 28 days) IVT injections 
of CLG561 as a monotherapy and in combination with LFG316 as compared 
to sham on the growth of GA lesion size as assessed by FAF based on the 
change from baseline to Day 337
Secondary 
Objectives
To evaluate the time course of the change in GA lesion size of the active 
arms as compared to sham as measured by FAF in the study eye
To evaluate the time course of the change in BCVA/low luminance visual 
acuity/low luminance visual acuity deficit up to Day 337 of the active arms as 
compared to shamin the study eye
To evaluate the average change in BCVA/low luminance visual acuity/low 
luminance visual acuity deficit from baseline to the period Day 281 to Day 337  
of the active arms as compared to shamin the study eye
To evaluate the time course of the proportion of study eyes losing or gaining 
≥15 letters, ≥10 letters, and ≥5 letters in BCVA from baseline up to Day 337 in 
each of the active arms as compared to shamin the study eye
To describe:
The systemic exposure of total CLG561 after IVT administration of 
CLG561 as a monotherapy up to Day 421
The systemic exposure of total CLG561 and total LFG316 after IVT 
administration of CLG561 in combination with LFG316 up to Day 421
To describe the immunogenicity of CLG561 after IVT administration of 
CLG561 as a monotherapy and the immunogenicity of CLG561 and LFG316 
after IVT administration of CLG561 in combination with LFG316 up to Day 
421
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Amended Protocol VersionNo. 01 (Clean)
Protocol No. CCLG561X2201A
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Amended Protocol VersionNo. 01 (Clean)
Protocol No. CCLG561X2201A
Study design
This study employs a multi-center, randomized, sham-controlled, single-masked 
design. Approximately 114 elig ble subjects with GA will be randomized in a 1:1:1 
ratio to obtain approximately 90 evaluable subjects completing the study per 
protocol. Subjects will receive one of three treatment modalities:
1. CLG561 (10 mg/100 µL)
2. CLG561 (5 mg/50 µL) + LFG316 (5 mg/50 µL)
3. Sham injection 
The treatment modalities will occur every 28 days for a total of 12 injections (or 
sham injections). 
Randomization is performed within an IRT system. The IRT will randomize the 
subject into 1 of 3 treatment modalities. 
The following are masked to treatment assignment:
•
Subjects
•
Visual acuity assessor at the study site
•
Technicians obtaining images at the study site
•
CRC staff
Both eyes must have GA. Only one eye mustmeet the other inclusion/exclusion 
criteria to be eligible for study participation. Randomization is 1:1:1 (CLG561: 
CLG561 + LFG316: Sham Injection).
The study consists of up to 30-Day screening period, approximately 336-Day 
treatment period (12 IVT injections occurring approximately every 28 days), and a 
follow up period consisting oftwo visits occurring 4 and 16 weeks after the last 
administered injection. 
If a subject prematurely exits the study, then he/she must return to the clinical site 
approximately 4 weeks after their last injection (or the earliest possible date after 
4 weeks) for the end of study (EOS) evaluation. In this case, all assessments 
must be completed at the EOS visit.
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Amended Protocol VersionNo. 01 (Clean)
Protocol No. CCLG561X2201A
Population
Male or female subjects(≥ 50 years old) with GA are deemed most appropriate 
for this study for the following reasons:
Both CLG561 and LFG316 are being developed for subjects with GA
Due to reduced visual acuity, eyes with GA are less likely to sustain 
incremental loss of visual acuity from an ocular AE
Eyes with GA may experience a benefit from CLG561 monotherapy or in 
combination with LFG316
Administration of multiple doses of CLG561 as a monotherapy and in 
combination with LFG316 to eyes with GA will provide information 
regarding the efficacy of monotherapy with CLG561 or its combination 
with LFG316
The age range of subjects over 50 corresponds to the typical age range 
of the subjects with advanced AMD
The study plans to recruit approximately 114 subjects(38 in each treatment arm)
in order to yield 30 evaluable subjects in each treatment arm.
Inclusion 
criteria
Subjects eligible for inclusion in this study have to fulfill all of the following criteria:
1. Able and willing to provide written informed consent and in the opinion of the 
Investigator, the subject is able to complete the duration of the study. Note: 
Informed consent must be obtained before any assessment is performed
2. Male or female GA subjects ≥ 50 years of age
3. GA in BOTH EYES. One eye MUST meet the following criteriawith lesion 
size assessed by FAF and measured by the CRC. 
IF GA lesion is multifocal, THEN the total lesion area must be 
between 3-16 mm2and at least one lesion with an area of at least 
1.25 mm2 
IF GA lesion is unifocal, THEN the lesion area must be between 8-16 
mm2
4. Presence of hyper-autofluorescence adjacent to at least 10% of perimeter of 
GAin the study eye
5. Best-Corrected Visual Acuityof 20/20or worse in both eyes at Screening
Exclusion 
criteria
Subjects fulfilling any of the following criteria are not eligible for inclusion in this 
study. No additional exclusions may be applied by the Investigator, in order to 
ensure that the study population will be representative of all eligible subjects.
1.
Pregnant or lactating women and women of child-bearing potential (defined 
as all women physiologically capable of becoming pregnant). 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)
• Total hysterectomy
• Surgical bilateral oophorectomy (with or without hysterectomy)
• Tubal ligation for at least six weeks
• Oophorectomy alone is acceptable ONLY when the reproductive status of 
the woman is confirmed by follow up hormone level assessments andshe 
is considered to be not of child bearing potential
2.
Subjects demonstrating any medical condition (systemic or ophthalmic) that 
may, in the opinion of the Investigator, and based on the content of the IB, 
preclude the safe administration of test article or safe participation in this 
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3.
Anycontraindications or hypersensitivities to any component of the LFG316 
or CLG561 solution
4.
Any contraindications to IVT injections
5.
Retinal disease, other than AMD, in either eye
Note: Benign conditions of the vitreous or peripheral retina are NOT 
excluded.Significant peripapillary atrophy either present at the time of 
Screening or which is expected to merge with the GA lesion during the 
course of the studyISexcluded.
6.
Any history of, or current evidence of, CNV in either eye, as determined by 
FA at screening 
7.
Media opacity that interferes with fundus imaging in either eye, or is likely to 
require surgery during the study period
8.
Any active ocular or periocular infection or active intraocular inflammation in 
either eye at screening or at baseline (e.g., infectious blepharitis, infectious 
conjunctivitis, keratitis, scleritis, endophthalmitis)
9.
Any history of the following in either eye at screening:
• herpes simplex keratitis
• herpes zoster keratitis
• infectious uveitis
10. Penetrating ocular surgery requiring cutting of ocular tissue (e.g., cataract 
surgery, PRK, LASIK, Epilasik, pterygium removal, etc.) or ocular trauma 
requiring medical or pharmacological treatment in the studyeye within 90 
days of screening. 
Note: Ocular laser procedures are not excluded
11. Macular atrophy in either eye due to anything other than AMD
12. Concomitant treatment for AMD in either eye within 90 days of screening
Note: Concomitant use of vitamins/supplements is not excluded
13. Any periocular or IVT injections in either eye within 90 days of baseline
14. Any of the following abnormal vital signs at screening: temperature > 100.5° 
F (38° C); heart rate> 100 bpm; systolic blood pressure <90 mmHg or > 160 
mmHg, diastolic blood pressure > 95 mmHg. 
Note: Out of range vital signs may be repeated once. If the values  are still 
out of range the visit must be rescheduled. If out of range vitals are observed 
again and persistent at re measurement, the subject must be disqualified 
from the study. Subjects may be rescreened when values have stabilized.
15. Uncontrolled ocular hypertension or glaucoma in the studyeye (IOP >25 
mmHg despite current pharmacological or non-pharmacological treatment)
16. Participation in any interventional clinical trial within 12 weeks prior to 
screening
17. Any history of participation in interventional clinical trials involving gene 
therapy or extended release products, or any product with expected long 
term efficacy
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Investigational 
and reference 
therapy
Investigational Products/Treatments:
CLG561 (anti-properdin Fab)
IVT Injection
10 mg/100 µL
Every 28 days for total of 12 injections
CLG561 (anti-properdin Fab) combined with  LFG316 (anti-C5 IgG)
IVT Injection (co-injection)
CLG 561 5 mg/ 50 µL mixed  with LFG316 5 mg/ 50 µL (total 100 
µL) are mixed in a vial and will be administered as a 100 µL total 
volume via a single syringe
Every 28 days for total of 12 injections
Control Products/Treatments:
Sham injections
Hub of an empty syringe (without a needle) will be placed against 
the eye
Every 28 days for total of 12 sham-injection procedures
Efficacy/PK/PD 
assessments
GA lesion as measured by FAF (both eyes)
BCVA (both eyes)
Low luminance visual acuity (both eyes)
Serum concentration of total CLG561 and total LFG316
Serumlevels of anti-drug antibodies (ADA; anti-CLG561 and anti-
LFG316 antibodies)
Safety 
assessments
AEs (AEs) (incidence, severity, overall assessment)
Vital signs (blood pressure, heart rate)
Laboratory evaluations
Hematology
Chemistry including liver function tests
Urinalysis
Complete ophthalmic exam (slit lamp, dilated fundus exam, BCVA, 
IOP)
Other 
assessments
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Data analysis Primary Endpoint
Change in GA lesion size from baseline to Day 337
Hypotheses
One-sided hypotheses of superiority of active related to the comparison of each 
of the two active arms vs control (sham injections). The comparison of the two 
active arms will be done descriptively.
Primary analysis data set
The primary efficacy analysis data set is a per-protocol (PP) set. Key PP criteria 
are compliance with the GA specificinclusion criteria, the monthly injection 
schedule up to Day 337 (not missing greater than 1 in any 6 months period or not 
missing 2consecutive doses) and available baseline and Day337 and/or 
Day253 lesion size assessments. Missing values of lesion size on Day 337 will 
be imputed based on linear regression/extrapolation.
Statistical testing strategy
For hypotheses–testing a global one-sided alpha of 0.2 is considered. With the 
two hypotheses being tested in parallel using the Bonferroni multiplicity 
adjustment, the nominal one-sided alpha for eachsingle hypothesis will be 0.1.
Statistical method 
The lesion size change from baseline to Day 337 will be analyzed by an ANOVA 
model including but not limited to the class variable representing categories of 
baseline lesion size (edge length) and categories of lesion location.
Sample size
A sample size of 30 per-protocol (PP) evaluable subjects per treatment arm will 
allow identification of a treatment difference of 0.67 mm2in lesion size change 
from baseline to Day 337 (representing a 33% reduction in lesion growth rate, 
assuming an average natural disease progression of 2.0 mm2per year) at a one-
sided alpha level of 0.1 with a power of 80% assuming a standard deviation of1.2 
mm2.
In anticipation of a drop-out /protocol deviation rate of 20%, a total sample size of 
~114 randomized subjects (~38 subjects/arm) is planned for the current study to 
ensure sufficient study completers for the above described PP analysis. 
Depending on ongoing monitoring of the drop-out/protocol deviation rate the need 
for additional recruitment will be assessed to ensure 90 PP evaluable subjects 
are available for the Day 337 analysis.
Key words
Geographic atrophy, GA, macular degeneration, dry AMD, IVT, intravitreal, retinal 
diseases, FAF
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1
Introduction
1.1
Background
The current study is designed to investigate monthly IVT doses of CLG561 as a monotherapy 
and in combination with LFG316. The protocol is designed to test the hypothesis that the 
inhibition of properdin by CLG561 either as a monotherapy or in combination with C5 
inhibition by LFG316 may slow or arrest GA lesion growth and thereby preserve visual 
function.
AMD is the leading cause of legal blindness in the United States and the rest of the developed 
world (Kleinet al2011). The early signs of AMD are common in individuals over the age of 
65 and precede the advanced forms, which are visually devastating. Advanced AMD is 
divided into two forms: neovascular AMD and GA, which affect approximately 1 million 
people in the United States (Kleinet al2011), and millions more worldwide. Besides 
nutritional practices of modest value, there is no treatment to prevent the progression of the 
early AMD to advanced AMD, or to slow GA once it begins. For the  neovascular form of 
advanced AMD, prompt initiation of anti-VEGF therapies such as Lucentis® can improve 
visual outcomes in many patients (Rosenfeldet al2006).
No therapy currently exists for GA, which is usually bilateral and relentlessly progressive. 
Once the  cells of the retina have  been lost, they cannot be replaced so improvement in 
anatomical or functional outcomes is not possible. The only approach to treating this disease 
is to delay the progression, and prolong the life of the functional retina.
Numerous independent  studies of patients with AMD have convincingly identified strong 
associations between the disease and single nucleotide polymorphism (SNPs) in genes 
encoding key members of the complement alternative pathway, including the negative 
regulator complement factor H, the protease complement factor B, and complement factor C3 
(Kleinet al2005, Haineset al2005, Malleret al2006, Yateset al2007, Hugheset al2006, 
Postelet al2006, vandeVenet al2013).  Many of the SNPs have allele frequencies greater 
than 5% and carrier frequencies among Caucasians over 10%.
In aggregate, the population attributable risk of these variants is greater than 50%, meaning 
that if one had a population of humans without the high-risk alleles, the prevalence of AMD 
would be substantially reduced (Desprietet al2006, Goldet al2006). Risk variants of factor 
H are found not only to be associated with lifetime incidence of early AMD but also with 
progression of early to late AMD (Gangnonet al2012). Increased activation of the alternative 
complement pathway in the vitreous was also found to be correlated to the AMD disease and 
genetic variation in the complement pathway, supporting a role for complement activation in 
AMD disease pathogenesis (Loyetet al2012).
Recently, human genetic studies of rare, highly penetrant mutations have further strengthened 
the causal link between complement upregulation and AMD pathogenesis 
(Raychaudhuriet al2010, Jozsiet al2006, Ferreiraet al2009, vandeVenet al2013, 
Seddonet al2013).
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The genetic data are supported by functional studies showing: i) immunohistochemical 
detection of C5 and MAC in drusen from AMD eyes (Mullinset al2000); ii) the presence of 
the complement activation products C5a and C3a in drusen, RPE cells, and Bruch’s 
membrane(Nozakiet al2006); iii) detection of complement proteins and immune complexes 
in drusen and retinal pigmented epithelial cells (Crabbet al2002, Johnsonet al2001, 
Hagemanet al2001); iv) AMD patients have increased serum concentrations ofcomplement 
activation products (Schollet al2007, Heckeret al2010); v) increased affinity of the AMD 
risk-associated variant of factor B protein (arginine 32) for C3b with associated enhanced 
formation of activated convertase (Monteset al2009); and vii) elevated levels of C5a and 
sC5b-9 in patients with AMD or associated complement risk polymorphisms 
(Schollet al2008, Reynoldset al2009).
A hallmark of AMD is the development of drusen, which are lipoproteinaceous deposits 
located between the retinal pigment epithelium and Bruch’s membrane and can be  a risk 
factor for disease progression. In membranoproliferative  glomerulonephritis type II (MPGN 
II), or more specifically C3 glomerulonephropathy (C3GN) and Dense Deposit Disease 
(DDD), systemic hyper-activation of the complement system, either by C3 nephritic factor or 
mutations in the complement regulatory protein factor H, leads to deposition of C3 activation 
products within the kidney glomerular basement membrane. Some patients with MPGN II 
also develop ocular drusen deposits within Bruch’s membrane at early ages that resemble 
drusen seen in AMD patients and the patients may progress to vision loss 
(Hagemanet al2001, Appelet al2005).
Investigator led Phase 2 clinicaltrials with intravenously administered eculizumab (Alexion) 
(anti-C5 antibody) have been conducted in patients with GA or intermediate AMD (drusen).
Eculizumab was administered at two different doses to cohorts of patients either with 
intermediate AMD or GA for 6 months with a further follow up period of 6 months 
(Yehoshuaet al2014, GarciaFilhoet al2014). The drug was well tolerated with no drug-
related AEs. There were no differences between the GA lesion sizes or drusen volume in the 
treatments versus placebo groups at 6 months. The reasons for inability of eculizumab to 
demonstrate efficacy in GA or intermediate AMD may be due to the short duration of 
treatment, the route of administration (IV) of the compound, or the small numbers of patients.
More recently, Genentech presented their Phase 2results with the  anti-factor DFab, 
lampalizumab, in patients with GA (Regilloet al2013). They observed a 20.4% reduction in 
GA lesion growth in overall patients  treated with monthly IVT injection of 10 mg of 
lampalizumab. The observed effect was larger (42%) in patients who had a complement factor 
I polymorphism. 
In summary, there are multiple converging lines of evidence that AMD involves over-
activation of the alternative complement cascade and provides a rationale for complement 
inhibition therapy.
CLG561 is a fully-human antibody Fab fragment that binds and neutralizes properdin activity 
to prevent alternative pathway activation. Inhibition of properdin blocks both the early and 
late nodes of AP activation, preventing the formation of the early activation products, C3a and 
C3b/iC3b, as well as the late activation products, C5a and C5b, and MAC.
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It is proposed to test the safety and efficacy of the combination of LFG316 and CLG561 for 
the treatment of GA. Other combinations of complement inhibitors were evaluated
pre-clinically, and only anti-C5 and anti-properdin were synergistic. The exact mechanism 
underlying the observed synergy remains unclear, but it could be related to target 
concentration, target half-life, or target function.  Ocular levels of properdin are much lower 
than other complement  proteins, such as C3 and C5, and, based on systemic data, the 
predicted half-life is longer than other complement proteins, such as Factor D. A lower target 
concentration coupled with a longer half-life might make properdin a more attractive target 
for complement suppression. However, properdin is a positive regulator of the alternative 
pathway, and while it is important for convertase stabilization, it is not essential. 
Consequently, it might be possible that over time, a small amount of terminal complement 
complex could be formed even in the presence of CLG561. Perhaps the addition of LFG316 
to a system containing CLG561 serves to block any low level pathway activation resulting in 
more potent complement inhibition. Enhanced blockade of the pathway could lead to a better 
inhibition of complement-dependent lesion growth and an improvement in patient disease.
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1.2
Study purpose
This study is designed as a POC study to identify whether CLG561 as a monotherapy and in 
combination with LFG316 has the desired clinical profile in the treatment of GA to warrant 
further development.
2
Study objectives
2.1
Primary objective(s)
Objective
Endpoint
To evaluate the safety of 12 (every 28 
days) IVT injections of CLG561 as a 
monotherapy and in combination with 
LFG316 as compared to sham.
Incidence and characteristics of 
treatment-emergent AEs.
Treatment-emergent changes from 
baseline through Day 421 in ocular 
and systemic parameters.
To evaluate in the study eye the 
efficacy of 12 (every 28 days) IVT 
injections of CLG561 as a 
monotherapy and in combination with 
LFG316 as compared to sham on the 
growth of GA lesion size as assessed 
by FAF based on the change from 
baseline to Day 337.
Change in GA lesion size from 
baseline to Day 337 as measured by 
FAF.
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2.2
Secondary objective(s)
Objective
Endpoint
To evaluate the time course of the 
change in GA lesion size of the active 
arms as compared to sham as 
measured by FAFin the study eye
Change in GA lesion size from 
baseline to Day 85, 169, 253, and 421 
as measured by FAFin the study eye
To evaluate the time course of the 
change in BCVA/low luminance 
visual acuity/low luminance visual 
acuity deficit up to Day 337of the 
active arms as compared to shamin 
the study eye
Change in BCVA/low luminance 
visual acuity/low luminance visual 
acuity deficit from baseline by visit 
up to Day 337 as measured by 
ETDRS in the study eye
To evaluate the average change in 
BCVA/low luminance visual 
acuity/low luminance visual acuity 
deficit from baseline to the period 
Day 281 to Day 337  of the active 
arms as compared to sham in the 
study eye
Average change in BCVA/low 
luminance visual acuity/low 
luminance visual acuity deficit from 
baseline to the period Day 281 to Day 
337 as measured by ETDRSin the 
study eye
To evaluate the time course of the 
proportion of study eyes losing or 
gaining ≥15 letters, ≥10 letters, and 
≥5 letters in BCVA from baseline up 
to Day 337 in each of the activearms 
as compared to shamin the study eye
Subject status regarding ≥15 letters, 
≥10 letters, and ≥5 letters change 
from baseline in BCVA by visit up to 
Day 337 as measured by ETDRSin 
the study eye
To describe:
The systemic exposure of total 
CLG561 after IVT 
administration of CLG561 as a 
monotherapy up to Day 421
The systemic exposure of total 
CLG561 and total LFG316 after 
IVT administration of CLG561 
in combination with LFG316 up 
to Day 421
Serum concentrations of total 
CLG561 (CLG561 monotherapy) and 
serum concentrations of total 
CLG561 and total LFG316 
(CLG561/LFG316 combination) by 
visit up to Day 421
To describe the immunogenicity of 
CLG561 after IVT administration of 
CLG561 as a monotherapy and the 
immunogenicity of CLG561 and 
LFG316 after IVT administration  of 
CLG561 in combination with 
LFG316 up to Day 421
Serum anti-CLG561 antibodies 
(CLG561 monotherapy) and serum 
anti-CLG561 and anti-LFG316 
antibodies (sham and 
CLG561/LFG316 combination) by 
visit up to Day 421
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3
Investigational plan
3.1
Study design
This study employs a multi-center, randomized, sham-controlled, single-masked design. 
Approximately 114 eligible subjects(38 in each treatment arm)with GA will be randomized 
in a 1:1:1 ratio to obtain approximately 90 evaluable subjects completing the study per 
protocol. Subjects will receive one of three treatment modalities:
1. CLG561 (10 mg/100 µL)
2. CLG561 (5 mg/50 µL) + LFG316 (5 mg/50 µL)
3. Sham injection 
The treatment modalities will occur every 28 days for a total of 12 injections (or sham 
injections). Subjects assigned to receive sham injections will be treated in the same manner as 
those assigned to the other two treatment arms, except  that the hub of an empty syringe 
(without a needle) is placed against the eye. For the subjects receiving the CLG561+ LFG316 
combination, the drugs are mixed extemporaneously and then injected in a single 
administration.
Both eyes must have GA. Only one eye MUST meet the other inclusion/exclusion criteria to 
be eligible for study participation. Randomization is 1:1:1 (CLG561: CLG561+LFG316: 
Sham Injection) and assigned by the IRT.
The study consists of up to 30-Day screening period, an approximate 336-Day treatment 
period (12 IVT injections occurring approximately every 28 days), and a follow up period 
consisting of two follow up visits occurring 4 and 16 weeks after the last administered 
injection.
If a subject prematurely exits the study, then he/she must return to the clinical site 
approximately 4 weeks after their last injection (or the earliest possible date after 4 weeks) for 
the EOS evaluation. In this case, all assessments mustbe completed at the EOS visit.
The following will be masked to treatment assignment:
Subjects
Visual acuity assessor at the study site
Technicians obtaining images at the study site
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Figure 3-1
Study design
3.2
Rationale of study design
The design of this study will address the primary objectives of efficacy and safety of every 
4weeks IVT injectionof monotherapy with CLG561 (10mg), as well as the combination of 
LFG316 and CLG561 (5 mg of each) in subjects with GA. Since there is currently no product 
approved for the treatment of GA, no active comparator is included in the current study. The 
control for this study will be a sham injection, which is a common and well-established 
method of control for studies of IVT medications.
Subjects and certain study personnel, but not the Investigator or Sponsor, will be masked to 
treatment randomization. This approach was chosen for two reasons:
1. Opalescence of the IVT formulation is likely to be visible in the peripheral vitreous, 
particularly at early visits and would identify actively treated subjects to the study 
ophthalmologists
2. The primary endpoint is basedon objective evaluations by a central reading facility, 
which will be masked to treatment assignment
Treatment randomization between the active arms and sham allows the evaluation of safety 
characters of CLG561 as a monotherapy and in combination with LFG316 in a balanced and 
objective manner. All study subjects will undergo the same study assessments and receive 
their assigned study treatments under the same dosing interval (every 28 days). All treatment 
arms will proceed in parallel to each other.
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3.3
Rationale of dose/regimen and duration of treatment
Rationale for treatment arms
Since GA is a slowly progressive disease, prolonged treatment and observation are required to 
detect any potential clinical efficacy with CLG561 as a monotherapy or combination of both 
CLG561 and LFG316. The every 28 day injection frequency is similar to the standard dosing 
frequency deployed in the LFG316 monotherapy study and in other GA studies conducted 
with anti-complement agents [the MAHALO trial by Roche testing every 4 week injection of 
lampalizumab (anti-factor D Fab)].
Based on power calculations, a 12-month treatment period is adequate to measure a clinically 
meaningful effect. This period of observation depends on available technology, which is 
currently FAF with semi-automated area quantification using RegionFinder software 
(Heidelberg Engineering).
Injection of the maximum deliverable concentration of CLG561 (10mg) is supported by the 
26-week IVT toxicity studies in cynomolgus monkeys. Injection of the maximum deliverable 
concentration of LFG316 (10 mg) is supported by the 26  week IVT toxicity studies in 
cynomolgus monkeys (605210) in accordance with ICHS6 (R1). The injection of 5mg 
CLG561 and 5 mg LFG316 is supported by the 3 month intravitreal CLG561/LFG316 
combinationtoxicology study in cynomolgus monkeys.
As there are no animal models of GA available, the dose-response relationship is unknown for 
CLG561 or its combination with LFG316. Thus it is proposed to test the highest safe dose of 
CLG561 (10 mg) as monotherapy.Further monotherapy dose ranging will take place in phase 
IIb/phase III studies. The combination of 5 mg of each molecule in 100µL is the maximum 
feasible volume that can be safely delivered into the vitreous. The combination of CLG561 
and LFG316 has shown synergistic efficacy invitroinhibition of complement activation, and 
in an in vivo murine in vivo model of complement-dependent ocular inflammation. Thus, it is 
expected that the combination of CLG561 and LFG316 will have superior efficacy in GA as 
compared to monotherapy.
3.4
Rationale for choice of comparator
A sham injection is selected as a comparator treatment because there are  currently no 
approved treatments available to subjects with GA.
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3.6
Risks and benefits
The risk to subjects in this trial is minimized by adherence to the eligibility criteria, close 
clinical and safety monitoring, and study/arm(s) stopping rules.
An estimated total of 288.5mL of blood is planned to be collected over a period of 
approximately 451days, from each subject. Additional samples for monitoring of safety 
findings may be necessary. Blood sampling is not considered to be a risk for this population.
Intravitreal LFG316 up to 5 mg has been administered to over 190 subjects. Over 
2000injections have been administered up to the 10 mg dose. No drug related AEs were 
noted. CLG561, as a single IVT injection, has been administered to 31 subjects in escalating 
doses of up to 10mg. No drug related AEs  were noted. A summary of the known and 
potential risks and benefits associated with CLG561 andLFG316 can be found in the IB.
All IVT injections carry the risk of endophthalmitis, retinal detachment, vitreous or retinal 
hemorrhage, cataract, elevated intraocular pressure, and ocular inflammation. All of the above 
conditions are apparent on eye exam, and most cause symptoms that prompt the subject to 
seek evaluation.
With respect to endophthalmitis, current best clinical practices are used to reduce the risk of 
endophthalmitis. Despite these practices, endophthalmitis rates may approximate 1 in 1,000 to 
1in 20,000.
As with any antibody, CLG561 or LFG316 are expected to carry the risk of anaphylaxis or 
hypersensitivity reactions. CLG561 and LFG316 may also elicit the formation of human ADA.
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Risks involved in systemic inhibition of properdin
Subjects with inherited properdin deficiency are at increased risks of meningococcal 
infections (Sjoholmet al1982; MathewandOverturf2006; Fijenet al1999). Meningococcal 
infections are the most common presentation of subjects due to properdin deficiency, although 
recurrent otitis and pneumonia has also been seen (Schejbelet al2009). The mortality rate in 
properdin deficient subjects from systemic infections is high (33–75%) (Bathumet al2006). 
The specific individual risk of meningococcal infection in properdin deficiency has been 
calculated at around 50%, a 250-fold increase over the baseline incidence of meningococcal 
infection inthe general population (LintonandMorgan1999). Investigators should also be 
aware of other possible infections involving meningococcus, streptococcus, or H.influenzae.
After IVT administration of CLG561  
there was no clear time-dependent or dose-dependent 
change in serum complementactivity at a dose of up to 10mg.
In theory CLG561 may predisposeto ocular infections, including endophthalmitis or 
herpesvirus infections. Investigators should be alert to possibleocular infection following 
IVTadministration. Any potential infections must be treated by the Investigator according to 
the standard of care.
Risks involved in systemic inhibition of C5
Risks involved in systemic inhibition of C5 in humans have been characterized and include 
risk of serious infections with meningococcus, other encapsulated bacteria, and other agents.
After IVT administration of LFG316 there was no evidence of time-dependent or 
dose-dependent change in serum complement activity at a dose of up to 5mg.
However, local immunosuppression  could in  theory increase the eye’s  susceptibility to 
infection, including endophthalmitis. Investigators must always follow strict preventative 
measures for IVT administration.
Adverse Drug Reactions
CLG561
In clinical study CCLG561X2101A, CLG561 was safely administered to 31 adult and elderly 
AMD subjects (57 to 86 years) up to a dose of 10 mg. Safety results from this study indicate 
no dose-dependent AEs associated with IVT administration of CLG561. CLG561 was well 
tolerated.
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LFG316
Four studies with LFG316 have been  completed at this time (CLFG316A2101, 
CLFG316A2102, CLFG316A2201 and CLFG316A2202) and another two studies are 
currently ongoing 
. The AE profiles
 
 are described in Section 5.1.1.1 of the Investigator’s Brochure.
In subjects with advanced AMD, there were no drug-related AEs, deaths, serious AEs, or 
discontinuations.
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CLFG316A2201 was a multicenter, multiple dose, 2-cohort study to assess the safety, 
tolerability, pharmacokinetics, pharmacodynamics, and efficacy of intravenousLFG316 in 
subjects with neovascular age-related macular degeneration. Both cohorts were to employ a 
randomized, placebo-controlled, double-masked design. Novartis terminated this study and 
stopped recruitment on  26 March 2013 after just 4 subjects were randomized to LFG316; 
none were randomized to placebo. The decision to terminate the CLFG316A2201 study was 
not due to any safety signal with LFG316. It was based upon a consideration of the reported 
number of subjects with meningococcal infection and unclear risk of death due to meningitis 
noted after repeated intravenous dosing with Soliris® (eculizumab), which is an approved 
antibody against complement factor5 (C5) for the treatment of paroxysmal nocturnal 
hemoglobinuria and atypical hemolytic syndrome. Overall, intravenous infusion of LFG316 
was safe and well tolerated and was not associated with any infections.
CLFG316A2202 was a repeat-dose POC study in subjects with neovascular (wet) AMD. This 
study used a multicenter, randomized study design to assessthe efficacy, safety, tolerability, 
and serum pharmacokinetics of 3 successive doses of intravitreally administered LFG316. The 
study was completed as planned. Forty-five subjects were randomized ina 2:1 ratio to either 
LFG316 5mg/50μL IVT injection (30 subjects) or to sham injection (15 subjects) for total of 
3 doses. Overall, single intravitreal doses of LFG316, up to 5 mg were found to be safe and 
well tolerated across all treatment groups. Conjunctival hemorrhage was the most frequently 
reported ocular AE which can be attributed to the IVT injection procedure. None of the AEs 
were dose dependent or suspected to be related to the study drug. Remaining clinical safety 
parameters (vital signs, ECG, etc.) and ocular assessments showed no clinically significant 
changes.
Results from all studies indicate no dose-dependent AEs associated with IV or IVT 
administration of LFG316. IV infusion and IVT injection of LFG316 were well tolerated in 
all doses studied.
Combination of CLG561 and LFG316
The combination of the two compounds, CLG561 5 mg combined with LFG316 5mg, has not 
been tested in humans.
There may be unknown risks of CLG561 or the combination of CLG561 and LFG316which 
may be serious and unforeseen.
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4
Population
The study population is comprised of male and female subjects (≥ 50 years old) with GA.
The study population is deemed most appropriate for this study because of the following:
1. Both CLG561 and LFG316 are being developed for subjects with GA
2. Due to reduced visual acuity, eyes with GA are less likely to sustain incremental loss 
of visual acuity from an ocular AE
3. Eyes with GA may experience a benefit from CLG561 monotherapy or in combination 
with LFG316
4. Administration of multiple doses of CLG561 as a monotherapy and in combination 
with LFG316 to eyes with GA will provide information regarding the efficacy of 
monotherapy with CLG561 or its combination with LFG316
5. The age range of subjects over 50 corresponds to the typical age range of the subjects 
with advanced AMD
A total of approximately 114 subjects will be enrolled in the study and randomized. At least 
90evaluable subjects are expected to complete the study. A maximum of 216 subjects (72per 
treatment arm) may be enrolled if additional subjects are required to replace drop-outs, and 
balance stratification factors.
The Investigator must ensure that  all subjects being considered for the study meet the 
following eligibility criteria. No additional eligibility criteria must be applied by the 
Investigator in order to make sure that the study population is representative of all  eligible 
subjects.
Subject selection is established by checking through all eligibility criteria at screening and 
confirmed at baseline. A relevant record (e.g. checklist) of the eligibility criteria must be 
stored with the source documentation at the study site.
Deviation from anyentry criterion excludes a subject from enrollment into the study.If 
BOTH eyes qualify, the eye with the worsevisual acuity will be selected as the study eye. 
4.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill all of the following criteria:
1. Able and willing to provide written informed consent and in the opinion of the 
Investigator, the subject is able to complete the duration of the study
Note: Informed consent must be obtained before any assessment is performed.
2. Male or female GA subjects ≥ 50 years of age
3. GA in BOTH EYES. One eye MUST meet the following criteriawith lesion size 
assessedby FAF and measured by the CRC. 
IF GA lesion is multifocal, THEN the total lesionarea must be between 3-16mm2and 
at least one lesion with an area of at least 1.25 mm2 
IF GA lesion is unifocal, THEN the lesion area must be between 8-16mm2 
4. Presence of hyper-autofluorescence adjacent to at least 10% of the perimeter of GAthe 
study eye
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4.2
Exclusion criteria
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the Investigator, in order to ensure that the study 
population will be representative of all eligible subjects.
1. Pregnant or lactating women and women of child-bearing potential (defined as all women 
physiologically capable of becoming pregnant). 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)
Total hysterectomy
Surgical bilateral oophorectomy (with or without hysterectomy)
Tubal ligation for at least six weeks
Oophorectomy alone is acceptable ONLY when the reproductive status of the woman 
is confirmed by follow up hormone level assessments and sheisconsidered to be not 
of child bearing potential
2. Subjects demonstrating any medical condition (systemic or ophthalmic) that may, in the 
opinion of the Investigator, and based on the content of the IB, preclude the safe 
administration of test article or safe participation in this study
3. Any contraindications orhypersensitivities to any component of the LFG316 or CLG561 
solution
4. Any contraindications to IVT injections
5. Retinal disease, other than AMD, in either eye
Note: Benign conditions of the vitreous or peripheral retina are NOTexcluded. Significant 
peripapillary atrophyeither present at the time of Screening or whichis expected to merge
with the GA lesion during the course of the study,ISexcluded.
6. Any history of, or current evidence of, CNV in either eye, as determined by FA at 
screening 
7. Media opacity that interferes with fundus imaging in either eye, or is likely to require 
surgery during the study period
8. Any active ocular or periocular infection or active intraocular inflammation in either eye 
at screening or at baseline (e.g., infectious blepharitis, infectious conjunctivitis, keratitis, 
scleritis, endophthalmitis)
9. Any history of the following in either eye at screening:
herpes simplex keratitis
herpes zoster keratitis
infectious uveitis
10.Penetrating ocular surgery requiring cutting of ocular tissue (e.g., cataract surgery, PRK, 
LASIK, Epilasik, pterygium removal, etc.) or ocular trauma requiring medical or 
pharmacological treatment in the studyeye within 90 days of screening
Note: Ocular laser procedures are not excluded
11Macular atrophy in either eye due to anything other than AMD
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12.Concomitant treatment for AMD in either eye within 90 days of screening
Note: Concomitant use of vitamins/supplements is not excluded
13.Any periocular or IVT injections in either eye within 90 days of baseline
14.Any of the following abnormal vital signs at screening: temperature > 100.5° F (38° C); 
heartrate> 100 bpm; systolic blood pressure <90mmHg or > 160mmHg, diastolic blood 
pressure >95mmHg. 
Note: Out of range vital signs may be repeated once. If the values are still out of range the 
visit must be rescheduled. If out of range vitals are observed again and persistent at 
re-measurement, the subject must be disqualified from the study. Subjects may be 
rescreened when values have stabilized.
15.Uncontrolled ocular hypertension or glaucoma in the study eye (IOP >25mmHg despite 
current pharmacological or non-pharmacological treatment)
16.Participation in any interventional clinical trial within 12 weeks prior to screening
17.Any history of participation in interventional clinical trials involving gene therapy or 
extended release products, or any product with expected long term efficacy
5
Restrictions for study subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informedand reminded of the following restrictions:
In general, systemic medications  are allowed; however, corticosteroids (ophthalmic or 
systemic) should only be used if necessary. 
For both eyes, topical ophthalmic corticosteroids are allowed, however, for the study 
eye, no IVT ophthalmic agents are allowed
For the fellow eye, there is no restriction to the use of any topical or IVT ophthalmic 
agents, provided they are not investigational products
5.1
Contraception requirements
Please refer to the exclusion criteria (Section 4) for details of contraception requirements for 
the study.
5.2
Prohibited treatment
ELECTIVEintraocular surgeries are prohibited in both eyes.
Any IVT treatments, other than the study treatment,to the study eye are prohibited. If needed, 
the study ophthalmologist should administer the required IVT treatment (e.g. Lucentis for new 
onset choroidal neovascularization) to the study eye promptly. However, the study subject 
who receives the intervention MUST be discontinued from the study and undergo the follow 
up visit and end of study evaluation.
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6
Treatment
6.1
Study treatment
Details on the storage and management of investigational product, randomization and 
instructions for preparing and administering study treatmentare outlined in the MOP.
6.1.1
Investigational treatment
The investigational products CLG561 and LFG316 will be provided by the Sponsor and 
supplied to the Investigator. The Investigator will be responsible for the preparation of 
CLG561 injection and the co-administered dose of CLG561 and LFG316 injection.
Subjects assigned to sham injections are treated in the same manner as those assigned to the 
other two treatment arms, except instead of an IVT injection, the hub of an empty syringe 
(without a needle) is placed against the eye.
6.2
Treatment arms
Subjects are assigned to one of the following 3 treatment arms in a ratio of 1:1:1.
1. IVT CLG561 (10 mg/100 µL), administered every 28 days for total of 12 injections
2. IVT CLG561 5 mg + LFG316 5 mg co-injected in 100 µL total volume via a single 
injection, administered every 28 days for total of 12 injections
3. Sham injections, administered every 28 days for total of 12 sham injections
6.3
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted.
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6.4
Treatment assignment
Subject numbers are assigned by the EDC in ascending, sequential order to all subjects who 
sign informed consent at each clinical site. The Investigator will enter the subject number in 
the IRT and EDC as required.
A randomization scheme is used to ensure that treatment assignment is unbiased and 
concealed from subjects and masked site staff. Arandomization list is produced by or under 
the responsibility of the Sponsor using a validated system that automates the random 
assignment of treatment arms to randomization numbers in the specified ratio. The 
randomization scheme for subjects will be reviewed and approved by a member of the 
Sponsor randomization group.
6.5
Treatment masking
This is a single maskedstudy. Subjects, the CRC, and select investigational staff (technicians 
performing visual acuity and obtaining images) are masked to the identity of study treatments.
6.6
Emergency breaking of assigned treatment code
The Investigator will have access to the assigned treatment code throughout the study because 
the study design is single masked. No emergency breaking of assigned treatment code is 
necessary based on the single masked design.
6.7
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) aredetermined in all subjects 
treated with CLG561 or the combination of CLG561 and LFG316, as detailed inSection 8.5.
6.8
Recommended treatment of adverse events
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies eCRF.
6.9
Rescue medication
Use of rescue medication is not allowed. Any IVT treatments, other than the study treatment,
to the study eye are prohibited. If needed, the study ophthalmologist should administer the 
required IVT treatment to the study eye promptly. However, the study subject who receives 
the intervention will be discontinued from the study and undergo the follow up visit and end 
of study evaluation. The required IVT treatment must be recorded on the Concomitant 
medications/Significant non-drug therapies eCRF after start of study drug.
6.10
Concomitant treatment
All prescription medications, over-the-counter drugs and significant non-drug therapies 
administered or taken within the timeframe defined in the entry criteriaprior to the start of the 
study and during the study, must be recorded on the Concomitant medications/Significant 
non-drug therapies section of the eCRF.
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In general, systemic medications  are allowed; however, corticosteroids (ophthalmic or 
systemic) should only be used if necessary. 
For both eyes, topical ophthalmic corticosteroids are allowed, however, for the study 
eye, no IVT ophthalmic agents are allowed.
For the fellow eye, there is no restriction to the use of any topical or IVT ophthalmic 
agents, provided they are not investigational products 
Medication entries must be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
7
Discontinuation and study completion
7.1
Discontinuation of study treatment
Subjects may voluntarily discontinue study treatment for any reason at any time.
The Investigator must discontinue study treatment for a given subject if he/she believes that 
continuation would be detrimental to the subject’s well-being.
Study treatment mustbe discontinued under the following circumstances: 
Subject withdraws consent
Pregnancy
Any condition in the study eye requiring additional IVT treatment
Any condition requiring intraocular surgery in the study eye
Use of any ocular (in either eye) or systemic investigational treatments 
Use of prohibited treatment as per Section5.2
Any other protocol deviation that results in a significant risk to the subject’s safety
Subjects 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 (seeSection 7.3). If they fail to return for these assessments for unknown 
reasons, every effort  (e.g. telephone, e-mail, and letter) must be made to contact them as 
specified inSection 7.2.1.
7.2
Study completion and post-study treatment
Each subject is required to complete the study in its entirety. No further study treatment will 
be made available to a subject after they have completed the study in its entirety. 
Study completion is defined as:
When the last subject completes the EOS visit
and
Any repeat assessments or follow-up associated with the EOS are documented 
appropriately by the Investigator
or 
The date of an early study termination decision
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At a minimum, subjects must be contacted for safety evaluations during the 28days following 
the follow up visit. Documentation of attempts to contact the subject must be recorded in the 
source documentation.
The Investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include:
Enrollment in an extension study
Standard of care treatment as determined by the nature of their condition
The following are recommendations for initiating other treatment outside the study:
Referral to another medical professional suitable to provide follow-up medical care
Inform current medical provideron subject’s current medical status
7.2.1
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the Investigator should show "due diligence" by 
documenting inthe source documents steps taken to contact the subject (e.g. dates of 
telephone calls, registered letters, etc.). A subject is not formally considered lost to follow-up 
until his/her scheduled end of study visit would have occurred.
7.3
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Subject withdrawal of consent includes the following conditions:
Does not want to participate in the study
Does not want any further visits or assessments
Does not want any further study related contact
Does not allow analysis of already obtained biologic material
If a subject withdraws consent, the  Investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. Allbiological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the subject 
are not allowed unless safety findings require communicating or follow-up.
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7.4
Study stopping rules
Under any of the following conditions, the current study/arm(s) are placed on temporary hold 
and potentially halted, pending full review of the clinical data by the Investigator and Sponsor:
Two or more incidents of the same SAE that, in the opinion of the Investigator, are 
related to the study drug(s) and not the injection procedure
The principal Investigator (or his/her designee) and the sponsor consider that the 
number and/or severity of AEs justify discontinuation of the study
The Sponsor requests it
7.5
Early study termination
The study may be terminated at any time for any reason by Sponsor. Should this be necessary, 
subjects must be seen as soon as possible and treated as a prematurely withdrawn subject. The 
Investigator may be informed of additional procedures as requested by the Sponsor in order to 
ensure that adequate consideration is given to the protection of the subject’s interests.
TheInvestigator is responsible for informing IRBs/IECs of the early termination of the trial. 
In the case of representation by a central IRB, the Sponsor may be delegated this 
responsibility.
8
Procedures and assessments
Subjects must be seen for all visits on the designated day, with the assessments performed as 
per schedule, within the allowed “visit/assessment window”, and as specified in the MOP. 
A single rescreening is permitted only for patients who failed screening under the original 
protocol but who would have qualified under the amendment 1 revised selection criteria. In 
addition to the criteria that were changed, the rescreened patients must fulfill the unchanged 
selection criteria at both screenings to be eligible. Since the inclusion criterion related to 
lesion size is now only relevant to a single eye (studyeye), for lesion size, the rescreening is 
limited to eyes which qualified in the original screening. For example if the left eye qualified 
in the original screening, only the left eye can be rescreened as the study eye. If both eyes had 
qualified previously on the basis of the lesion size but the eyes had failed on the basis of the 
visual acuity both eyes are candidates for rescreening.
The subject number previously used will be retained in the database. A new subject number is 
not required. The original informed consent date is retained in the database. The new 
informed  consent date is captured in the source. A new screening date with data for the 
assessments is captured in the database.
All data obtained from  these assessments must be supported in the subject’s source 
documentation. Source documentation must be available for all data collected during the 
study. IF it becomes necessary to repeat an evaluation, THEN the results of the repeat 
evaluation must be recorded in the source documents and the valid measurements and 
evaluation must be recorded on the eCRF.
All screening, baseline and pre-injection assessments must be completed prior to drug 
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Unscheduled Visits are allowed at the Investigator’s discretion. During an unscheduled visit, 
the Investigator may perform any of theocular and non-ocularprotocol assessments as 
necessary to treat the subject(imaging is not requiredbut may be obtained as needed by the 
investigator).Assessments performed during an unscheduled visit will be documented in the 
EDC.The Investigator may provide comments in the EDC to clarify unscheduled visit data as 
necessary. 
For additional details of specific study procedures, please reference the MOP.
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CCLG561X2201A
Screen
Treatment Phase
FU
EOS10
Visit Number
N/A
V1
V2
V3
V4 V5 V6 V7 V8
V9 V10 V11 V12 V13 V14 V15 V16 V17
V18
(V777)
Day
-30 to -1 BL / D1
D2
D8
D15D29D30D57D85D113D141D169D197D225D253D281D309D337
D421
All ocular examinations may be performed at the physician
's discretion
2OU: both eyes
3SE: study eye
4For all visits requiring an IVT injection, IOP MUST be measured before and after the injection in the study eye
5For all visitsrequiring an IVT injection  dilated ophthalmoscopy MUST be performed before the injection and immediately after the injectionin the study eye
8To be done at select sites only, see MOP for additional details
9 Assessment at screening is for source documentation purposes only
10Unscheduled visit assessments as needed and as determined by the investigator, imaging not required
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Table 8-3
Post-injection exams at injection visits
Visit
BL / V1
All injection visits
Day
D1
Injection
Inj 1
Time point
Pre-Injection
Immediately Post-Inj
30 minutes Post-Inj
60 minutes Post-Inj, if required
Q 30 minute interval, if required
Pre-Injection
Immediately Post-Inj
30 minutes Post-Inj
60 minutes Post-Inj, if required
Q 30 minute interval, if required
Gross visual acuity
SE
SE
IOP
OU
SE 
SE 
SE1
SE2
SE 
SE 
SE 
SE1
SE2
Dilated Fundus
OU
SE
OU
SE
Anterior Chamber Paracentesis, 
if required 
3
SE
SE
1If the pressure is elevated >10 mmHg above pre-injection or above 30 mmHg when measured at 30 minutes 
post-injection it must be measured again at 60 minutes post-injection.
2If IOP still elevated at 60 min post-injection, repeat at 30 minute intervals until pressure is < 10 mmHg above 
pre-injection pressure or < 30 mmHg.
3Perform anterior chamber paracentesis if no retinal perfusion 2 or more minutes after injection.
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8.1
Informed consent procedures
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents. 
Eligible subjects are included in the study after providing written (witnessed, whererequired 
by law or regulation) IRB/IEC-approved informed consent. Ifincapable of doing so, in cases 
where the subject’s representative gives consent, the subject will be informed about the study 
to the extent possible given his/her understanding. If the subject is capable of doing so, he/she 
should indicate assent by personally signing and dating the written informed  consent 
document or a separate assent form. The date of signing of informed consent (and withdrawal, 
iflater withdrawn) must be documented in the eCRF.
The Sponsor will provide the Investigators with a proposed informed consent form that 
complies with the ICH GCP guideline  and regulatory requirements. Any changes to the 
proposed informed consent form suggested by the Investigator must be agreed to by Sponsor 
before submission to the IRB/IEC.
A copy of the approved version of all consent forms must be provided to the Sponsor monitor 
after IRB/IEC approval.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data is collected on all subjects as stated in 
the MOP.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. When possible, diagnoses (not symptoms) must be recorded. Medical 
history/current medical conditions are confirmed at Visit 1 prior to drug administration.
Investigators have the discretion to record abnormal test findings that occurred prior to the 
informed consent signature on the medical history eCRF.
Ocular and AMD History
Past or current ocular history and history of AMD diagnosis, history of GA diagnosis, 
progression, and treatments must be captured on the appropriate eCRF. Ocular function 
questions must be reviewed as stated in the CLG561-2201 MOP.
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Family History
First degree family history of ocular, renal and cardiovascular diseases must be gathered and 
captured on the appropriate eCRF as part of the medical history assessment.
Dietary History
Subjects must be asked to estimate their weekly consumption of fish (servings per week) and 
daily consumption of fruits and vegetables (servings per day). Subjects must be asked whether 
they use an AREDS-type supplement oromega-3 fatty acid supplement.
Alcohol and Drug Dependence History
All subjects must be asked to provide a verbal history of alcohol and drug dependence (e.g., 
alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, etc.). 
The Investigator must use good clinical judgment based on the subject’s verbal history in 
regard to the inclusion or exclusion of the subject.
Smoking History
Subjects must be asked to provide smoking history induring screening.
Hepatitis and HIV History
All subjects are screened for history of Hepatitis B, HepatitisC, and HIV. Screening will be 
based on a verbal history and confirmed by central lab analysis. Results are available as 
source data only. In the event of a positive case, the subject must be informed of the result. 
The Investigator must instruct the subject to seek appropriate medical care and provide 
physician referrals as necessary.
8.3
Efficacy / pharmacodynamics
Pharmacodynamic assessments are specified below. Assessments are performed and samples 
and images are collected at the time point(s) defined in the assessment schedule.
8.3.1
Pharmacodynamic sample collection
Concentrations of total C5 concentrations of total properdin, and 
 
 All samples are given a unique sample number as 
indicated in the log that is included in the MOP. Further details on sample collection, 
numbering, processing and shipment can be found in the MOP.
8.3.2
Pharmacodynamic analytical methods
Determination of the concentration of total properdin and total C5 in serum is performed 
using either an immunoassay or Liquid Chromatography  –Tandem Mass Spectrometry 
(LC/MS/MS) method. A detailed description of the methods used to  quantify the 
concentration of total properdin and total C5 is included in the bioanalytical raw data of the 
study and in the bioanalytical data report. The LLOQ is documented in the bioanalytical data 
reports.
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8.3.3
Ocular pharmacodynamic assessments
The methods for assessment and recording  are specified in the IAG for the sites and in the 
IRC and Reviewer Training Manual for the CRC.
Certification of the equipment and examiners at each investigative site will occur prior to the 
evaluation of study subjects.The methods for assessment and recording are specified in the 
IAG for the sites and in the IRC and Reviewer Training Manual for the CRC.
8.3.3.2 Fluorescein angiography (FA)
FA is performed using a standardized technique. FA is performed for each subject according 
to the assessment schedule. The methods for assessment and recording  are specified in the 
IAG for the sites and in the IRC and Reviewer Training Manual for the CRC.
Certification of the equipment and examiners at each investigative site will occur prior to 
evaluation of study subjects.
8.3.3.3 Fundus autofluorescence (FAF)
FAF is performed on each  subject according to the assessment schedule. The methods for 
assessment and recording are specified in the IAG for the sites and in the IRC and Reviewer 
Training Manual for the CRC.
Certification of the equipment and examiners at each investigative site will occur prior to 
evaluation of study subjects.
8.3.3.4 Color fundus photography (CFP)
CFP will be performed on each subject according to the assessment schedule. The methods 
for assessment and recording  are specified in the IAG for the sites and in the IRC and 
Reviewer Training Manual for the CRC.
Certification of the equipment and examiners at each investigative site will occur prior to 
evaluation of study subjects.Color fundus photography is undertaken for assessment of safety 
if needed. The sponsor may request reading of the color fundus photos if needed or may not 
assess these if not needed.
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8.4
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the MOP, with the assessment schedule detailing when each assessment is performed.
8.4.1
Vital signs and body measurements
Vital signs measured include:
Body temperature
BP
Pulse Rate
Body measurements include:
Height
Body weight
BMI will be calculated (Body weight (kg) / [Height (m)]
2)
8.4.2
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Sponsor personnel. The results must be 
evaluated for criteria defining an AE and reported 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, Sponsor personnel must be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count are measured.
Clinical chemistry/blood chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total  bilirubin, LDH, GGT, AST, ALT, aPTT, PT/INR, CK, glucose, total 
cholesterol, triglycerides. If the total bilirubin concentration is increased above 1.5 times the 
upper limit of normal, direct and indirect reacting bilirubin is differentiated.
Urinalysis
Urine test by dipstick: leucocytes, nitrite, pH, protein, glucose, ketones, urobilinogen, 
bilirubin, blood/ hemoglobin.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample must 
be sent for microscopic analysis of WBC, RBC and casts.
8.4.3
Post-injection safety assessments
Post-injection safety assessments are described in Table8-3Post-Injection Exams at Injection 
visits. Within 0-5 minutes after an IVT injection, perfusion of the central retinal artery must 
be verified by indirect ophthalmoscopy; in case of non-perfusion  treat with anterior chamber 
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paracentesis 2 or more minutes after injection. Normalization of intraocular pressure must be 
verified within 30 minutes of the injection. Intraocular pressure must be re-measured again at 
60minutes post injection if the pressure is elevated > 10mmHg above the pre-dose valueor if 
the pressure is above 30mmHg.
8.4.4
Pregnancy
Women of childbearing potential are excluded from participation in this study.
8.5
Other assessments
8.5.1
Immunogenicity
IG samples will be collected at the time points defined in the assessment schedule. All 
samples will be given a unique sample number as indicated in the log that is included in the 
MOP. Further details on sample collection, numbering, processing and shipment can be found 
in the MOP. 
Validated immunoassays are used for the detection of anti-CLG561 and anti-LFG316 
antibodies. 
 
8.5.2 
Pharmacokinetics
PK samples must be collected at the time points defined in the assessment schedule.
All samples are given a unique sample number as indicated in the log that is included in the 
MOP. Further details on sample collection, numbering, processing and shipment can be found 
in the MOP. Total CLG561 and total LFG316 is determined by avalidated immunoassay 
method. A detailed description of the methods used to quantify the concentration of total 
CLG561 and total LFG316 will be included in the bioanalytical raw data of the study and in 
the bioanalytical data report. The LLOQ will be documented in the bioanalytical data reports.
Samples from the sham group is not analyzed fortotal CLG561 or total LFG316. 
Concentrations below the LLOQ is reported as “zero” and missing data is labeled as such in 
the Bioanalytical Data Report.
8.5.3
Drug administration
IVT or Sham Injections will be administered as described in the assessment schedule and in 
the MOP.
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8.5.4
Ocular examination
In addition to ocular efficacy endpoint assessments, the following must be conducted as part 
of the ocular examination: 
Best Corrected Visual Acuity
Low Luminance Visual Acuity
Intraocular Pressure
Slit-lamp Biomicroscopy
Dilated Ophthalmoscopy (Dilated Fundus Exam)
Immediately post-injection, gross visual acuity must be performed.
8.5.8
General comments
The Investigator may record general comments as deemed necessary in the source and eCRF 
to document important and scientifically notable details throughout the trial.
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9
Safety monitoring
9.1
Adverse events -general information
An AE is any untoward medical occurrencein a subject who is administered a study treatment 
regardless of whether or not the event has a causal relationship with the treatment. An AE, 
therefore, can be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the study treatment, whether or not 
related to the treatment. In clinical studies, an AE can include an untoward medical 
occurrence occurring at any time, including run-in or washout  periods, even if no study 
treatment has been administered. The determination of clinical relevance is based upon the 
medical judgment of the Investigator.
9.2
Monitoring for adverse events
At each visit, after the subject has had the opportunity to spontaneously mention any problems, 
the Investigatorshould inquire about AEs by asking the standard questions:
“Have you had any health problems since your last study visit?”
“Have there been any changes in the medicines you take since your last study visit?”
AEs must be reported for any clinically relevant change in concomitant medication(s)that is 
the result of an untoward (unfavorable and unintended) change in a subject
's medical health.
Changes in any protocol-specific parameters and questionnaires (if applicable) evaluated 
during the study are to be reviewed by the Investigator. Any untoward (unfavorable and 
unintended) change in a protocol-specific parameter or questionnaire response that is 
clinically relevant is to be reported as an AE. These clinically relevant changes will be 
reported regardless of causality.
9.3
Procedures for recording and reporting AEs and SAEs
Subsequent to signing an informed consent form, all untoward medical occurrences that occur 
during the course of the study must be documented on an Adverse Event Form (AEF). A 
separate AEF must be filled out for each event. When possible, signs and symptoms 
indicating a common underlying pathology must be documented as one comprehensive event. 
For each recorded event, the AE documentation must include the onset date, outcome, 
resolution date (if event is resolved), intensity (e.g., severity), any action with study treatment 
taken as a result of the event, and an assessment of the AE’s relationship to the study 
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Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects that are already known about the investigational drug 
can be found in the IB or Core Data Sheet (for marketed drugs) or will be communicated 
between IB updates in the form of Investigator Notifications. This information will be 
includedin the subject informed  consent and must be discussed with the subject during the 
study as needed.
The Investigator should also instruct each subject to report any new AE (beyond the protocol 
observation period) that the subject, or the subject’s personalphysician, believes might 
reasonably be related to study treatment. This information must be recorded in the 
Investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Sponsor.
Non-serious Adverse Events
A non-serious AE is defined as any untoward change in a subject
's medical health that does 
not meet serious criteria noted below (e.g., is not life-threatening, does not require 
hospitalization, does not prolong a current hospitalization, is not disabling, etc.). All AEs must 
be reported regardless of  whether  or not they are related to the study treatment. For non-
serious AEs, an AEF containing all available information will be collected on a routine basis 
according to instructions provided by the study sponsor.
Serious Adverse Events
A SAE is defined as any adverse experience that meets any of the following criteria:
Results in death
Is life-threatening
Note: Life-threatening means that the subject was at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction which hypothetically might 
have caused death had itoccurred in a more severe form
Requires hospitalization or prolongation of existing hospitalization
Note: In general, hospitalization signifies that the individualremained at the hospital 
or emergency ward for observation and/or treatment (usually involving an overnight 
stay) that would not have been appropriate in the physician
's office or an out-subject 
setting. Complications that occur during hospitalization areAEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalization” occurred, the event must be considered 
serious.
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Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability toconduct normal life functions
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption
Is a congenital anomaly/birth defect
Is an important medical event. An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered an 
SAE when, based upon appropriate medical judgment, it may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed 
in the definitions for SAEs. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in a subject’s hospitalization, or the 
development of drug dependency or drug abuse
All available information on a SAE(s) must be forwarded to the study Sponsor immediately 
(i.e., within 24 hours of the Investigator’s or site’s knowledge of the event) as follows:
In studies utilizing EDC (electronic data capture), all available information for the 
SAEmust be entered immediately into the EDC system. Note: Should the Electronic 
Data Capture (EDC) system become non-operational, the site must complete the 
appropriate paper SAE Form. The completed form is faxed to the study Sponsor at 1-
817-302-1927 within 24 hours of the Investigator’s or site’s awareness; however, the 
reported information must be entered into the EDC system once it becomes 
operational.
Sponsor representatives and their contact information are provided in the MOP that 
accompanies this protocol.
Additional information for any applicable event is tobe reported as soon as it becomes 
available.
In addition to the reporting of SAEs to the study sponsor, the SAE must be reported to the 
IRB / IEC according to their requirements.
If the SAE was due to a hospitalization of the subject, a copy of the discharge summary is to 
be forwarded to the study Sponsor as soon as it becomes available. In addition, a letter from 
the Investigator that summarizes the events related to the case as well as results of any 
relevantlaboratory tests also may be requested. Further, depending upon the nature of the 
SAE, the Sponsor may request copies of applicable portions of the subject’s medical records.
An assessment of seriousness will also be performed for all AEs by a study Sponsor physician 
utilizing the same criteria. If an AE reported for an Investigator’s subject is upgraded to a 
SAE by a study Sponsor physician, the Investigator will receive a notification by the study 
Sponsor.
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Adverse Events of Special Interest
An AE  of special interest is one of scientific and medical concern specific to the sponsor’s 
product, route of administration or program where ongoing monitoring and rapid 
communication by the Investigator to the sponsor may be appropriate. These AEs may be 
serious or non-serious. Applicable  AEs may require further investigation in order to 
characterize and understand, and depending upon the nature of the event,  rapid 
communication by the trial sponsor to other parties may also be required. These AEs of 
special interest must be reported using the same mechanism (EDC or fax) and timeframe (i.e., 
within 24 hours of the Investigator’s or site’s knowledge of the event) as described previously 
for SAEs.
The AEs of special interest include the following:
Endophthalmitis
Grade ≥ 3 aqueous flare and/or Grade 4 aqueous cells(see MOP for grading scale)
Grade 2 aqueous flare and/or Grade 2 or 3 aqueous cells that fail to decrease to 1 or 
less within 30 days of the onset of the event (see MOP for grading scale)
Grade ≥ 2vitreous hazeand/or Grade ≥3vitreous cells (see MOP for grading scale)
≥ 30 letter decrease in BCVA compared with Baseline visual acuity
Sustained (> 15 minutes) loss of light perception due to elevated IOP
IOP > 30 mmHg at/past 60 minutes post injection
New retinal tear or detachment
New vitreous hemorrhage > 2+ severity that does not resolve within 30 days of the 
onset of the event (see MOP for grading scale)
If an ESI occurs in a study subject, a decision will be made by the Sponsor concerning further 
exposure to study treatment. The study subject will be followed for resolution of the ESI and a 
decision will be made by the Sponsor concerning further participation in the study.
9.4
Intensity and causality assessments
For every AE, the Investigator must assess the intensity (severity) and causality (relationship 
to study treatment). Specifically, events must be classified as mild, moderate, or severe. The 
assessment of causality will be based upon the categories of related and not related. These 
classifications must be based on the following definitions:
Intensity(Severity)
Mild
An event is mild if the subject is aware of, but can easily tolerate the sign or 
symptom.
Moderate 
An event is moderate if the sign or symptom results in discomfort significant 
enough to cause interference with the subject’s usual activities.
Severe
An  event is severe if the sign or symptom is incapacitating and results in the 
subject’s inability to work or engage in their usual activities.
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Causality
Related 
AEs classified as related may be either definitely related or possibly related 
where a direct cause and effect relationship between the study treatment and 
the event has not been demonstrated but there is a reasonable possibility that 
the event was caused by the study treatment.
Not Related AEs classified as not related may either be definitely unrelated or simply 
unlikely to be related (i.e., there are other more likely causes for the AE).
An assessment of causality will also be performed by a study sponsor physician utilizing the 
same definitions. For a serious AE reported by an Investigator as not related that upon review 
of the available data by the study sponsor physician is assessed (upgraded) to be related, the 
Investigator will receive a notification.
9.5
Unmasking of study treatment
Not applicable; this study is single masked (subject masked).
9.6
Follow-up of subjects with adverse events
The Investigator is responsible for adequate and safe medical care of subjects during the trial 
and for ensuring that appropriate medical care and relevant follow-up procedures are 
maintained  after the trial. Any additional data from  these follow-up procedures must be 
documented and available to the Sponsor who will determine when the data need to be 
documented on the case report forms.
Pregnancy reporting
Women of childbearing  potential are defined as all women physiologically capable of 
becoming pregnant. Women of childbearing potential are excluded from this study.
Pregnancy is not reportable as an AE; however, complications may be reportable and will be 
decided on a case by case basis. A Sponsor specific pregnancy form is utilized to capture all 
pregnancy-related information until birth of the child or termination of pregnancy.
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10
Data review and database management
10.1
Site monitoring
Before study initiation, the Sponsor representative will review the protocol and other study 
documentation with the Investigators and their staff. Training may occur at a site initiation 
visit or at an Investigator’s meeting.
During  
the study Sponsor employs several methods of ensuring protocol compliance, GCP 
compliance, and the quality and integrity of the sites’ data. The Clinical Site Manager (CSM) 
will visit the site to review:
Completeness of subject records
Accuracy of entries on the eCRFs
Adherence to the protocol and to Good Clinical Practice
Progress of enrollment
Ensure that study drug is being stored, dispensed, and accounted for according to 
specifications
Key study personnel must be available to assist the CSM during the study monitoring visits.
Continuous remote monitoring of each site’s data may be performed bythe Sponsor. A central 
analytics team may analyze data, identify risks, identify trends for site operational parameters, 
and provide reports to Sponsor Clinical Teams to assist with trial oversight.
The nature and location of all source documents will be identified to ensure that original data 
required to complete the eCRFs exist and are accessible for verification by the site manager. If 
electronic records are maintained, the method of verification must be determined in advance 
of starting the study. The Investigator must maintain source documents for each subject in the 
study. Source documents consist of case and visit notes (e.g. hospital or clinic medical records) 
that may include demographic and medical information, laboratory data, and the results of any 
other tests or assessments. All information on eCRFs must be traceable to the source 
documents. It is required that all entries in the source documents are identified by the author. 
The Investigator must also keep the original informed consent form signed by the subject. The 
Investigator must provide a signed copy is to the subject.
The Investigator must give the clinical site manager access to all relevant source documents to 
confirm their consistency with the eCRF entries. Sponsor monitoring standardsrequire full 
verification for the presence of informed consent, adherence to the eligibility criteria, 
documentation of SAEs, and the recording of data that is used for all primary and safety 
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 subjects, beyond subject number and demographic 
information, is disclosed.
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10.2
Data collection
The EDC uses fully validated software that conforms to 21CFRPart11  requirements. 
Designated Investigator site staff are required to enter the data specified by the protocol into 
the  eCRFs. Designated Investigator site staff must not be given access  
to the EDC system 
until they have been trained.
TheInvestigator must certify that the data entered into the eCRFs are complete and accurate. 
After database lock, the Investigator will receive electronic files of the subject data for 
archiving at the investigational site.
All data captured for this study will have an external originating source (either written or 
electronic) with the eCRF not considered as source.
All data must be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Sponsor staff will review the data entered into the eCRFs by investigational staff for 
completeness and accuracy. Sponsor staff may instruct the site  personnel to make required 
corrections or additions. Queries are  sent to the investigational site using an electronic data 
query. Designated Investigator site staff are required to respond to the query and confirm or 
correct the data.
Concomitant medications entered into the database are coded using the WHO Drug Reference 
List, which employs the Anatomical Therapeutic Chemical classification system. Medical 
history/current medical conditions and AEs will be coded using the MedDRA terminology.
Laboratory samples are processed centrally or at an external laboratory. The results are sent 
electronically to the Sponsor.
The Interactive Response Technology (IRT) is used to:
Store randomization codes
Store data in reference to dispensing of study products to the subject
The system is supplied by a vendor that manages the IRT database. The IRT database is sent 
electronically to the Sponsor.
Theoccurrence of any protocol deviations must be determined  prior to database lock. Once 
the database is declared to be complete and accurate, it is locked and the data becomes 
available for data analysis. Any changes to the database after that database lock can only be 
made by joint written agreement between the Global Head of Clinical Information Sciences 
and the Clinical Franchise Head.
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10.3
Data monitoring committee
Not required.
10.4
Adjudication committee
Not required.
10.5
Safety committee
The study team, consisting of Investigators and a Sponsor internal clinical team, MUST 
provide rigorous AE monitoring oversight of each individual subject following their first dose, 
and prior to their second and third doses. Ifthe number or severity of drug-related AEs are of 
concern, the safety committee may put a treatment arm  or the whole study on hold until 
further review of the available safety data.
10.6
Regulatory documentation and records retention
The Investigator is requiredto maintain updated and complete regulatory documentation. The 
Investigator’s files are reviewed as part of ongoing study monitoring. Financial information is 
not subject to regulatory inspection and MUST be kept separately.
Additionally, the InvestigatorMUST keep study records and source documents until the 
Sponsor provides written approval for their destruction. IF the Investigator retires, relocates, 
or withdraws from responsibility of the study records, THEN study record custody MUST be 
transferred tothe Sponsor or a designee.
11
Data analysis
11.1
Analysis sets
The final subject evaluability will be determined prior to locking the database.
The full analysis set will be used for assessment of efficacy and the data from both the study 
eye and fellow eye (fellow eye as reference for the within subject comparison) will be used 
for analysis. The full analysis set will include all subjects who receive any study treatment and 
have at least one follow-up visit with an assessment of the GA lesion size. The full analysis 
set will use the treatment as randomized.
The per-protocol (PP) set will be used for assessment of efficacy and the data from both the 
study eye and fellow eye will be used for analysis.  The PP set will be comprised of all full 
analysis set subjects who have no critical protocol deviations, and have a valid assessment of 
the primary efficacy endpoint (change in geographic atrophy lesion size from baseline to 
Day337 as assessed by FAF). Key per protocol criteria are compliance regarding the monthly 
injection schedule up to Day 337 (not missing greater than 1 in any 6months period or not 
missing 2consecutive doses) and in addition to baseline lesion size assessment the 
corresponding assessment on Day 337 and/or Day 253. Protocol deviations will be identified 
and classified before database lock. The PP analysis set will use the treatment as randomized. 
The PP set is the primary efficacy analysis set.
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The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with available PK data and no protocol 
deviations with relevant impact on PK data.
The PD analysis set will include all subjects with available PD data and no protocol 
deviations with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
Summary statistics will be provided for demographic and baseline characteristics by
 treatment 
group and overall. Baseline characteristics will be presented for both the study and fellow eye. 
Number and percentage will be presented for categorical variables and descriptive statistics, 
including mean, standard deviation, quartiles, minimum and maximum will be presented for 
continuous variables.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be summarized by treatment group. Ocular parameters 
will be presented separately for study and fellow eye.
11.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration, concomitant therapies, and compliance will be 
summarized by treatment group with separate presentation for study and fellow eye.
11.4
Analysis of the primary variable(s)
The primary objective aim of this study is to evaluate, in the study eye, the efficacy of 12 
(every 28 days) IVT injections of CLG561 as a monotherapy and in combination with 
LFG316 as compared to sham on the growth of GA lesion as assessed by FAF.
11.4.1
Variable(s)
The primary endpoint of this study is the change in geographic atrophy lesion size [mm
2] in 
the study eye between Day 337 and Baseline as measured by FAF.
11.4.2
Statistical model, hypothesis, and method of analysis
The primary efficacy hypotheses are that the change in geographic atrophy lesion size in the 
study eye under CLG561 as a monotherapy and/or in combination with LFG316 is lower than 
the sham arm.  The null and alternative hypotheses are:
H01: µ
CLG- µ
Sham≥ 0 mm2vsHA1: µ
CLG- µ
Sham< 0 mm2
H02: µ
CLG+LFG- µ
Sham≥ 0 mm2vs HA2: µ
CLG+LFG- µ
Sham< 0 mm2
µCLG,µCLF+LFG andµSham beingthe corresponding unknown true treatment specific mean 
changes from Baseline to Day 337.
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The comparison of the two active arms will be done descriptively.
The lesion size change from baseline to Day 337 will be analyzed by an analysis of variance 
model including, but  not limited to, the class variables representing categories of baseline 
lesion size (edge length) and categories oflesion location.
The primary efficacy analysis set will be the PP set.
11.4.3
Handling of missing values/censoring/discontinuations
In the primary efficacy analysis which is based on the PP set, a subject will have in the study a 
baseline lesion size assessment and a corresponding assessment on Day 337 and/or Day253. 
For subjects with missing values of lesion size in the study eye on Day 337, the missing value 
will be imputed based on linear regression/extrapolation (which at minimum will be based on 
the Day253assessment).
11.4.4
Supportive analyses
The primary efficacy analysis will be performed using the PP set with treatment as 
randomized. Sensitivity analysis regarding major protocol deviations will be performed on the 
primary efficacy endpoint sing the full analysis set as randomized. In case of deviations from 
the treatment allocation as randomized the full analysis set will also be analyzed on an as ‘as 
treated’ basis.
An additional sensitivity analysis will be performed assuming linear lesion growth in the 
study for all treatment for the one year observation period using a Mixed-Effect Model 
Repeated Measure (MMRM) model with random slops and including class-variables as 
specified for the primary analysis.
11.4.5
Subgroup analyses
The following subgroups will be analyzed for the primary efficacy endpoint using the same 
approach:
Age category (< 75 years and ≥ 75 years)
Gender (male and female)
Baseline BCVA categories (<60 letters, 60 –73 letters, and> 73 letters)
Baseline lesion size (edge-length)
Baseline lesion location
Baseline lesion type: uni-focal vs multi-focal

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11.5
Analysis of secondary and exploratory variables
11.5.1
Efficacy endpoints
Analyses will be performed for both the PP set and the FAS.
Potential treatment effects will primarily be assessed based on the difference in change from 
baseline in the study eye between active treatment and sham treatment. In addition, the
corresponding difference between study and fellow eye will be explored within the active 
treatment arms. 
At time points assessed, each efficacy endpoint will be presented graphically and by 
descriptive statistics provided for observed absolute values and changes from baseline. 
Changes from baseline will be compared between treatment arms using ANOVA models 
and/or stratified/unstratified Cochran-Mantel-Haenszel Tests. 
 
 
For treatment differences and differences between study and fellow eye 80% confidence 
intervals will be provided. 
The following secondary endpoints will be evaluated:
Change in geographic atrophy lesion size from baseline to Days 85, 169, 253, 337 and 
421 as measured by fundus auto-fluorescence
Change in BCVA, low luminance visual acuity and low luminance visual acuity 
deficit from baseline by visit up to Day 337 as measured by ETDRS in the overall 
population and in subsets of patients with baseline visual acuity < 73 letters
Subject status regarding ≥15 letters, ≥10 letters, and ≥5 letters change from baselinein 
BCVA by visit up to Day 337
Average change in BCVA/low luminance visual acuity/low luminance visual acuity 
deficit from baseline to the period Day 281 to Day 337
For the changes in geographic atrophy lesion size from baseline between either of the active 
arms and sham as measured by FAF, the same analysis model used for the primary hypothesis 
(Section 11.4.2) will be used.
11.5.2
Pharmacodynamic endpoints
Total properdin, total C5 concentrations 
 
(%change from baseline) data will be listed by treatment, subject, and visit/sampling time 
point. Descriptive summary statistics will be provided by treatment and visit/sampling time 
point.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. 
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11.5.3
Immunogenicity endpoints
A positive or negative result will be generated from the immunogenicity assay indicating the 
presence or lack of presence of anti-CLG561 or anti-LFG316 antibodies. Results from 
immunogenicity assay will be listed by treatment group, subjects and visit/time. Summary 
statistics (n, % of subjects with positive/negative results) will be provided by treatment group 
and visit/time.
11.5.4
Pharmacokinetic endpoints
Total CLG561 and total LFG316 serum concentration data will be listed by treatment, subject, 
and visit/sampling time point. Descriptive summary statistics will be provided by treatment 
and visit/sampling time point, including the frequency (n, %) of concentrations below the 
LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum.
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11.5.6
Safety
Adverse events
All information obtained on AEs will be displayed by treatment and subject.
The number and percentage of subjects with AEs will be tabulated by body system and 
preferred term with a breakdown by treatment. A subject with multiple AEs within a body 
system is only counted once towards the total of this body system.
Vital signs
All vital signs data will be listed by treatment, subject, and visit and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject and visit and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit.
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Ocular assessments
Ocular assessments for safety analyses will include slit lamp examination, dilated fundus 
examination, best corrected visual acuity and intraocular pressure. All data will be listed by 
treatment group and subjects. Summary statistics will be provided by treatment group and 
visit.
For each continuous variable,  observed values will be presented descriptively (N, mean, 
standard deviation, median, minimum and maximum) at each visit by treatment group. 
Change from Screening (Day -30 to Day -1) will be summarized similarly. Also, categorical 
summaries depending on the parameter will be presented. These reports will be supported by 
individual subject listings. Details will be described in the statistical analysis plan.
11.5.7
Other assessments
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11.6
Sample size calculation
A sample size of 30 PP evaluable subjects per treatment arm will allow identification of a 
treatment difference of 0.67 mm
2in lesion size change from baseline to Day 337 (representing 
a 33% reduction in lesion growth rate,  assuming an average natural disease progression of 
2.0mm2per year) at a one-sided alpha level of 0.1 with a power of 80% assuming a standard 
deviation of 1.2 mm2.
In anticipation of a drop-out /protocol deviation rate of 20%, a total sample size of 
~114randomized subjects (~38 subjects /arm) is planned for the current study to ensure 
sufficient study completers for the above described PP analysis. Depending on ongoing 
monitoring of the drop-out / protocol deviation rate the need for additional recruitment will be 
assessed to ensure 90 PP evaluable subjects are available for the Day337 analysis.
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study will be conducted in accordance with the ethical principles of the 
Declaration of Helsinki, and in compliance with the International Conference on 
Harmonization (ICH) E6 Good Clinical Practice (GCP) Consolidated Guideline and other 
regulations as applicable. 
12.2
Responsibilities of the Investigator and IRB/IEC
The Investigator and all clinical study staff MUST conduct the clinical study in compliance 
with the protocol. The Investigator must make sure that all personnel involved in the conduct 
of the study are qualified to perform their assigned responsibilities through relevant education, 
training, and experience. 
Investigator is required to:
Sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance all of the instructions and procedures found in this protocol 
Give access to all relevant data and records to the Sponsor including:
Monitors
Auditors
Sponsor Quality Assurance representatives
Designated agents of Sponsor
IRBs/IECs
Regulatory authorities
NOTE: If an inspection of the clinical site is requested by a regulatory authority, 
the Investigator MUST inform the Sponsor immediately.
Obtain approval/favorable opinion from the IRB/IEC and provide documentation of 
the IEC/IRB approval to the Sponsor. The approval must be dated and must include:
The clinical trial protocol
Written informed consent form
Consent form updates, if applicable
Subject recruitment procedures (e.g. advertisements)
Written information to be provided to subjects
Subject compensation programs
Provide the IEC/IRB with a copy of the IB, any periodic safety updates, and all other 
information as required by local regulation and/or the IEC/IRB. 
Notify the IEC/IRB that the study is complete or if the study is terminated prematurely
Report to the IEC/IRB on the progress of the study at intervals stipulated by the 
IEC/IRB
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Voluntary informed consent MUST be obtained from every subject (and/or legal 
representative, as applicable) prior to any study-related procedures. 
The Investigator MUST:
Have a defined process for obtaining consent
Explain the clinical study to each potential subject 
Provide the subject with a copy of the consent form written in a language the subject 
understands
Keep the original, signed copy of the consent and must providea duplicate copy to 
each subject
The Subject MUST:
Indicate voluntary consent by signing and dating the approved informed consent form
Be provided an opportunity to ask questions of the Investigator, and if required by 
local regulation, other qualified personnel
The consent document MUST meet all applicable local laws and MUST provide subjects with 
information regarding:
Purpose of the study
Procedures of the study
Requirements of the study
Restrictions of the study
Known risks and potential benefits
Available compensation
Established provisions to maintain confidentiality of protected health information
Explain the voluntary nature of participation in the study 
Provided with contact information for questions or concerns during the study
Explain that the records may be accessed by appropriate authorities and Sponsor-
designated personnel
12.3
Publication of study protocol and results
The Sponsor assures that the key design elements of this protocol is posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. For multi-center trials, 
a Coordinating Investigator will be selected by the Sponsor around the time of Last Subject 
Last Visit to be a reviewer and signatory for the clinical study report.
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13
Protocol adherence
This protocol defines the study objectives, the study procedures and the datato be collected 
on study participants. IF additional assessments are required to ensure safety of subjects, Then
the Investigator must administer the appropriate care as deemed necessary on a case by case 
basis. The Investigator is not allowed under any circumstance to collect additional data or 
conduct additional procedures for research related purposes outside of the protocol.
Investigators must apply due diligence to avoid protocol deviations. All significant protocol 
deviations will be recorded and reported in the CSR. The Investigator MUST NOT implement 
any protocol deviations, even if the Investigator believes it is warranted to improved conduct 
of the study.
Modification of the protocol is prohibited without prior written agreement in the form of a 
protocol amendment. All amendments are created by the Sponsor and must be approved by 
the IEC/IRB prior to implementation except when required to mitigate immediate safety risks 
or when the changes involve only logistical or administrative revisions.
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the Sponsor 
must be informed and (serious) AE reporting requirements (Section 9) followed as appropriate.
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14
References
Available upon request
Adamus G, Chew EY, Ferris FL et al(2015) Prevalence of anti-retinal autoantibodies in 
different stages of Age-related macular degeneration. BMC Ophthalmol;2014 Dec 8;14:154.
Appel GB, Cook HT, Hageman G et al (2005) Membranoproliferative Glomerulonephritis 
Type II (Dense Deposit Disease): An Update. JAmSocNephrol; 16 (5):1392-1403. 
Bathum L, Hansen H, Teisner B et al (2006) Association between combined properdin and 
mannose-binding lectin deficiency and infection with Neisseria meningitis. MolImmunol; 43 
(5):473-479.
Bhavsar AR, Stockdale CR, Ferris FL 3rd et al (2012) Update on risk of endophthalmitis after 
intravitreal drug injections and potential impact of elimination of topical antibiotics. Arch 
Ophthalmol;130(6):809-10.
Crabb JW, Miyagi M, Gu X et al (2002) Drusen proteome analysis: an approach to the 
etiology of age-related macular degeneration. Proc Natl Acad Sci USA;99(23):14682-7.
Despriet DD, Klaver CC, Witteman JC, et al (2006) Complement factor H polymorphism, 
complement activators, and risk of age-related macular degeneration. JAMA;296(3):301-9.
Ferreira, VP,Herbert AP, Cortes Cet al (2009) The binding of factor H to a complex of 
physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome. 
JImmunol;182(11): 7009-7018.
Fijen CA, Kuijper EJ, te Bulte MT et al (1999) Assessment of complement deficiency in 
subjects with meningococcal disease in The Netherlands. ClinInfectDis; 28 (1):98-105. 
Gangnon RE, Lee KE, Klein BE et al (2012) Effect of the Y402H variant in the complement 
factor H gene on the incidence and progression of age-related macular degeneration: results 
from multistate models applied to the Beaver Dam Eye Study. Arch 
Ophthalmol;130(9):1169-76.
Garcia Filho CA, Yehoshua Z, Gregori G et al (2014) Change in drusen volume as a novel 
clinical trial endpoint for the study of complement inhibition in age-related macular 
degeneration. Ophthalmic Surg Lasers Imaging Retina; 45(1):18-31.
Gold B, Merriam JE, Zernant J et al (2006) Variation in factor B (BF) and complement 
component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet; 
38(4):458-62.
Hageman GS, Luthert PJ, Victor Chong NH et al (2001) An integrated hypothesis that 
considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch
's membrane 
interface in aging and age-related macular degeneration. ProgRetinEye Res; 20 (6):705-732.
Haines JL, Hauser MA, Schmidt S et al (2005) Complement factor H variant increases the 
risk of age-related macular degeneration. Science; 308 (5720):419-421.
Hecker LA, Edwards AO, Ryu E et al (2010) Genetic control of the alternative pathway of 
complement in humans and age-related macular degeneration. HumMolGenet; 19 
(1):209-215.
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Herold KC, Gitelman SE, Masharani U et al (2005) A single course of anti-CD3 monoclonal 
antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and 
clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes; 54(6):1763-9.
Hughes AE, Orr N, Esfandiary H et al (2006) A common CFH haplotype, with deletion of 
CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration.Nat 
Genet; 38 (10):1173-1177.
Johnson LV, Leitner WP, Staples MK et al (2001) Complement activation and inflammatory 
processes in Drusen formation and age related macular degeneration. ExpEye Res; 73 
(6):887-896.
JozsiM,Heinen S, Hartmann A et al (2006)Factor H and atypical hemolytic uremic 
syndrome: mutations in the C-terminus cause structural changes and defective recognition 
functions. J Am Soc Nephrol;17(1): 170-177.
Kabat EA (1991) Sequences of proteins of immunological interest. Us Department of Health 
and Human Services, Public Health Service, NIH Publication; 91:3242.
Klein RJ, Zeiss C, Chew EY, et al (2005) Complement factor H polymorphism in age-related 
macular degeneration. Science; 308 (5720):385-389. 
Klein ML, Francis PJ, Ferris FL 3rd, et al (2011) Risk assessment model for development of 
advanced age-related macular degeneration. Arch Ophthalmol;129(12):1543-50.
Linton SM, Morgan BP (1999) Properdin deficiency and meningococcal disease--identifying 
those most at risk. Clin ExpImmunol; 118 (2):189-191.
Loyet KM, Deforge LE, Katschke KJ Jr et al (2012) Activation of the alternative complement 
pathway in vitreous is controlled by genetics in age-related macular degeneration. Invest 
Ophthalmol Vis Sci; 53(10):6628-37.
Maller J, George S, Purcell S et al (2006) Common variation in three genes, including a 
noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat 
Genet; 38 (9):1055-1059.
Mathew S, Overturf GD (2006) Complement and properidin deficiencies in meningococcal 
disease. PediatrInfectDisJ; 25 (3):255-256. 
Montes T, Tortajada A, Morgan BP et al (2009) Functional basis of protection against 
age-related macular degeneration conferred by a common polymorphism in complement 
factor B. ProcNatlAcadSciUSA;106(11):4366-71.
Mullins RF, Russell SR, Anderson DH et al (2000) Drusen associated with aging and age-
related macular degeneration contain proteins common to extracellular deposits associated 
with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J; 14 (7):835-
846.
Nentwich MM1, Yactayo-Miranda Y, Schwarzbach F et al (2014) Endophthalmitis after 
intravitreal injection: Decreasing Incidence and Clinical Outcome-8-year Results from a 
Tertiary Ophthalmic Referral Center. Retina;0:1-8.
Nozaki M, Raisler BJ, Sakurai E et al (2006) Drusen complement components C3a and C5a 
promote choroidal neovascularization. Proc Natl Acad Sci USA; 103(7):2328-33.
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Amended Protocol VersionNo. 01 (Clean)
Protocol No. CCLG561X2201A
Postel EA, Agarwal A, Caldwell J et al (2006) Complement factor H increases risk for 
atrophic age-related macular degeneration. Ophthalmology; 113 (9):1504-1507.
Raychaudhuri S, Ripke S, Li M et al (2010) Associations of CFHR1-CFHR3 deletion and a
CFH SNP to age-related macular degeneration are not independent. Nat Genet; 42 (7):553-
555.
Regillo CD, Yaspan BL, Li Z et al (2013) Lampalizumab (anti-factor D) in patients with 
geographic atrophy: the MAHALO phase II results. Proceedings of the 117
thannual meeting 
of the American Academy of Ophthalmology (AAO), New Orleans.
Reynolds R, Hartnett E, Atkinson JP et al (2009) Plasma complement components and 
activation fragments: associations with age-related macular degeneration genotypes and 
phenotypes. Invest Ophthalmol Vis Sci; 50(12):5818-27.
Rosenfeld PJ, Rich RM, Lalwani GA (2006) Ranibizumab: Phase III clinical trial results. 
Ophthalmol Clin North Am;19(3):361-72. 
Schejbel L, Rosenfeldt V, Marquart H et al (2009) Properdin deficiency associated with
recurrent otitis media and pneumonia, and identification of male carrier with Klinefelter 
syndrome. Clin Immunol; 131 (3):456-462.
Scholl HP, Issa PC, Walier M et al (2008) Systemic complement activation in age-related 
macular degeneration (abstract).PLoS ONE; 3(7): e2593.
Scholl HP, Fleckenstein M, Issa PC et al (2007) An update on the genetics of age-related 
macular degeneration. Mol Vis; 13:196-205.
Seddon JM, Yu Y, Miller EC et al (2013) Rare variants in CFI, C3 and C9 are associated with 
high risk ofadvanced age-related macular degeneration. Nat Genet; 1366-1370.
Sjoholm AG, Braconier JH, Soderstrom C (1982) Properdin deficiency in a family with 
fulminant meningococcal infections. Clin ExpImmunol; 50 (2):291-297.
van de Ven JP, Nilsson SC, Tan PL etal (2013) A functional variant in the CFI gene confers a 
high risk of age-related macular degeneration. Nat Genet;45(7):813-817.
Xu D, Alegre ML, Varga SS, et al (2000) In vitro characterization of five humanized OKT3 
effector function variant antibodies. Cell Immunol; 200:16-26.
Yates JRW, Sepp T, Matharu BK et al (2007) Complement C3 variant and the risk of 
age-related macular degeneration. N Engl J Med;357(6):553-61.
Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al (2014) Systemic complement 
inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the 
complete study.Ophthalmology;121(3):693-701.
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Novartis Institutes for BioMedical Research
CLG561 
Protocol CCLG561X2201A 
(Alcon Protocol CLG561-2201)
A randomized, multi-center, single masked, sham 
controlled, proof-of-concept study of intravitreal CLG561 
as a monotherapy and in combination with LFG316 in 
subjects with geographic atrophy 
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Page 1 of 40
Clinical Development
CLG561
CCLG561X2201A
A randomized, multi-center, single-masked, sham controlled, proof-of-
concept study of intravitreal CLG561 as a monotherapy and in 
combination with LFG316 in subjects with geographic atrophy
Author:
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V1.1
Release date:
08-Jan-2018
Personal Data


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Table of Contents
Table of Contents .......................................................................................................................3
Table of Figures .........................................................................................................................4
Table of Tables...........................................................................................................................4
List of abbreviations ..................................................................................................................6
1
Study Objectives and Design..................................................................................8
1.1
Study Objectives.................................................................................................8
1.2
Study Description .............................................................................................10
1.3
Randomization..................................................................................................11
1.4
Masking ............................................................................................................11
2
Baseline and Visit Windows .................................................................................13
2.1
Baseline ............................................................................................................13
2.2
Relative Day.....................................................................................................13
2.3
Visit Windows ..................................................................................................13
3
Analysis Sets.........................................................................................................13
3.1
Efficacy Analysis Sets ......................................................................................14
3.2
Safety Analysis Set...........................................................................................14
3.3
Pharmacokinetics and Immunogenicity Analysis Set.......................................15
3.4
Pharmacodynamic Analysis Set .......................................................................15
4
Subject Characteristics and Study Conduct Summaries.......................................15
5
Efficacy Analysis Strategy....................................................................................15
5.1
Efficacy Endpoints ...........................................................................................15
5.2
Efficacy Hypotheses.........................................................................................20
5.3
Statistical Methods for Efficacy Analyses........................................................21
5.3.1
Primary efficacy analyses.............................................................................21
5.3.2
Secondary Efficacy Analyses .......................................................................23
5.4
Multiplicity Strategy.........................................................................................26
5.5
Treatment of Missing Values............................................................................26
5.6
Subgroup Analyses and Effect of Baseline Factors..........................................27
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5.7.1
Sample Size Reassessment...........................................................................28
6
Safety Analysis Strategy.......................................................................................29
6.1
Safety Assessments...........................................................................................29
6.2
Safety Hypotheses ............................................................................................30
6.3
Statistical Methods for Safety Analyses...........................................................30
6.3.1
Extent of Exposure .......................................................................................30
6.3.2
Adverse Events.............................................................................................30
6.3.3
Best Corrected Visual Acuity (BCVA) .........................................................31
6.3.4
Low Luminance Visual Acuity.....................................................................31
6.3.5
Biomicroscopy Findings/Slit Lamp Examination ........................................31
6.3.6
Intraocular Pressure......................................................................................32
6.3.7
Dilated Fundus Examination ........................................................................32
6.3.8
Vital Signs.....................................................................................................33
6.3.9
Laboratory Results........................................................................................33
7
Pharmacokinetic Analysis Strategy ......................................................................34
7.1
Pharmacokinetic Endpoints..............................................................................34
7.2
Pharmacokinetic Hypotheses............................................................................34
7.3
Statistical Methods ...........................................................................................34
9
Sample Size and Power Calculations ...................................................................36
10
References.............................................................................................................37
Table of Figures
Figure 1.2-1 Study Design.......................................................................................................11
Figure 1 Sample Size Reassessment and Conditional Power (Bonferroni Procedure)............39
Table of Tables
Table 1 Conditional Probability of Arm A Significant with Current Sample Size (Bonferroni 
Procedure)........................................................................................................39
Table 2 Conditional Probability of Arm A Significant with Current Sample Size (Hochberg 
Procedure)........................................................................................................39
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Table 3 Conditional Probability of At Least One Active Arm Significant with Current Sample 
Size (Hochberg Procedure)..............................................................................40


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List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
AMD
age-related macular degeneration
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
BCVA
best corrected visual acuity
BLQ
below the limit of quantitation
BPM
beats per minute
CRC
central reading center
CSR
clinical study report
CV
coefficient of variation
DEP
Deviations and Evaluability Plan
EOS
end of study
ETDRS
Early Treatment Diabetic Retinopathy Study
FAF
fundus autofluorescence
FCS
Fully conditional specification
FU
follow up
GA
geographic atrophy
GGT
gamma-glutamyl transferase
HIV
human immunodeficiency virus
IOP
intraocular pressure
IRT
interactive response technology
IVT
intravitreal
LLOQ
lower limit of quantification
mmHg
millimeters of mercury
MMRM
mixed-effect model repeated measure
PK
pharmacokinetic(s)
PP analysis set
per protocol analysis set
PPS
Predictive probability of success
RBC
red blood cell(s)


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SD-OCT
spectral domain optical coherence tomography
TBL
total bilirubin
ULOQ
upper limit of quantification
WBC
white blood cell(s)


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1
Study Objectives and Design
1.1
Study Objectives
Primary Objectives

To evaluate the safety of 12 (every 28 days) IVT injections of CLG561 as a 
monotherapy and in combination with LFG316 as compared to sham.

To evaluate in the study eye the efficacy of 12 (every 28 days) IVT injections of 
CLG561 as a monotherapy and in combination with LFG316 as compared to sham on 
the growth of GA lesion size as assessed by FAF based on the change from baseline to 
Day 337.
Secondary Objectives

To evaluate the time course of the change in GA lesion size of the active arms as 
compared to sham as measured by FAF in the study eye.

To evaluate the time course of the change in BCVA, low luminance visual acuity and 
low luminance visual acuity deficit up to Day 337 of the active arms as compared to 
sham in the study eye.

To evaluate the average change in BCVA, low luminance visual acuity and low 
luminance visual acuity deficit from baseline to the period Day 281 to Day 337 of the 
active arms as compared to sham in the study eye.

To evaluate the time course of the proportion of study eyes losing or gaining ≥15 
letters, ≥10 letters, and ≥5 letters in BCVA from baseline up to Day 337 in each of the 
active arms as compared to sham in the study eye.
To describe:
•
The systemic exposure of total CLG561 after IVT administration of CLG561 
as a monotherapy up to Day 421.
•
The systemic exposure of total CLG561 and total LFG316 after IVT 
administration of CLG561 in combination with LFG316 up to Day 421.


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
To describe the immunogenicity of CLG561 after IVT administration of CLG561 
as a monotherapy and the immunogenicity of CLG561 and LFG316 after IVT 
administration of CLG561 in combination with LFG316 up to Day 421.
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1.2
Study Description
This is a multi-center, randomized, sham-controlled, single masked, proof-of-concept study 
in geographic atrophy (GA) subjects.  On Day -1, subjects will be randomized in a 1:1:1 ratio 
to receive one of three treatments: CLG561 (10 mg/100 µL), CLG561 (5 mg/50 µL) + 
LFG316 (5 mg/50 µL) or sham injection.  Starting on Day 1, subjects will receive IVT 
injections from the randomized treatment regimen.
Both eyes must have GA but only one eye must meet the other inclusion/exclusion criteria to 
be eligible for study participation.
After the initial injection, there will be an additional 12 injections occurring approximately 
every 28 days. This will result in approximately 336 day treatment period of active drug or 
sham injection. There will be two follow up visits, occurring approximately 4 weeks and 16 
weeks after the last administered injection.
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Figure 1.2-1 Study Design 
 
1.3
Randomization
A member of the Randomization Programming group at Alcon who is not part of the study 
team will generate the randomized allocation schedule(s) for study treatment assignment. 
Randomization will be implemented in an Interactive Response Technology (IRT) system.
Qualified subjects will be randomized in a 1:1:1 manner through the interactive response 
technology (IRT) system, at Day -1, to receive either the CLG561 injection, the CLG561 + 
LFG316 injection or the sham injection on Day 1 and then every 28 days for a total of 336 
days to the study eye.
1.4
Masking
This is a single-masked study and the following will be masked to treatment assignment:

Subjects

Visual acuity assessor at the study site

Technicians obtaining images at the study site

CRC staff
The primary investigator and the sponsor will be unmasked to treatment assignment.


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1.5
Interim Analysis
One interim analysis (IA) will be conducted when all subjects complete all of their 
assessment at the visit following the 6th injection (Day 169).
Purposes of this interim analysis include (Protocol Section 3.5):

Unmasked assessment of the safety of the treatment arms

To enroll additional subjects if the treatment arms are not balanced based on the GA 
lesion phenotype

Allow a reassessment of the sample-size calculations regarding the assumed lesion 
growth in the control arm (based on linear growth of the GA lesion)

Support internal decision making concerning the current clinical study or the 
Sponsor’s clinical development projects in general.
The subject numbers may be augmented up to a maximum of 72 subjects per treatment arm
(refer to Section 5.7.1 for more details), or one of the study arms or the entire study may be 
stopped based on the safety signal.
Preliminary evaluation of the treatment efficacy to slow down GA lesion growth will be 
performed based on interim data, although the purpose is not to make an efficacy claim.
Additional interim analyses may be conducted based on a safety signal from the study, or if 
necessary to make internal decisions on the program.
Interim analysis results may be communicated to relevant sponsor teams for information, 
consulting and/or decision purposes. Further distribution of the interim analyses results can 
only be made upon sponsor team decision. 
For data query and cleaning purposes, a cut-off date will be applied for the interim analysis. 
All visits which occurred prior to the clinical cut-off date (not limited to day 169) will be 
used for the IA. Data collected after the cut-off date will not be used for the IA. 


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2
Baseline and Visit Windows
2.1
Baseline
Baseline will be defined as the last measurement prior to first dose of study drugs. If the
baseline visit (Day 1) measurement is missing, the screening values (if available) will be used 
instead. 
2.2
Relative Day
The date of first dose of study drugs will be considered relative Day 1, and the day before the 
first dose of study drug will be relative Day -1.  Relative days will be calculated as follows 
only when the full assessment date is known (i.e., partial dates will have missing relative 
days):
For days on or after the first dose of study drug:
Date of Assessment – Date of First Dose of Study Drug + 1.
For days before the first dose of study drug:
Date of Assessment – Date of First Dose of Study Drug.
2.3
Visit Windows
All nominal visits in the database will be assigned at site per protocol scheduled visit window. 
For the purpose of statistical analysis, the actual visit numbers and visits will only need to be 
calculated for the EOS visit of patients who discontinued early. Since the protocol requires 
the EOS visit to be completed approximately 4 weeks after the last injection, the actual visit 
number for the EOS visit will be the last injection visit number +1. Otherwise the study visit 
numbers and visits assigned in the database will be used as is. Unscheduled visit will not be 
considered for analyses. 
3
Analysis Sets
The detailed criteria that qualify a subject for exclusion from each analysis set will be 
identified in the Deviations and Evaluability Plan (DEP). The final subject evaluability will 
be determined prior to locking the database. Number of subjects in each analysis set will be 
summarized, and reasons for exclusion will be listed for subjects who did not qualify.


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3.1
Efficacy Analysis Sets
The full analysis set will include all subjects who receive any study treatment and have 
baseline GA lesion size, and at least one follow-up GA lesion size assessment.  The full 
analysis set will use the treatment as randomized.
The Per Protocol (PP) analysis set will be comprised of all full analysis set subjects who 
have no critical protocol deviations and have baseline lesion size assessment and the 
corresponding assessment on Day 337 or Day 253. Critical protocol deviations criteria will 
be identified in the Deviations and Evaluability Plan (DEP). Protocol deviations will be 
identified and classified before database lock. The PP analysis set will use the treatment as 
randomized.
The primary efficacy analysis will be performed using the PP analysis set with treatment as 
randomized.  Sensitivity analyses will be performed on the primary efficacy endpoint using 
the full analysis set as randomized.  If any subjects received a different treatment than the one 
they were randomized to, additional sensitivity analyses will be performed using full analysis 
set with the actual treatment most frequently exposed to in the study.
3.2
Safety Analysis Set
The safety analysis set will include all subjects who received any study treatment.
Safety analyses will be conducted using the safety analysis set. Subjects will be analyzed by
the actual treatment received. Subjects exposed to an incorrect study treatment for the entire 
treatment period or a portion of the treatment period will be accounted for under the actual 
treatment the subject was most frequently exposed to in the study.
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3.3
Pharmacokinetics and Immunogenicity Analysis Set
The pharmacokinetic analysis set will include all subjects with available PK data (total 
LFG316 and total CLG561) or immunogenicity data (anti-LFG316 antibodies and anti-
CLG561 antibodies) and no protocol deviations with relevant impact on pharmacokinetic or 
immunogenicity data. The pharmacokinetics and immunogenicity analysis set will use the 
treatment as treated.
3.4
Pharmacodynamic Analysis Set
The pharmacodynamic (PD) analysis set will include all subjects with available 
pharmacodynamic data (total C5, total properdin and serum complement activity measured 
by Wieslab assay) and no protocol deviations with relevant impact on pharmacodynamic 
data. The pharmacodynamic analysis set will use the actual treatment.
4
Subject Characteristics and Study Conduct Summaries
Subject characteristics and study conduct summaries will be provided for subject disposition, 
demographic (age, age group (<75 years, ≥75 years), gender, race, ethnicity), baseline 
characteristics (BCVA, lesion size, lesion location and lesion type). Ocular and AMD history, 
family history, and smoking history will be listed. Medical history and prior/concomitant
medication will be listed and summarized by treatment groups. Number and percentage will 
be presented for categorical variables and descriptive statistics including mean, standard 
deviation, median, minimum and maximum will be presented for continuous variables.
Subject disposition and study completion status or reason for early exit will be listed and 
summarized by treatment group. 
5
Efficacy Analysis Strategy
The detailed criteria that exclude certain observed data from analyses due to protocol 
deviations will be identified in the Deviations and Evaluability Plan (DEP).
5.1
Efficacy Endpoints
Primary Endpoints
The primary endpoint is the change in GA lesion size (mm2) in the study eye from baseline to 
Day 337 as measured by FAF.  


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Each post-screening imaging time point will be reviewed by two FPRC graders (double 
read). Each Grader will independently complete the assessments. Adjudication will be 
triggered in the following situations:

10% difference between the two graders’ area measurements

Any difference in qualitative assessments
The adjudicator will have the option of selecting either Grader1 or Grader 2’s assessments, or 
providing their own assessment. 
The adjudicator assessments will be considered the final assessments for the subject.
When there is no adjudication:
1) If the two graders’ area measurements are within 10% of each other (i.e. percentage 
of absolute difference over the average of the two measurements), the results will be 
averaged and used for statistical analyses. 
2) If only 1 grader result is presented or two graders’ results difference are >10%, the 
assessment will be treated as missing. 
Secondary Endpoints
The secondary efficacy endpoints are 
•
Change in GA lesion size from baseline to Day 85, 169, 253, 337 and 421 as 
measured by FAF in the study eye
•
Change in BCVA, low luminance visual acuity and low luminance visual 
acuity deficit from baseline by visit up to Day 337 as measured by ETDRS in 
the study eye.
Low luminance visual acuity deficit is defined as the difference between 
BCVA and low luminance visual acuity, i.e.
Low luminance visual acuity deficit= BCVA- low luminance visual acuity


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•
Average change in BCVA, low luminance visual acuity and low luminance 
visual acuity deficit from baseline to the period Day 281 and to Day 337 as 
measured by ETDRS in the study eye
The average change is defined by arithmetic mean of change from baseline of 
all observed time points between Day 281 and Day 337.
•
Subject status regarding ≥15 letters, ≥10 letters, and ≥5 letters change from 
baseline in BCVA by visit up to Day 337 as measured by ETDRS in the study 
eye
•
Serum concentrations of total CLG561 (CLG561 monotherapy) and serum 
concentrations of total CLG561 and total LFG316 (CLG561/LFG316 
combination) by visit up to Day 421
•
Serum anti-CLG561 antibodies (CLG561 monotherapy) and serum anti-
CLG561 and anti-LFG316 antibodies (sham and CLG561/LFG316 
combination) by visit up to Day 421
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5.2
Efficacy Hypotheses
Primary Hypotheses
The primary efficacy hypotheses are that the mean change in GA lesion size from baseline at 
Day 337 in the two active treatment groups (CLG561 and CLG561 + LFG316) separately is 
lower than in the sham group at Day 337. The null and alternative hypotheses are:
H01: µCLG561 ≥ µsham
HA1: µCLG561 < µsham
H02: µCLG561+ LFG316 ≥ µsham
HA2: µCLG561 + LFG316 < µsham,
where µCLG561, µCLG561+ LFG316 and µsham are the mean change from baseline at Day 337 in the 
CLG561 monotherapy group, the CLG561 + LFG316 combination group and the sham 
group, respectively.
Secondary Hypotheses
The secondary efficacy hypotheses for BCVA and low luminance visual acuity are that the 
mean change from baseline at Day 337 in the two active treatment groups (CLG561 and 
CLG561 + LFG316) separately is higher than in the sham group at Day 337. The null and 
alternative hypotheses are:
H01: vCLG561 ≤ vsham
HA1: vCLG561 > vsham
H02: vCLG561+ LFG316 ≤vsham
HA2: vCLG561 + LFG316 > vsham,
where vCLG561, vCLG561+ LFG316 and vsham are the mean change from baseline at Day 337 in the 
CLG561 monotherapy group, the CLG561 + LFG316 combination group and the sham 
group, respectively.
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The secondary efficacy hypotheses for low luminance visual acuity deficit is that the mean 
change from baseline at Day 337 in the two active treatment groups (CLG561 and CLG561 + 
LFG316) separately is lower than in the sham group at Day 337.
5.3
Statistical Methods for Efficacy Analyses
5.3.1
Primary efficacy analyses
In the primary efficacy analysis which is based on the PP set, a subject will have in the study 
a baseline lesion size assessment and a corresponding assessment on Day 337 and/or Day 
253. For subjects with missing values of lesion size in the study eye on Day 337, the missing 
value will be handled by multiple imputations detailed in section 5.5. Multiplicity adjustment 
based on Hochberg procedure and detailed in section 5.4 will be applied to the primary 
statistical modeling and all sensitivity analyses. Day 421 GA lesion size will only be 
summarized descriptively, and will not be included in any statistical modeling. 
A basic summary statistics table will be provided for the observed value and change from 
baseline in study eye GA lesion size at each scheduled time points by treatment. Individual 
profile plot of GA lesion size and change from baseline will be produced by treatment 
groups, together with line charts of observed mean change from baseline+/- SD against study 
days with all treatment groups overlaying.
An ANCOVA model with treatment, baseline lesion location (foveal vs exfoveal), and 
baseline lesion size, baseline lesion type (unifocal vs multifocal) as covariates will be fit to
the change from baseline in study eye GA lesion size at day 337. The least-squares means at 
the observed mean baseline covariates and associated two-sided 80% confidence intervals for 
each treatment group and the estimated mean treatment difference, the p-value, and the 
corresponding two-sided 80% CI will be extracted from the model.
A sensitivity analysis will be performed on the change from baseline in study eye GA lesion 
using the full analysis set with ANCOVA method.  
Another sensitivity analysis of the change from baseline in study eye GA lesion size up to 
day 337 will be performed using a mixed-effect model repeated measure (MMRM) model 
with treatment, visit (categorical) and treatment by visit interaction, baseline lesion location, 
baseline lesion type, and baseline lesion size as fixed effects. Baseline lesion location*visit 
interaction, baseline lesion type, and baseline lesion size*visit interaction may also be added 
if adding the interactions provide a better fit statistics (BIC). Unstructured covariance 
structure will be used for the repeated measures. Unstructured covariance structure will be 


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used for the repeated measure. If the model fails to converge under unstructured covariance,  
other covariance structures such as heterogeneous Toeplitz, Ante-dependence , heterogeneous 
compound symmetry,  heterogeneous AR(1), AR(1), and compound symmetry will be used 
in order until convergence is achieved. The least-squares means at the observed mean 
baseline covariates and associated two-sided 80% confidence intervals for each treatment 
group and the estimated mean treatment difference, the one-sided p-value, and the 
corresponding two-sided 80% CI will be extracted from the model for each time point and 
summarized in a table. The least-squares mean and associated two-sided 80% confidence will 
also be plotted against study days with different treatment groups overlaying. Under the 
assumption of missing at random, no imputations of missing values are needed for the 
MMRM model and it will be performed on the PP set. 
The above analyses (ANCOVA and MMRM) will be also performed for the square root of 
GA lesion size on the PP set. Square root of baseline lesion size will be used as the covariate 
instead for these analyses. 
In addition, a post-hoc analysis using similar MMRM model will be implemented to day 253 
and day 337 lesion size (and square root of lesion size) changes from day 169.  Day 169 
lesion size will be used as the baseline covariate in the MMRM model. The estimated relative 
lesion size reduction for 2nd 6 month will be extracted from this analysis and be compared to 
the primary endpoint’s result at 12 month. 
An additional sensitivity analysis will be performed on change from baseline in GA lesion 
size up to day 337 using a linear growth mixed model. The model will include year and 
treatment*year interaction, and random subject effect on the slope for the year. Possible 
choices of additional covariate effects are: 1. Treatment, baseline lesion location, baseline 
lesion type and baseline lesion size as fixed effects, and a random subject effect on the 
intercept; 2. Baseline lesion location, baseline lesion type and baseline lesion size as fixed 
effects on the slope for the year (i.e. the interaction of year and listed effects). Inclusion of 
either or both of these above additional covariate effects will be chosen based on the 
information criteria fit statistics (BIC). Year is defined as (actual study day-1) divided by 
365.25 in order to facilitate report of annual growth rate. Results will be reported in the same 
fashion as the above MMRM model. In addition, least-squares means and treatment 
difference at one year will be reported, together with estimate and confidence intervals for the
annual growth rate (i.e. the slope for year in the model).  The linear growth mixed model will 
be performed on the PP set.


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In order to assess the growth rate change before and after 6 month, a similar piecewise linear 
growth mixed model will be used for analysis. The model differs from the above model by 
adding a treatment specific slope change after 6 month (day 169). More specifically, 
treatment interaction with the spline function (defined as [study day-169]/365.26 for study 
days greater than 169, 0 otherwise) will be included as additional covariates in the model. 
Such analysis will be performed on the PP set. 
At last, a sensitivity analysis of change in lesion size at day 337 will be analyzed by an 
ANCOVA model with treatment and baseline lesion size as covariates. Missing day 337 
result will be imputed by last observation carried forward (LOCF), i.e. day 253. The analysis
will be performed on the PP set. 
In order to assess the impact of missing doses, the below sensitivity analyses will be 
performed, and MMRM model will be used as the statistical models for these analyses.

Sensitivity analysis 1:  Lesion size observed at visits with less than 50% exposure will 
be dropped from analysis. Percent of exposure is defined as number of actual doses 
taken divided by number of scheduled doses per protocol prior to the visit*100.  

Sensitivity analysis 2:  Lesion size after 2 or more missed doses (consecutive or 
within 6 months) will be dropped from analysis. 

Sensitivity analysis 3:  The lesion size occurred after 1 or more missed doses in the 
local dosing window (i.e. any of 3 doses between last scheduled lesion assessment 
and the current lesion assessment) will be dropped from analysis.
5.3.2
Secondary Efficacy Analyses
Secondary efficacy analyses will be performed on full analysis data sets and per protocol 
analysis set. There will be no imputation or multiplicity adjustment for all secondary efficacy 
analyses. Day 421 measurements of all secondary endpoints will only be summarized 
descriptively, and will not be included in any statistical modeling.
Secondary efficacy endpoints (BCVA, low luminance visual acuity, and low luminance visual 
acuity deficit for the study eye) will be analyzed by basic summary tables, individual profile 
plots, line charts and the MMRM model in a similar fashion as the primary endpoint. 
Linear growth model will not be used for these endpoints. The number and percentage of 
patients gaining/losing ≥15 letters, ≥10 letters, and ≥5 letters in study eye BCVA will be 
presented for each time point by treatment group. The average change in study eye BCVA, 


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low luminance visual acuity, and low luminance visual acuity deficit of Day 281, Day 309 
and Day 337 will be calculated and summarized by treatment group. 
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5.4
Multiplicity Strategy
With two primary hypotheses to be tested, the Hochberg step-up procedure for multiplicity 
adjustment will be applied as follows:
p[1], p[2] are the 2 ordered one-sided p values, p[1]<p[2]. α=0.2
Step 1. If p[2] < α, reject both null hypothesis H0[1] and H0[2] and stop; otherwise accept 
H0[2] and go to Step 2. 
Step 2. If p[1] < α/2, reject H0[1] otherwise accept H0[1].
There will be no multiplicity adjustment for any other endpoints. 
5.5
Treatment of Missing Values
Missing values will be handled by multiple imputation methods. For the primary efficacy
analysis ANCOVA model on the PP set, a subject will have a baseline lesion size and a 
corresponding lesion size on Day 337 and/or Day 253. For subjects with missing lesion size 
on Day 337, the missing value will be treated as missing at random and imputed based on a 
regression model including covariates such as observed lesion sizes at previous time points
(day 253 and baseline minimally), baseline lesion location, baseline lesion type and other 
covariates when applicable. The imputation can be performed either within each treatment 
groups, or when within treatment groups is not feasible, combing all treatment groups 
together with treatment group as additional covariate in the imputation model. Monotone 
regression model can be used if all covariates in the imputation model are available or 
follows a monotone missing pattern. Fully conditional specification (FCS) method (Brand 
1999; van Buuren 2007) with regression model can be used if arbitrary missing pattern is 
present. For the sensitivity analysis of GA lesion size by ANCOVA model on the full analysis 
set, the imputation can be done similarly.
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Following recommendation of Bodner (2008) and Royston et al. (2011), the number of 
imputations should be similar to the percentage of cases that are incomplete, with 5 as 
minimum. For example, 20% of the cases in your data set have missing data, 20 imputed data 
sets will be generated.  PROC MI may be used to generate imputed data sets. These imputed 
data sets will then be analyzed with the primary ANCOVA model under SAS PROC 
MIANALYZE.
There will be no imputation of other missing endpoints. 
5.6
Subgroup Analyses and Effect of Baseline Factors
The following subgroups will be analyzed for the primary efficacy endpoint using similar
MMRM approach as described in Section 5.3.3:
•
Age category (<75 years and ≥75 years)
•
Gender (male and female)
•
Baseline BCVA categories (<60 letters, 60-73 letters, ≥73 letters)
•
Baseline lesion location (Foveal, Extrafoveal)
The MMRM model used within each lesion location will be same as one as described 
in Section 5.3.3, except that baseline lesion location will not be used as a covariate.  
•
Baseline lesion type (unifocal vs multi-focal)
The MMRM model used within each lesion location will be same as one as described 
in Section 5.3.3, except that baseline lesion type will not be used as a covariate.  
•
Genetic subgroups (ARMS/HTRA1=2 and ARMS2/HTRA1 + CFH ≥3)
5.7
Interim Analyses for Efficacy
Interim analyses will be performed on the interim per protocol analysis set, defined as 
subjects who belong to full analyses datasets and do not have major protocol deviations that 
could impact the efficacy assessment. Examples of such major protocol deviations include 
deviations to inclusion/exclusion criteria. 
For the per protocol analysis, at the time of lesion size assessment, if the patient in either 
CLG561 arm or the combo arm had 50% or more injections required by the protocol, the 


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lesion size will be treated as analyzable, otherwise the lesion size will be excluded. Such 
criteria will not apply to the sham arm. Additional sensitivity analyses may be performed by 
relaxing this exposure requirement.
Aforementioned analyses in Section 5.3 and the above criteria will be performed in the 
following endpoints: GA lesion size, BCVA, Low luminance visual acuity, and low 
luminance visual acuity deficit.as a preliminary evaluation of efficacy:
Observed values, as well as change from baseline for the study eye and fellow eye will be 
included for the interim efficacy analyses.
Since there will be a significant amount of unobserved data at day 337 for the ANCOVA 
analysis at the time of the IA, MMRM model will be used as the primary analysis for interim 
analysis. Under missing at random (MAR) assumption, MMRM does not require imputation. 
The detailed set of outputs will be specified in the output shell document.      
5.7.1
Sample Size Reassessment 
The protocol sample size calculation assumed an average natural disease progression of 
2.0mm2 per year and a standard deviation of 1.2mm2 for the change from baseline at 12 
month for the study population. One key objective of the IA is to verify these assumptions 
using the interim data and reassess the sample size calculation. On the other hand, the 
preliminary efficacy evaluation based on unmasked interim data, e.g. treatment difference at 
Day 169, may also inform the effect size assumption and sample size re-assessment.
The sample size for the study as per protocol may be augmented up to a maximum of 72 
subjects per treatment arm.
5.7.1.1
Sham arm growth rate assessment
Sham arm growth rate and standard deviation at Day 169 will be analyzed using descriptive
statistics. These observed Day 169 results will then be extrapolated to Day 337 based on 
linear assumption, which will be used to assess whether the current sample size is adequate.
The linear growth of GA lesion size in sham treated patients is well established and supported 
by previous GATE and GAP studies for GA.


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5.7.1.2
Effect size evaluation and sample size re-assessment
Given the uncertainty in the effect size at Day 337 in this very first study of efficacy in 
humans, the effect size for each active arm and variance of change in lesion size at day 337 
will be estimated from the interim observed data. 
At the IA, all patients will have the opportunity to complete their Day 169 visit, but fewer 
patients will have the opportunity to reach later visits. For example, around half of the 
patients are expected to reach their Day 253 visits, yet only up to 30 patients are expected to 
have reached their planned Day 337 visit. Therefore the effect size at Day 337 will be 
estimated or extrapolated using the Day 169 data as well as other already observed data.
Extrapolation to Day 337 will be based on growth trajectory models suggested by the interim 
data. Although the linearity assumption in the sham arm is plausible based on historical data, 
growth trajectories in the CLG+LFG combo and CLG mono-therapy arms are unknown. 
Therefore various models including random effect linear growth model and more flexible 
(nonlinear) models such as random-effect quadratic growth model and random-effect power
model, as well as MMRM will be fitted. Lack of fit statistics, information criteria (BIC), or 
external validation may be considered for final model selection.
The data available at interim analysis will be used to check if the growth of GA size follows a 
linear pattern and based on this analysis the sample size may be revised.
6
Safety Analysis Strategy
6.1
Safety Assessments
The safety assessments are:
•
Extent of exposure
•
Adverse events
•
Best Corrected Visual Acuity (letters read)
•
Low Luminance Visual Acuity
•
Biomicroscopy Findings/Slit Lamp Examinations (lens, aqueous flare, 
aqueous cell, corneal edema, corneal haze, corneal staining)
•
Intraocular pressure


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•
Dilated Fundus Examination (retinal hemorrhage, vitreal hemorrhage, vitreal 
cells, retinal tear/detachment)
•
Vital signs (body temperature, pulse rate and blood pressure)
•
Laboratory Results (hematology, blood chemistry, urinalysis)
6.2
Safety Hypotheses
There are no formal safety hypotheses in this study. The focus of the safety analysis will be a 
comprehensive descriptive assessment of occurrence of adverse events and safety 
assessments listed in Section 6.1.
6.3
Statistical Methods for Safety Analyses
Analysis set for all safety analyses is the safety analysis set as defined in Section 3.2. All 
safety analyses will also be performed by eye specific safety endpoints by eye (study eye 
versus fellow eye) as well.
6.3.1
Extent of Exposure
Duration of exposure to each treatment is defined as the last day of exposure to each 
treatment minus the first day of exposure plus 1. Duration of exposure will be summarized as 
a continuous measure (N, mean, median, standard deviation, minimum and maximum). 
Total number of injections and percent of compliance will also be summarized descriptively.
6.3.2
Adverse Events
For treatment-emergent AEs, defined as events that occur after exposure to first treatment, 
descriptive summaries (frequency and percentages) for specific AEs will be presented by 
system organ class and preferred term. Ocular events for study eye, ocular adverse events for 
fellow eye, and non-ocular events will be summarized separately. In addition to an overall 
presentation of all AEs, reports will be generated for special classes of AEs such as drug 
related/procedure related AEs, serious AEs and AEs leading to discontinuation. Presentation 
of ocular AEs will be by eye (study eye versus fellow eye). These reports will be supported 
by individual subject’s listings, as necessary. For pre-treatment AEs, only individual subject 
listings will be provided.  An additional listing will be provided for those subjects who had 
adverse events after exiting the study. 


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6.3.3
Best Corrected Visual Acuity (BCVA)
Visual acuity will be measured based on the procedures developed for the Early Treatment 
Diabetic Retinopathy Study (ETDRS) and the results will be reported in letters read correctly.
Visual acuity assessment will be conducted in both eyes at Day -1, Day 1, Day 2, Day 8, Day 
15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169, Day 197, Day 225, Day 
253, Day 281, Day 309, Day 337 and Day 421.  
Worst change from baseline across all post-baseline visits will be summarized.
6.3.4
Low Luminance Visual Acuity
Visual acuity will be measured based on the procedures developed for the Early Treatment 
Diabetic Retinopathy Study (ETDRS) and the results will be reported in letters read correctly.
Visual acuity assessment will be conducted in both eyes at Day 1, Day 2, Day 29, Day 57, 
Day 85, Day 113, Day 141, Day 169, Day 197, Day 225, Day 253, Day 281, Day 309, Day 
337 and Day 421.  
Worst change from baseline across all post-baseline visits will be summarized. 
6.3.5
Biomicroscopy Findings/Slit Lamp Examination
A slit-lamp examination will be performed on Day -1, Day 1, Day 2, Day 8, Day 15, Day 29, 
Day 30, Day 57, Day 85, Day 113, Day 141, Day 169, Day 197, Day 225, Day 253, Day 281, 
Day 309, Day 337 and Day 421 to evaluate the anterior segment of the eye, including lens, 
aqueous reaction (flare and cells), corneal edema and corneal haze. Ocular signs will be 
captured for the below:
•
Lens
•
Aqueous flare
•
Aqueous inflammatory cell
•
Corneal Epithelial Edema
•
Corneal Stromal Haze
Slit lamp examination data will be listed for all subjects. 


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6.3.6
Intraocular Pressure
Intraocular pressure (IOP) measurements will be recorded in mmHg and rounded to the 
nearest whole mmHg. IOP measurements will be conducted on Day -1, Day 1, Day 2, Day 8, 
Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169, Day 197, Day 225, 
Day 253, Day 281, Day 309, Day 337 and Day 421.  
Intraocular pressure data will be listed for all subjects by treatment, subject and visit/time. 
Observed values and change from baseline will be presented descriptively (N, mean, median, 
standard deviation, minimum and maximum) at each study visit (pre-injection and 30 minutes 
post injection) by treatment group for study eyes). 
Worst change from baseline across all post-baseline visits will be summarized. 
6.3.7
Dilated Fundus Examination
The dilated fundus examination will be performed on Day -1, Day 1, Day 2, Day 8, Day 15, 
Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169, Day 197, Day 225, Day 253, 
Day 281, Day 309, Day 337 and Day 421. The dilated fundus examination will be performed 
to evaluate the health of the retinal or vitreal hemorrhage, vitreous hemorrhage density, 
vitreal cells and retinal tear/detachment. Below fundus examination parameters will be 
captured:
•
Retinal Hemorrhage (Macular)
•
Retinal Hemorrhage (Non-Macular)
•
Vitreal Hemorrhage
•
Vitreous hemorrhage density
•
Vitreal cells
•
Retinal tear/detachment
All dilated fundus examination data will be listed by treatment, subject and visit/time. For 
each fundus parameter, a shift table showing fundus parameter grade at baseline relative to 
the grade at all post-baseline visits (pre-injection) will be presented by treatment group for 
study eyes


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6.3.8
Vital Signs
Vital signs measurements including pulse rate, body temperature and diastolic and systolic 
blood pressures will be performed at Screening, Day 29, Day 57, Day 85, Day 113, Day 141, 
Day 169, Day 197, Day 225, Day 253, Day 281, Day 309, Day 337 and Day 421. 
All vital signs data will be listed by treatment, subject and visit/time. 
6.3.9
Laboratory Results
Clinical laboratory evaluations consist of hematology, blood chemistry and urinalysis. 
Evaluations will be performed at Day -1, Day 337 and Day 421. A listing will be provided 
which lists all abnormal values for each clinical laboratory parameter.
6.3.9.1
Hematology (Complete Blood Count)
The following hematology parameters will be collected: hemoglobin, hematocrit, red blood 
cell (RBC) count, white blood cell (WBC) count with differential (absolute and percentage of 
neutrophils, lymphocytes, monocytes, eosinophils and basophils) and quantitative platelet 
count.
A subject listing will be provided which contains data for each hematology parameter. 
6.3.9.2
Blood Chemistry
The following blood chemistry parameters will be collected: sodium, potassium, creatinine, 
urea, chloride, albumin, calcium, alkaline phosphatase, total bilirubin (TBL), GGT, AST and 
ALT.
A subject listing will be provided which contains data for each blood chemistry parameter. 
6.3.9.3
Urinalysis
The following urinalysis parameters will be collected: leucocytes, nitrite, pH, protein, 
glucose, ketones, urobilinogen, bilirubin, blood/hemoglobin and microscopic examination 
(WBC, RBC and casts).
A subject listing will be provided which contains data for each urinalysis parameter. 


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7
Pharmacokinetic Analysis Strategy
The PK endpoints include ocular and serum concentration of CLG561 and LFG316 based on 
samples collected at the protocol-specified timepoints.
The pharmacokinetic analyst will generate and provide a SAS data set based on the 
pharmacokinetic concentration data. Using this data set, Biostatistics will provide a listing of
ocular and serum concentration of CLG561 and LFG316 by treatment, subject, and 
visit/sampling time of post dose. Biostatistics will also provide descriptive summary statistics 
by treatment and visit/sampling time point (post dose elapsed time), including the frequency 
(n, %) of concentrations below the lower limit of quantification (<LLOQ). <LLOQ will be 
treated as zero for calculation of descriptive statistics when necessary.
7.1
Pharmacokinetic Endpoints

Serum concentration of total CLG561 and total LFG316

Ocular concentrations of CLG561 after IVT administration of CLG561 as a 
monotherapy and ocular concentrations of CLG561 and LFG316 after IVT 
administration of CLG561 in combination with LFG316 
7.2
Pharmacokinetic Hypotheses
There are no formal PK hypotheses in this study.
7.3
Statistical Methods
Ocular (aqueous humor) and serum concentration will be listed by treatment, subject and 
visit/time. Descriptive summaries of ocular and serum concentration (including geometric 
means, coefficient of variation, median, minimum and maximum) will be presented by 
treatment and study day. Geometric means will be calculated by taking the exponential of the 
arithmetic mean of the log-transformed parameter values. 
For the purpose of calculating descriptive statistics for serum analyte concentrations, all post-
dose serum concentrations below the limit of quantification (BLQ) will be replaced by zero.
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A listing of individual subject’s ocular (aqueous humor) and plasma concentration values for 
the active treatment groups by time will be presented. Corresponding PK parameters 
(AUC/Cmax) will also be presented.
Each of the PK parameters (AUCtau, Cmax) will be listed by subject and visit and 
summarized by subject and visit. Descriptive statistics will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum, and maximum. 
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9
Sample Size and Power Calculations
A sample size of 30 PP evaluable subjects per treatment arm will allow identification of a 
treatment difference of 0.67 mm2 in lesion size change from baseline to Day 337 
(representing a 33% reduction in lesion growth rate, assuming an average natural disease 
progression of 2.0 mm2 per year) at a one-sided alpha level of 0.1 with a power of 80% 
assuming a standard deviation of 1.2 mm2. 
In anticipation of a drop-out /protocol deviation rate of 20%, a total sample size of 114 
randomized subjects (38 subjects/arm) is planned for the current study to ensure sufficient 
study completers for the above described PP analysis. Depending on ongoing monitoring of 
the drop-out/protocol deviations rate the need for additional recruitment will be assessed to 
ensure 90 PP evaluable subjects are available for the Day 337 analysis.


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10
References
Bodner, Todd E. (2008) “What improves with increased missing data 
imputations?” Structural Equation Modeling: A Multidisciplinary Journal 15: 651-675.
Brand, J. P. L. (1999), "Development, Implementation and Evaluation of Multiple Imputation 
Strategies for the Statistical Analysis of Incomplete Data Sets," Ph.D. dissertation, Erasmus 
University, Rotterdam.
Cui L, Hung HM, Wang SJ (1999). Modification of sample size in group sequential clinical 
trials. Biometrics; 55:853–7.
Cyrus R. Mehta, Stuart J. Pocock (2010) “Adaptive Increase in Sample Size when Interim 
Results are Promising: A Practical Guide with Examples” Statistics in Medicine 00:1–6
van Buuren, S. (2007), "Multiple Imputation of Discrete and Continuous Data by Fully 
Conditional Specification," Statistical Methods in Medical Research, 16, 219–242.
White, Ian R., Patrick Royston and Angela M. Wood (2011) “Multiple imputation using 
chained equations: Issues and guidance for practice.” Statistics in Medicine 30: 377-399.


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