Conditions: Non-infectious Intermediate Uveitis Non-infectious Posterior Uveitis Non-infectious Panuveitis
Keywords: Non-infectious uveitis Panuveitis Visual acuity Vitreous Haze Inflammation of the uvea inflammation of the middle, pigmented vascular structures of the eye, iris, ciliary body, choroid plexus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
This was a multi-center, randomized, active-controlled, open-label study. Approximately 24 patients with active, non-infectious intermediate-, posterior-, or panuveitis requiring systemic immunosuppressive therapy were enrolled.

Safety, efficacy, and PK assessments occurred at scheduled visits over a 12-week period. Low-molecular-weight non-steroidal immunosuppressive medications were allowed up to the baseline day as long as the dose had not changed in the 3 weeks prior to baseline, except for corticosteroid doses for which might have changed.

Patients responding to treatment were offered up to 6 months of extended treatment. Assessments for safety included laboratory safety tests, ECGs, physical exams, ocular exams, vital signs and the monitoring of adverse events. Study participation varied from a minimum of 3 months to a maximum of 9 months.

Detailed description:
Approximately 24 patients with active non-infectious uveitis, in at least one eye, requiring intensification of systemic immunosuppressive therapy were enrolled and randomized to receive intravitreal LFG316 or conventional therapy (investigator's discretion). Only one eye (the study eye) were treated with LFG316 and the other eye (fellow eye) were treated at the investigator's discretion.Throughout the study, the fellow eye might have been treated as needed; except that certain systemic medications were prohibited. There was 1 screening and 8 scheduled visits over 85 days for a total of 9 site visits for all patients.

At Day 85, patients receiving LFG316 treatment who met the criteria for a 'responder', were offered an additional 6 months of LFG316 treatment on a PRN basis. Additional 3 scheduled visits were attended by LFG316-responder patients during the extension period. However, patients could have unscheduled visits as needed and as determined by the investigator. Safety evaluation and ocular assessments were performed throughout the study duration. Patients in the treatment extension phase, who experienced a flare post their last dose and required treatment, might have received a dose of LFG316. These patients were assessed for a response at their next PRN visit as scheduled by the investigator. Visit frequency was determined by the investigator. If they continued to respond to LFG316 therapy, they might have remained in the PRN treatment arm. They might have received up to 7 additional doses of LFG316 in the PRN period. Throughout the trial LFG316 were not administered more frequently than monthly. Patients in the extension phase, who discontinued treatment prematurely were asked to return approximately 1 month after their last dose. Low molecular weight non-steroidal immunosuppressive medications were allowed up to the baseline day as long as the dose had not changed in the 3 weeks prior to baseline, except for corticosteroid doses which might have changed.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: LFG316 intervention 2: Conventional Therapy
Intervention descriptions: intervention 1: LFG316 administered intravitreally (IVT) intervention 2: Conventional Therapy administered in accordance with its prescribing info.

Protocol document:
Prot_001.pdf: 
l') N O VA RT I S 
 
 
Novartis Institutes for BioMedical Research 
 
 
LFG316 
 
 
Protocol No. CLFG316A2204 
 
 
A randomized, active-controlled, open-label, multiple-dose, 
proof-of-concept study of intravitreal LFG316 in patients 
with active non-infectious intermediate-, posterior-, or 
panuveitis requiring systemic immunosuppressive therapy 
 
 
 
 
 
 
Authors: 
Document type: 
Version number: 
Development phase: 
Release date: 
Personal Data 
Amended Protocol Version 
v05 Clean 
II 
 
07-Sep-2015 
 
 
 
 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents ....................................................................................................................... 2 
List of tables .............................................................................................................................. 6 
List of figures .................................................................................................................................. 6 
List of abbreviations ...................................................................................................................... 7 
Glossa1y of terms ...................................................................................................................... 9 
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Protocol synopsis .................................................................................................................... 25 
Assessment schedule .............................................................................................................. 32 
1 
Introduction ............................................................................................................................. 36 
1.1 
Background ........................................................................................................... 36 
1.2 
Study purpose ............................................................................................................. 46 
2 
Study objectives ............................................................................................................................ 47 
2.1 
Prima1y objectives ........................................................................................................... 47 
2.2 
Seconda1yobjectives ......................................................................................... 47 
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3 
Investigational plan ........................................................................................................................... 48 
3.1 
Study design ..................................................................................................................... 48 
3.2 
Rationale of study design ...................................................................................52 
3.3 
Rationale of dose/regimen, dmation of treatment .................................................... 53 
3.4 
Rationale for choice of comparator ............................................................................... 54 
3.5 
Risk / Benefit for this study ....................................................................................... 54 
3.6 
Purpose and timing of interim analyses/design adaptations .................................... 55 
4 
Population ............................................................................................................................... 56 
4.1 
Inclusion cliteria ................................................................................................ 56 
4.2 
Exclusion criteria ........................................................................................................ 57 
4.2.1 
Interpretation ofl aborato1y  and electrocardiogram results ...................... 58 
5 
Treatment. ............................................................................................................................... 59 
5.1 
Investigational treatment ............................................................................................... 59 
5.1.1 
Bio-batch Retention samples ............................................................. 59 
5.2 
Treatment aims ..................................................................................................... 59 
5.3 
Treatment assignment .................................................................................................... 59 


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5.4 
Treatment masking ......................................................................................................... 59 
5.5 
Treating the patient ..................................................................................................... 59 
5.5.1 
Patient numbering ......................................................................................... 59 
5.5.2 
Dispensing the study treatment. ...................................................................... 60 
5.5.3 
Supply, storage and tracking of study treatment ........................................ 60 
5.5.4 
Instrnctions for prescribing and taking of study treatment ..................... 61 
5.5.5 
Permitted dose adjustment ........................................................................ 61 
5.5.6 
Rescue ........................................................................................................ 62 
5.5.7 
Concomitant, pennitted, and prohibited treatments ................................ 63 
5.5.8 
Prohibited treatment ...................................................................................... 64 
5.5.9 
Tapering schedule for oral co1ticosteroids ................................................. 64 
5.5.10 
Discontinuationof study treatment and premature subject 
withdrawal .......................................................................................................... 65 
5.5.11 
Emergency unblinding of treatment assignment. ................................66 
5.5.12 
Study completionand post-study treatment. ........................................ 66 
6 
Visit schedule and assessments .................................................................................................. 67 
6.1 
Dietary , fluid and other restrictions ............................................................................... 67 
6.2 
Patient demographics/other baseline characteristics ................................................ 67 
6.3 
Treatment exposure and compliance ............................................................................ 68 
6.4 
Efficacy / Pharrnacodynamic assessment ............................................................. 69 
6.4.1 
Vitreous haze .................................................................................... 69 
6.4.2 
Anterior Chamber cells ............................................................................. 69 
6.4.3 
Chorioretinal lesions .................................................................................. 69 
6.4.4 
Papillitis ...................................................................................................... 69 
6.4.5 
Vasculitis ...........................................................................................69 
6.4.6 
Visual acuity .............................................................................................. 69 
6.4.7 
Optical coherence tomography (sd-OCT) ................................................ 69 
6.4.8 
Total CS .................................................................................................... 70 
6.5 
Safety ........................................................................................................................... 70 
6.5.1 
Physical examination ................................................................................ 70 
6.5.2 
Vital signs ...................................................................................................... 71 
6.5.3 
Height and weight ............................................................................. 71 
6.5.4 
Laborato1y evaluations .................................................................................. 71 
6.5.5 
Electrocardiogram (ECG) ............................................................................ 72 
6.5.6 
Pregnancy .................................................................................................. 72 
6.5.7 
Meal Record .............................................................................................. 72 
6.5.8 
Chest X-ray ................................................................................................ 72 


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6.5.9 
Ocular assessments ........................................................................................... 73 
6.6 
Pharmacokinetics ................................................................................................................. 74 
6.6.1 
PK Blood Collection and Processing ....................................................... 74 
6.6.2 
Urine Collection and processing .............................................................. 74 
6.6.3 
Pha1macokinetic analytical method(s) .................................................... 74 
6.7 
Other assessments ........................................................................................................... 75 
6.7.1 
Hea lth-related qu ality of Life ................................................................ 75 
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Safety monitoring ........................................................................................................................ 76 
7.1 
Adverse events ...................................................................................................76 
7.2 
Serious adverse event repmt ing ........................................................................................ 78 
7.3 
Pregnancies ...................................................................................................................... 78 
7.4 
Data Monitoring Committee ...................................................................................... 79 
8 
Data  review and database management........................................................................................ 79 
8.1 
Site monitoring ................................................................................................................ 79 
8.2 
Data collection ................................................................................................................. 79 
8.3 
Database management and quality control ................................................................. 80 
9 
Data analysis ...................................................................................................................................... 80 
9.1 
Analysis sets ................................................................................................................80 
9.2 
Subject demographics and other baseline characteristics ......................................... 81 
9.3 
Treatments (study dmg, rescue medication,  other concomitant therapies, 
compliance) ..................................................................................................................... 81 
9.4 
Analysis  of the p1imaiy vai·iable(s) ...................................................................................... 81 
9.4.1 
Response rate .............................................................................................81 
9.5 
Analysis of seconda1y vai·ai bles  ................................................................................81 
9.5.1 
Efficacy / Pharm aco d ynamics........................................................................ 81 
9.5.2 
Safety .........................................................................................................82 
9.5.3 
Health-related quality of Life ...................................................................82 
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9.5.7 
PK/PD ........................................................................................................83 
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9.6 
Sample size calculation ..............................................................................................83 
9.7 
Power for analysis of key secondaiy variables .........................................................83 
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10 Ethical cons iderat ions .............................................................................................................84 
10.1 
Regulatory and ethical compliance ........................................................................ 84 
10.2 
Info1med consent procedure s .....................................................................................84 
10.3 
Responsib ilities  of the investigator and IRB/IEC .................................................. 84 
10.4 
Publication of study protocol and results .............................................................. 85 
11 Protocol adherence .................................................................................................................85 
11.1 
Protocol Amendments ................................................................................................85 
12 References ...............................................................................................................................86 
13 Appendix 1: Blood collection log: blood sampling schedule for safety, PG, PK, PD, 
and immunogenicity ................................................................................................................88 
14 Appendix 2: Sample  labeling and shipping information ......................................................89 
14.1 
Sample labeling ..................................................................................................... 89 
14.2 
Sample shipment instructions .................................................................................... 90 
14.2.1 
Instructions for shipment of PK, PD, PG, and immunogenicity 
samples to the central lab ...................................................................... 91 
14.2.2 
Instructions for shipment of PK, PD, and immunogenicity samples 
from central lab to the bioanalytical lab ................................................ 91 


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List of tables 
Table 1-1 
Table 1-2 
Table 1-3 
 
Table 1-4 
Table 1-5 
 
Table 1-6 
 
Table 1-7 
 
Table 1-8 
 
Table 1-9 
Table 3-1 
Table 5-1 
Table 5-2 
 
Table 6-1 
Table 6-2 
 
List of figures 
LFG316 Completed Studies ..................................................................... 40 
Adverse events by treatment condition from study CLFG316A2101 ..41 
Adverse events by treatment condition from study CLFG316A2102 
(n=24) .................................................................................................... 41 
Summa1y of Adverse Events from CLFG3l 6A2201 .............................. 42 
System Organ Class and Adverse  Events  Observed in 
CLFG316A2202 ............................................................................................ 43 
Incidence of Ocular Adverse Events Obse1v ed in Subjects in 
CLFG316A2202 ....................................................................................... 43 
Incidence of Fatal Adverse Events Obse1ved in Subjects in 
CLFG316A2203-Part A ..................................................................... 44 
Incidence of non-fatal ocular Serious Adverse Events Obse1v ed in 
Subjects in CLFG316A2203-Pa1iA ........................................................ 44 
Mean PK parameters of total LFG316 ...................................................... 46 
Overall study scheme....................................................................................51 
Pe1mitted and concomitant therapies .......................................................... 64 
Prednisone tapering schedule (100 to 10 mg/day prior to Day 1 of 
study) .................................................................................................65 
Vitreous haze scoring ................................................................................ 69 
Anterior chamber cell grading .............................................................. 69 
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List of abbreviations 
 
AC 
Anterior chamber cells 
AE 
Adverse event 
ALT 
Alanine transaminase 
AMD 
Age-related macular degeneration 
AREDS 
Age-Related Eye Disease Study 
AST 
Aspaliate trnnsaminase 
AUC 
Area under the concentration time curve 
-hCG 
Beta human chorionic gonadotropin 
B:MI 
Body mass index 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CFR 
(United States) Code of Federal Regulations 
CK 
Creatine kinase 
CSR 
Clinical study rep01t 
eCRF 
Electrnnic case report / record form 
EDC 
Electronic data capture 
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ETDRS 
Early treatment in diabetic retinopathy study 
FAF 
Fundus autofluorescence 
FDA 
Food and Drng Administration 
FSH 
Follicle stimulating hormone 
GA 
Geographic atrophy 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
IB 
Investigator's brochure 
IMT 
Immuno-Modulat01y Therapy 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
IVT 
Intravitreous(ly), intravitreal(ly) 
LC/MS 
Liquid chromatography/mass spectrometry 


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LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification 
MAC 
Membrane attack complex 
MFC 
Multifocal choroiditis 
mmHg 
Millimeters of mercury 
MRSD 
Maximum recommended staiting dose 
NOAEL 
No-observed adverse effect level 
NIU 
Non-infectious intermediate- , posterior- or panuveitis 
PD 
Phan nacodynamics 
PG 
Phan nacogenomic s 
pH 
Negative log hydrogen ion concentration 
PK 
Pharmacokinetics 
PRN 
Pro re nata (as needed) 
RBC 
Red blood cell/c01puscle 
RPE 
Retinal pigment epithelium 
SAE 
Serious adverse event 
sd-OCT 
Spectral domain ocular coherence tomography 
SUSAR 
Suspected unexpected serious adverse reaction 
TME 
Translational Medicine expe1i 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 


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Glossary of terms 
Screening 
 
 
Emollment 
Investigational drng 
 
Phase 
 
Treatment Period 
 
 
 
Premature 
subject/patient 
withdrawal 
 
Study chug 
 
 
Point/time of subject/patient entry into the study; the point at which 
informed consent must be obtained (i.e., prior to sta1ting any of the 
procedures described in the protocol) 
Point/time of subject/patient randomisation into the study / 
assignment of a randomization number. 
The study chu g whose propert ies  are  being  tested  in  the  study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with "investigational new drug". 
A major subdivision of the study tin1eline; begins and ends  with 
major study milestones such as, Screening, or Study Completion. 
A minor subdivision of the study timeline that divides phases  into 
smaller functional segments, i.e., the time starting from Baseline prior 
first study drug administ:J·.at  i on    unti   l  t h e last day prior the next 
Baseline, or the Study Completion visit. 
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments. At this 
time all study chug administration is discontinued. Study Completion 
assessments must be completed. 
Any  chu g  administered  to  the  subject  as  pa.rt  of  the   req uired 
study procedures; includes investiga.tiona l ch11g and any control and 
comparator chu gs. 


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Protocol synopsis 
LFG316 
 
Title of study: A randomized, active-controlled, open-label, multicenter proof-of concept study of 
intravitreal LFG316 in patients with active non-infectious intermediate-, posterior-, or panuveitis 
requiring systemic immunosuppressive therapy 
Objectives: 
Primary objective(s) 
• 
To assess the effect of intravitreal LFG316 Corporta e Co  n fid  ent  i al  Inf  o n nat i  on   on   t h e p rotocol 
- 
d efin e d , Day 
85 r e s p onse 
ra t e i n t he s t udy eye of patients who meet the inclusion criteria. 
Secondary objective(s) 
• 
To assess the safety and tolerability of intravitreal LFG316 (5 mg q 4 weeks x 3 doses) in 
patients who meet the inclusion criteria. 
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• 
To assess the effect of intravitreal LFG316 Corporate Confidential Information on vitreous haze as 
measured on the Nussenblatt scale, ETDRS visual acuity, macular edema, presence or 
absence of chorioretinal lesions, and anterior chamber cells score in the study eye of patients 
who meet the inclusion criteria, and compare these between Baseline and Days 2, 8, 15, 29, 
43, 57, and 85. 
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• 
To evaluate the serum concentrations of total LFG316 and total CS during the course of the 
study. 
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Study Design: 
Approximately 24 patients with active NIU, in at least one eye, requiring intensification of systemic 
immunosuppressive therapy will be enrolled and randomized in a 2:1  ratio  to  receive  intravitreal 
LFG316 
Corporate Confidential Inform at ion 
. Thr ou g h out the 
stud y , th e fello w e ye m ay be treated as needed; except that certain systemic medications are 
prohibited (see Section 5.5.7 and Section 5.5.8). There will be 1 screening and 8 scheduled  visits over 
85 days for a total of 9 site visits for all patients. 
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Assess ments are listed in the Assessment schedule. Efficacy assessments (ocular assessments and 
photos) will be conducted by personnel masked to the treatment assignment. Low molecular weight 
non-steroidal immunosuppressive medications are allowed up to the baseline day as long as the dose 
has not changed in the 3 weeks prior to baseline, except for corticosteroid doses which may change. 


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Patient Safety 
Safety assessments will include ocular evaluations, adverse events, and serious adverse events. 
Cumulative safety listings will be reviewed by the Principal Investigator and the Novartis Medical 
Director periodically during the study, and ad hoc when necessary. 
Population: 
Approximately 24 patients with active NIU requiring intensification of systemic immunosuppressive 
therapy will be enrolled. 
Inclusion/Exclusion criteria: 
Full inclusion / exclusion criteria are presented in Section 4.1 and Section 4.2, respectively. 
Key inclusion criteria: 
• 
Male or female patients 18 years or older. 
• 
Active NIU, in at least one eye, as defined below, in patients requiring intensification of 
systemic immunosuppressive therapy; 
• 
Vitreous haze at least 1+ on the scale of Nussenblatt et al 1985,or 
• 
Chorioretinal lesions due to uveitis (chorioretinal lesions due to infectious uveitis will 
excludethe patient) 
• 
Patients who present with a flare and who are at the time of the enrollment on systemic 
corticosteroid or non-steroidal immunosuppressants will have their therapy tapered or 
stopped, respectively, at the time of intravitreal LFG316 administration. 
• 
Visual acuity (ETDRS method) of 20 letters (20/400 Snellen equivalent) or better in the study 
eye. 
• 
Female patients must not be pregnant or lactating and must, unless post-menopausal, use 
effective contraception as specified in Section 4.1 of this protocol. 
• 
Ability to provide informed consent and comply with the protocol. 
Key exclusion criteria: 
• 
Uveitis so severe that, in the investigator's judgment, it is too risky to test an experimental 
drug. 
• 
Bilateral uveitis for which, in the opinion of the investigator, systemic immunosuppressive 
therapy is required to manage the inflammation in the fellow eye; use of local therapy in the 
fellow eye is acceptable and not an explicit exclusion (See Section 5.5.7 for acceptable 
concomitant treatments) 
• 
Uncontrolled glaucoma or ocular hypertension in either eye, defined as an intraocular 
pressure (IOP) >30 mmHg while on medication for the specific condition 
• 
Forms of uveitis that may spontaneously resolve such as multiple evanescent white dot 
syndrome (MEWDS). 
• 
In the opinion of the investigator clinically significant abnormality in screening laboratory 
results or electrocardiogram. 
• 
In the study eye, cataract that is expected to interfere with study conduct or require surgery 
during the study. 
• 
History of infectious uveitis or endophthalmitis in either eye. 
• 
History of retinal detachment 
• 
Patients taking corticosteroids or other systemic immunosuppressive medication for any other 
disease (e.g., asthma or other autoimmune disease) where the tapering of the 
immunosuppressant would not be safe because of the risk of exacerbation of the extraocular 
disease 
• 
Any biologic immunosuppressive agent given via intravitreal, intravenous or subcutaneous 
route within 4-12 months of screening depending on the agent. 


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• 
Any intraocular surgery, intravitreal injection, periocular injection, or laser photocoagulation to 
the study eye within 90 days prior to dosing. 
lnvestigational and reference therapy: 
Approximately twenty-four (24) patients will be enrolled and will be randomized 2:1 to either LFG316 
(n=16) Corporate Confidential Infonnation 
LFG316 will be administered to patients randomized to LFG316 on days 1, 29 and 57. 
 
Corporate Cont1ctentl a l 1nt01mat1on 
 
• 
LFG316 solution for injection is a liquid solution provided in vials containing 
 
 
 
Rescue to Conventional Therapy throughout the study: 
Study drug will be discontinued and conventional therapy instituted for any patient that meets the 
following criteria in the study eye: 
• 
Loss of >10 letters in best corrected visual acuity (BCVA) at any visit, as compared to 
baseline that, in the opinion of the investigator, is due to worsening of uveitis. 
• 
Active vitritis, anterior chamber inflammation, or chorioretinitis at least 28 ±3 days after their 
last dose that, in the opinion of the investigator, is significantly worse as compared to the 
previous visit and requires alternate therapy 
• 
Unilateral flare in fellow / non-study eye which does not respond to local treatment (including 
ozurdex® implant) or bi latera l flare in both eyes which require the intensificationof systemic 
immunosuppressivetherapy. 
Concomitant medications/Significant non-drug therapies: 
lntravitreal administration involves certain protocol-specified anesthetics and antibiotics. See the full 
protocol for a complete list of concomitant, permitted, and prohibited medications. 
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Primary endpoint: response rate at Day 85, LFG316 treatment arm. 
A response will be defined by any one of the following criteria in the study eye: 
• 
An improvement of 2 or more steps in vitreous haze, relative to baseline. For the purpose of 
"step" calculation, 0.5 shall count as one of the increments. Thus, improvement from a score 
of 2 to 0.5 or from 1 to 0 would constitute a 2-step improvement or, 
• 
An improvement of 10 or more letters in visual acuity, relative to baseline or 
• 
An improvement of 2 or more steps in anterior chamber cells, relative to baseline , or 
• 
Resolution of chorioretinal lesions as determined by the investigator, or 
• 
Change in central retinal thickness from baseline to Day 85 of 50 micrometer 


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Remission (complete response)  will  be  defined  as  any  patient  who has  a  vitreous haze score of  O or 
0. 5 in the stud y e ye , w ho has an anter ior chamber cell score of O and no chor ioretinal les ions in the 
study eye and is off all immune modulatory therapy (systemic, corticosteroids and topical), without any 
worsening of uveitis during the trial. 
Secondary endpoints: 
• 
Mean changes in BCVA, vitreous haze score, AC cell score, and central retinal thickness on Days 
2, 8, 15, 29, 57 and 85 for both eyes of all patients. 
• 
Mean changes in BCVA, vitreous haze score, AC cell score, and central retinal thickness in 
LFG316 responders on Days 169, 253, and/or 281 (EOES) 
• 
Percentage of eyes that respond (as per responder criteria) on days 2, 8, 15, 29, 57. 
 
 
• 
AE and SAE rates on days 2, 8, 15, 29, 57 and 85 for all patients 
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Sample size determination 
The target sample size for this study is approximately 24 patients, randomized in a 2:1 ratio 
Power calculations are not based 
upon a comparison between LFG316 Corporate Confidential Info1mation but rather on the null 
hypothesis that the response rate in the LFG316 arm (PL FG ) will not diffe r from the lower bound of the 
expected C01porate Confide ntia l fufo n nat ion response rate which is assumed to be 60%. With 16 patients 
in the LFG316 arm,  the null hypothesis  H0: PLFG  :::; 0.60will  be rejected  in  favor  of H1: PLF G  >  0.60,  if 
11 / 1 6 patients in the sample are responders. Such a rejection rule has 17% false positive rate 
(incorrectly reject H0 when it is true) and 45% (80%, 92%) power to correctly reject H0 when the true 
PLFG is 70% (80%, 85%). 


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Analysis methods 
The 90% confidence intervals for the proportion of responders at Day 85 in the LFG316 
as well as the 90% confidence interval for the difference in response 
rates will be reported. The response rates at other time points (e.g., at Days 15, 29, 57) will be 
analyzed similarly. 
Summary statistics for the secondary endpoints and their changes from baseline will be provided by 
treatment group and visit/time. A longitudinal analysis of the secondary PD endpoints may  be 
performed if deemed relevant. Graphical displays of mean time profiles may be constructed as 
appropriate. 
Descriptive statistics of safety data will be provided by treatment group. Adverse events will also be 
analyzed by treatment group. Ocular adverse events will be separately listed and analyzed by study 
eye vs. fellow eye. 


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Protocol No. CLFG316A2204 
 
 
Assessment schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
Study phase 
J 
g> 
c 
u 
en 
Treatment Period 
""-""""'"'""-
Treatment extension for LFG316 
Responders 
c..,.,,,.c. 
Day - 14 
lo -1 
Day 1 
Day 2 
(+1 day) 
Day 8 
(±1 day) 
Day 1 5 
(+/-1 
.-bv\ 
Day 29 
(+/-3 
.-bvsl 
Day 43 
(+/-3 days)
Day',! 
(+/-3days) 
Day85" (± 3 days ) 
PRN
Day 169 
(+/-5 days) 
PRN
Day253 
(+/-5 
davsl 
Day281 
(+/-5 days)
Visit flumbers 
5 
N 
5 
M 
"""' 
5 
... 
"""' 
5 
· ""'' 
5"' 
U) 
-;; 
5 
.... 
5 
"""' 
5"' 
Visi t 9 or 777 
· .; 
5 
;:: 
·0 > 
I"::' 
Informed Consent 
X 
CorporateConfidential Information 
X 
Inclus ion /Excu sion cr iteria 
X 
Relevantmedical historv / Curren t medical conditions 
X 
Den-vv>r nhv 
X 
Ocular historv 
X 
ECG 
X 
X 
X 
I><an,tifis and HIV historv 
X 
Ak:ohol abuse and dn deoendence historv 
X 
Smokino hist= • 
X 
Phvsical exarrina1ion 
X 
X 
X 
Laboratory Safety Tests; incl hematology. blood cherristry and 
urinalvsis 
X 
X 
X 
P""' nancv lest (obtained ore-dose) 
X (serum X (urinel 
X (urinel 
X (urine) 
X (urinel 
X (urine) 
X (urinel 
X (urinel 
Roctv hei<Jht 
X 
Roctv v.eiaht 
X 
X 
X 
X 
X 
X 
X 
ll<XIV ,......,.,,,,ture 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood aressure / Puse rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study co etion infornteion 
X 
Comrnen1s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACM!rse Ew nts (cantured followina initial dose adrrinistrationl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAEs (captureduponsigning ICF until4 v.eeksfollov.ing final 'Asit) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concorri1ant rnedsfTheraoies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LFG316 lntra"1real Dose adrrinistration(sh.fv <Ne onlvl'->A 
X 
X 
X 
x' 
x' 
x' 
x 2,J 
P K sa ecollection (pre-dose) 
Oc •- ••••~ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD /total C5l samnt<> collection Cor e-dosel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corporate ConfidentialInfonnation 
- , 
- 
- - -- 
,  - 
X 


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Protocol  No. CLFG316A2204 
 
 
Corporate Confidential Information 


Novartis 
Amended Protocol Version v05 Clean 
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Protocol  No. CLFG316A2204 
 
 
Ocular Assessment schedule 
 
 
 
CmpooteConfid.mr:ia.lInfannaOOII. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Corporate Confidential Informa 
l 
Study phase 
Screening 
Vis it 
Treatment Period 
End of Study 
(EOS)3 
C01porate Confidentia l Informatio n 
D-14 to -1 
Day 1 
Day 2 
(+1) 
Day 8 
(+1) 
Day 15 
(+/-1) 
Day 29 
(+/3) 
Day 43 
(+/3) 
Day 57 
(+/-3) 
Day 854 (± 3 
day) 
PRN 
Day 169 
(+/-5 
days) 
PRN 
Day 253 
(+/-5 
days) 
Visit Numbers 
Visit 1 
Visit 2 Visi t 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 Visit 9 or 7774
Visit 10 
Visit 11 
Best corrected visual 
acuity (ETDRS) 
ou1 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
lntraocular pressure(IOP) 
OU 
ou2 
OU 
OU 
OU 
ou2 
OU 
ou2 
ou3 
ou2 
ou2 
ou2 
ou2 
;:,,n Iamp oiomIcroscopy 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Spectral domain ocular 
coherence tomography (sd-
OCT) 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Dilated ophthalmoscopy 
OU 
ou2 
ou2 
ou2 
OU 
ou2 
OU 
ou2 
ou2 
ou2 
ou2 
ou2 
ou2 
Color fundus photo 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Standardized Vitreous 
Haze Score 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Anterior Chamber cells 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Chorioretinal lesions 
(absenUpresent per Pl) 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Macular edema due to 
u iti s (absenUpresent per 
P l\ 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 


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Protocol  No. CLFG316A2204 
 
 
1. OU--both eyes and all assessments will be done pre-dose 
Pl: Principal Investigator 
2. Patients receiving LFG316 will have dilated ophthalmoscopyto verify perfusion of the retinal vessels in the study eye immediately after each LFG316 
in jection. IOP should be checked approximately 30 minutes followinQ each LFG316 intravitreal injection in the study eve (SE). 
Corporate Confidential Information 


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Protocol No. CLFG316A2204 
 
 
 
1 
Introduction 
1.1 
Background 
Uve itis refers to approximately 25 different disorders characterized by the presence of 
intraocular inflammation. The major causes of uveitis are infections, systemic immune- 
mediated disease and autoimmune syndromes confined primarily to the eye (Pan et al 2014). 
These diseases are not confined to the uveal tract, comprised of the iris, cilia1y body and 
choroid, but may also include the retina, retinal vessels and other stmctures (Jabs 2008). 
Uveitis is the 5th leading cause of visual impainnent and blindness in the United States 
(Pan et al 2014) and responsible for 10% of blindness worldwide (Jabs 2008). 
Epidemiological studies rep01ied that the incidence of uveitis in the general population varies 
between 17 and 52 cases per 100,000 people per year with a prevalence of approximately 38 
to 714 cases per 100,000 in the population (Miserocchiet al 2013). 
In Western countiies, anterior uveitis accounts for at least 50% of  all  cases  of  uveitis, posterior 
uveitis for 15-30% (Wakefieldand Chang 2005),  and  intermediate  and  panuveitis for the 
balance. The cmTen t conventiona l tl'eatment for non-infectious intermediate-posterior and 
panuveitis includes local and systemic co1ticosteroids with or without the addition of 
co1ticosteroid-sparing  immunomodulato1y  therapy.  Although  these  therapeutic  options  are 
effective in suppressing the inflammation,m ug related co-morbidities and toxicities limit the 
use. 
Noninfectious uveitis is thought to result from inappropriate activation of the immune system 
and is often associated with systemic autoimmune or autoinflammat01y diseases , however 
when no such disease is present these cases are te1med idiopathic. Considering the immune 
mediated natme of uveitis, co1t icosteroids are typically the first line of  therapy  for 
noninfectious uveitis. The route and dose of co1t icosteroids depend on the  severity  of  the 
uveitis and whether the ocular inflammation is confined to the anterior segment (ie, anterior 
uveitis   or   iritis),   the   posterior   segment   (ie,   inte1mediate-,   posterior-uveitis)   or   both 
(ie, panuveitis). Local steroids, which often cause  glaucoma  and cataract,  can  be attempted, 
but systemic steroids are usually necessa1y to control the disease. Many cases of uveitis are 
not controlled with c01t icosteroids alone, or the dose of c01t icosteroids required to persistently 
suppress inflammation is higher than the Cushing threshold (about 8-10 mg prednisone 
equivalent/day). In such cases, one or more steroid-sparing immunosuppressivem u gs are 
used, many of which are used off-label. Many of these steroid sparing therapies, including the 
commonly used methotrexate, take weeks to achieve full efficacy. Cyclosporine has a more 
rapid onset of activity, but at therapeutic levels is commonly associated with other co-
morbidities such as  nephrotoxicity  and  hype1tension,  requiring  frequent  monitoring. Thus, 
there is an unmet need for highly effective rescue therapy for patients with acute or relapsing 
disease, precluding the need for high dose co1ticosteroid therapy  or  prolonged systemic biologic 
therapy (Hazirolan and Pleyer 2013). 


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Protocol No. CLFG316A2204 
 
 
The complement system is pait of the innate immune defense mechanism and is involved in 
modulating various immune and inflammatory respo nses (Yanget al 2012). Within the eye, 
complement plays an important role in the generation and maintenance of tolerogenic/ 
suppressive antigen-presenting cells (APCs). By regulating the production/expression of 
immune mediators, the complement system is required to mount the antigen specific CD4+ 
T-cell-mediated immune responses that cause inflammation in the eye (Jha et al 2010). 
Recent studies have demonstrated that complement system activation is critical for the 
development of autoimmune uveoretinitis. Both local (intravitreal) and systemic suppression 
of the host's complement system with an anti-CS antibody was shown to completely inhibit 
the development and progression of an antigen specific T-cell mediated murine model 
(experimental autoimmune uveitis, EAU) of intraocular inflammation (Copland et al 2010). 
Under norm al condi tions, the complement system is active at baseline level and tightly 
regulated by vai·ious complement regulatory proteins (CRegs) such as complement factor H 
(CFH). CFH is one of the most important regulators in the  alternative complement  pathway 
and is involved in the pathogenesis of immunological diseases. Recent studies suggested that 
variants in the CFH  gene are  associated  with  several  immune-mediated  diseases. 
Activated complement, due to loss of CRegs regulation by CFH, might cause  self-tissue 
damage in sensitive organs like the eyes. In vivo studies have revealed that human RPE cells 
can synthesize and express CFH, and upregulated secretion of CFH by RPE can suppress the 
development of EAU (Yanget al 2012). In previous studies by Yang and Ng, it  has  been 
found that polymorphisms in the CFH gene ai·e assoc iated with the development of 
neovascular age-related macular degeneration (AMD) as well as anterior uveitis in females 
(Yang et al 2011; Ng et al 2008). In addition, CFH polymorphisms have also been found to be 
associated with other immune-mediated diseases such as multi.focal choroiditis, hemolytic- 
uremic syndrome (HUS) and glomernlonephri tis. 
In patients with non-infectious intermediate and posterior uveitis, an association with the 
specific rs800292 (CFH 184 G/A) polymorphism was identified and showe d a recessive effect 
(GG/AG versus AA genotype; odds ratio (95% CI) was 2.74 (1.13-6.62)). In addition, the 
frequency of can iers of the G allele was significantly higher in uveitis patients than  in 
controls (Yang et al 2012). This inform ation, comb ined with non-clinical EAU results and the 
considerable unmet need in noninfectious uveitis, has prompted the hypothesis that 
complement inhibition will be beneficial in this patient; the present study will test this 
hypothesis. 


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Protocol No. CLFG316A2204 
 
 
1.1.1.1 
Relevant data summary 
Corporate Confidential Information 


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Protocol No. CLFG316A2204 
 
Corporate ConfidentialInformation 


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Protocol No. CLFG316A2204 
 
 
Table 1-1 
LFG316 Completed Studies 
Study 
Design 
Route of 
Doses 
N 
Administration 
 
Corporate Confidential Info1mation 
 
 
 
CLFG316A2102 A single-ascending dose 
IVT 
Co1porate C onfide ntial Informa tion 
24; 
Safety and tolerance, 
PK/PD study in age- 
24 LFG316 
related macular 
degeneration 
CLFG316A2201 A multiple dose Safety and 
IV 
4; 
tolerance PK/PD study in 
neovascular age- related 
4 LFG316 
macular degeneration 
 
 
 
 
 
CLFG316A2202 Multiple dose Safety and 
tolerance PK/PD study in 
neovascular age- related 
macular degeneration 
IVT 
45; 
30 LFH316 
15 Sham 
 
 
Corporate Confidential Information 


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Protocol No. CLFG316A2204 
 
 
Corporate Confidential Information 
 
 
 
 
 
 
 
 
CLFG316A2102 
This was a single ascending dose study conducted to assess the safety and tolerability, as well 
as PK and PD of intravitreally administered LFG316 in patients with advanced AMD. 
Corporate Confidential Information 
Overall, There were no drng related adverse events, deaths, 
serious adverse events, or discontinuations. Table 1-3 below summari zes the top 5 most 
frequently repo1et d adverse events obse1ved in this study. Conjunctiva! hemonhage was the 
most frequently reported ocular AE which can be attributed to the intravitreal injection 
procedure. None of the AEs were dose dependent or suspectedto be related to the study drng. 
There was no increase in total CS or inhibition of alternative complement pathway activity. 
Anti-LFG316 antibodies were not detected in this study. The remaining safety assessments 
(e.g. vital signs, ECG, etc) and ocular assessments showedno clinically significantchanges. 
 
Table 1-3 
Adverse events by treatment condition from study CLFG316A2102 
(n=24) 
Corporate Confidential Infonnation 
 
LFG316 
N=6 
LFG316 
N=6 
LFG316 
N=6 
LFG316 
N=6 
Total 
N=24 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Pat ients with AE(s) 
6 (100) 
6 (100) 
3 (50) 
4 (67) 
19 (79) 
Conjunctiva! haemorrhage 2 (33) 
5 (83) 
2 (33) 
2 (33) 
11 (46) 
Eye pain 
2 (33) 
0 
1 (17) 
2 (33) 
5 (21) 
Eye irritation 
1 (17) 
2 (33) 
1 (17) 
0 
4 (17) 
Lacrimation increased 
1 (17) 
1 (17) 
1 (17) 
0 
3 (12) 
Vitreous detachment 
1 (17) 
0 
0 
1 (17) 
2 (8) 
 
Source: CLFG316A2102 CSR, Table 14.3.1-1.1 


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Protocol  No. CLFG316A2204 
 
 
CLFG316A2201 
This study was a multicenter, multiple dose, 2-cohmt trial to assess the safety, tolerability, 
phaimacokinetics, phaimacodynamics, and efficacy of intravenous (IV) LFG316 in patients 
with neovascular age-related macular degeneraiton. Novartis terminated this study and 
stopped recrnitment after 4 subjects had been randomized to the c,..,...Camda,ml..... treatment aim. 
The decision to terminate the study was not due to any safety signal with LFG316. It was 
based upon a consideration of the repmted number of patients with meningococcal infection 
and uncleai· risk of death due  to  meningitis  noted  after  repeated  dosing  with  Soliris® 
(Ec ulizumab), which is an approved antibody against complement factor 5 (C S ) for the 
treatment  of  pai·oxysmal  nocturnal  hemoglobinuria  and  atypical hemolytic   syndrome. 
See Table 1-4 for a summaiy of adverse events. 
 
Table 1-4 
Summary of Adverse Events from CLFG316A2201 
10 mg/kg LFG316 
N=4 
Patients with at least 1 AE 
Anaemia 
Eye pain 
Lacrimation increased 
Photophobia 
Visual acuity reduced 
Vitreous detachment 
Vitreous floaters 
Otitis media 
Diabetes mellitus 
Chronic obstructive pulmonary disease 
Dyspnea 
Source: CLFG316A2201 CSR, Table 14.3.1-1.1 
4 (100) 
1 (25) 
1 (25) 
1 (25) 
1 (25) 
1 (25) 
1 (25) 
1 (25) 
1 (25) 
1 (25) 
1 (25) 
1 (25) 
 
CLFG316A2202 
This study was a repeat-dose Proof-of-Concept study in patients with neovascular (wet) 
AMD. This study used a multicenter, randomized study design to assess the efficacy, safety, 
tolerability, and sernm phaimacokinetics of 3 successivedoses of intravitreally administered 
LFG316. Forty-five (45) subjects were randomized in a 2:1 ratio to either LFG316 "-
""......,...,...... intravitreal injection (30 subjects) or to sham injection. There were no differences 
between the 2 treatment aims in the rate or use of rescue therapy with anti-VEGF on Day 85: 
the number of subjects who required anti-VEGF rescue therapy was 18 (62.1%) and 10 
(66.7%) in the LFG316 and sham-injection aims, respectively. The mean (± SD) anti-VEGF 
rescue therapy rate up to Day 85 was 0.10 (± 0.097) and 0.08 (±0.078)retreatment per week 
in the LFG316 and sham-injectionaims, respectively(15 subjects)for total of 3 doses. 


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Protocol  No. CLFG316A2204 
 
 
fu patients with neovascular (wet) AMD, monthly treatment with LFG3 l 6 eo,p.m.c.., IVT was well 
tolerated with similar safety profile in both treatment groups. None of the AEs resulted in 
discontinuation from the study. No deaths or drug-related SAEs were rep01ted. See Table 1-5 
and Table 1-6 for Systemic and Ocular Adverse Events respectively. 
Table 1-5 
System Organ Class and Adverse Events Observed in CLFG316A2202 
 
LFG316 
N=30 
n(%) 
Sham 
N=15 
n(%) 
Total 
N=45 
n(¾) 
Patients with at leas t 1 AE 
16 (53.3) 
9 (60) 
25 (55.6) 
Infections and infestat ions 
6 (20) 
4 (26.7) 
10 (22.2) 
Injury , poiso ning, and procedura l complications 
5 (16.7) 
1 (6.7) 
6 (13.3) 
Gastro intest inal disorders 
3 (10) 
3 (20) 
6 (13.3) 
Vascular disorders 
2 (6.7) 
3 (20) 
5 (11.1) 
Investigat ions 
3 (10) 
2 (13.3) 
5 (11.1) 
Nervous system disorders 
3 (10) 
1 (6.7) 
4 (8.9) 
Musculoskeletal and connective tissue disorders 
2 (6.7) 
2 (13.3) 
4 (8.9) 
Metabolism and nutrition disorders 
2 (6.7) 
1 (6.7) 
3 (6.7) 
Immune system disorders 
2 (6.7) 
1 (6.7) 
3 (6.7) 
General disorders and administration site conditions 
2 (6.7) 
1 (6.7) 
3 (6.7) 
Cardiac disorders 
1 (3.3) 
2 (13.3) 
3 (6.7) 
Source CLFG316A2202 CSR Table 14.3.1-1.1 
 
Table 1-6 
Incidence of Ocular Adverse Events Observed in Subjects in 
CLFG316A2202 
 
LFG316 
N=30 
n(%) 
Sham 
N=15 
n(%) 
Total 
N=45 
n(%) 
Pat ients with at leas t 1 AE 
10 (33.3) 
4 (26.7) 
14 (31.1) 
Conju nctiva! haemorrhage 
6 (20) 
1 (6.7) 
7 (15.6) 
Source CLFG316A2202 CSR Table 14.3.1-1.3 
CLFG316A2203: 
This is a two-part (A and B) study; 
CLFG316A2203-Pa1t A 
Part A is an ongoing, multicenter, double masked, randomized, multiple dose study to assess 
the efficacy, safety, tolerability, and serum pha1macokinetics of intravitreally administered 
LFG3l 6 (5 mg) in subjects with geographic atrophy. Pait A of the study has recruited the 
planned number of patients (n = 150), all of whom were randomized to receive monthly 
intravitreal LFG316 or sham (2:1 respectively) for 18 months. The cut-off date for the 
following safety rep01t is 8th of May 2015. 


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Protocol  No. CLFG316A2204 
 
 
Serious adverse events: Dmi ng this study, 5 deaths (4 in the LFG3l6 treatment arm , 1 in the 
sham control group) have been rep01t ed and are tabulated below (See Table 1-7). 
 
Table 1-7 
Incidence of Fatal Adverse Events Observed in Subjects in 
CLFG316A2203-Part A 
Cause of death 
Study day 
Causality assessment 
Severe internal bleeding 
Bladder Cancer 
Acute exacerbation of congestive cardiac failure 
Severe clostridium difficile infection 
Deep Vein thrombosis 
87 
81 
200 
308 
172 
Not related to study medication 
Not related to study medication 
Not related to study medication 
Not related to study medication 
Not related to study medication 
Fifty nine non-fatal, non-ocular SAEs were reported by 33 patients. None were deemed to be 
related to the study medication. For further details on these systemic SAEs please refer to 
LFG3161B Edition 9-Table 5-10. 
There were 4 ocular SAEs (Table 1-8). The reduction in visual acuity in the 2 subjects was 
thought to be related to headache or to worsening of the disease. Two subjects developed 
endophthalmitis, 1 on day 400 and the other on day 367. The endophthalmiits cases were 
considered to be procedme related, and were not considered to be related to the study 
medication. In both cases the identified organism was Staph. Epidermidis. The cases occun ed 
in 2 separate geographical locations and based on the differences in antibiotic resistance, are 
likely to be due to 2 different strains of staph epidermidis. To date over 2000 injections of 
LFG316 had occun ed, resulting in an incidence of 0.099%. Therefore, the cun ent rate of 
endophthalmitis per injection of LFG316 is similar to that observed for IVT injections in 
general (0.03% -0.13%) (Nentwichet al 2014, Bhavsar et al 2012). One of the subjects with 
endophthalmitis was discontinueddue to the SAE. 
 
Table 1-8 
 Incidence of non-fatal ocular Serious Adverse Events Observed in 
Subjects in CLFG316A2203-Part A 
Study Day 
Preferred term 
Severity 
Eye type 
269 
Visual acuity reduced 
Moderate 
Both 
401 
Endophthalmitis 
Moderate 
Study 
368 
Endophthalmitis 
Moderate 
Study 
29 
Visual acuity reduced 
Severe 
Both 
Adverse Events: 
The most common non-ocular AEs were upper respiratory tract infection which occmTed in 
17 subjects (11.3%) and hypertension which occun ed in 13 subjects (8.7%), followed by 
nausea, pharyngitis and bronchitis in 12 subjects each (8%). None of the AEs were deemed to 
be related to the study medication. 
The most common ocular AE was conjunctiva! hemonhage which occurred in 99 subjects 
(66%), followed by vitreous floaters (25 subjects; 16.7%), eye pain (19 subjects; 12.7%), 
foreign body  sensation  (17  subjects;  11%),  and  eye  irritation  (16  subjects;  10.7%). 
Two subjects discontinued  due to developing  moderate  choroidal neovascularizationin the 


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Protocol  No. CLFG316A2204 
 
CapamaC 
Ia 
 
study eye. None of the AEs were deemed to be related to the study medication. Instead they 
were deemed to be related to the study procedure. 
CLFG316A2203-Pa1tB 
Part B of the study is a single dose, masked, randomized trial to assess the safety, tolerability 
and sernm pha1macokinetics of intravitreally administered  LFG31_6   . ..  .. ...u.. in patients with 
advanced AMD is completed. 
Eight patients completed the study (7 receiving LFG316 and 1 receiving sham). One patient 
discontinued treatment on Day 15 after developing mild subretinal hemonhage. This was 
deemed to be due to pre-existing condition (neovascular AMD) and not related to the study 
medication. One patient had 3 SAEs of mild severity on Day 87 of the study. These included 
atrial fibrillation, gastrointestinal reflux disease and muscle weakness. None of the SAEs were 
deemed to be related to the study diug. There were no ocular SAEs. 
Three patients receiving LFG316 had AEs. These included one patient with moderate corneal 
dystrophy  in  both  eyes,  abno1mal  visual  acuity  test  and  Charles  Bonnet   syndi·ome. 
The patient, who had discontinued on Day 15, also developed conjunctiva!  hemonhage  on 
Day 1. The third patient developed conjunctiva! hemonhage and vitreous floaters on Day 1. 
None of the AEs were deemed to  be related  to the study medication. Conjunctiva! hemonhage 
is a known side effect of IVT injections. 
Single dose of LFG316 
was safe and well tolerated without any diug related adverse 
events. 
 
 
 
Corporate Confidential Information 


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Protocol  No. CLFG316A2204 
 
Corporate Confidential Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 
Study purpose 
The overall purpose of this study is to assess whether int:ravitreal LFG 316 redu ces int:rao cu lar 
inflammation in patients with active non-infectious intermediate--, posterior--, or  panuveitis 
(NIU) who require intensification of systemic immunosuppressive therapy.  If  positive,  the 
results would enable development of a more effective and specific therapy for various f01ms 
ofNIU. 


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Protocol No. CLFG316A2204 
 
 
2 
Study objectives 
2.1 
Primary objectives 
To assess the effect of intravitreal LFG316 Corporate Confidential Information on the protocol-
defined, Day 85 response rate in eyes of patients who meet the inclusion criteria 
The above objective applies to the study eye only. A response will be defined by any one of 
the following criteria in the study eye: 
• 
An improvement of 2 or more steps in vitreous haze, relative to baseline. For the purpose 
of "step" calculation, 0.5 shall count as one of the increments. Thus, improvement from a 
score of 2 to 0.5 or from 1 to 0 would constitute a 2-step improvement, or 
• 
An improvement of 10 or more letters in visual acuity, relative to baseline, or 
• 
An improvement of 2 or more steps in anterior chamber cells score, relative to baseline or 
• 
Absence of chorioretinal lesions as determined by the investigator 
• 
Change in central retinal thickness from baseline to Day 85 of 50 micrometer 
Remission (complete response) will be defined as any patient who has a vitreous haze score of 
0 or 0.5 and who has an anterior chamber cell score of 0 and no chorioretinal lesions in the 
study eye and is off all immune modulat01y therapy (syste mic, c01ticosteroids and topical), 
without any worsening of uveitis during the trial. 
2.2 
Secondary objectives 
• 
To  assess  the safety and tolerabilityof intrnvitreal LFG3l 6 CorporateCo nfiden  t  ia lI  nfo rmta ion 
in 
pa tients  who  meet  the inclusion criteria. 
Corporate Confidential lntormation 
 
• 
To assess the effect of intrnviti-eal LFG3 l 6 CoiporateCon  fdien t ia  l   Infonn    at   io n     on vitreous haze as 
measured on the Nussenblatt scale, ETDRS visual acuity, macular edema,  presence  or 
absence of chorioretinal lesions, and anterior chamber cells score in eyes with active NIU, 
in at least one eye, requiring intensification of systemic immunosuppressive therapy, and 
compared between Baseline and Days 2, 8, 15, 29, 43, 57, and 85. corporateConiirlentiallnfonnation 
 
 
• 
To evaluate the sennn concentrations of total LFG316 and total CS during the course of 
the study. 
The above objective applies to the study eye only. 
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3 
lnvestigational plan 
3.1 
Study design 
This is a multi-center, randomized, active-controlled, open-label, proof-of-concept study. 
The study will be canied out at ocular inflammation specialty clinics globally. Approximately 
24 patients with active N ill , in at least one eye, requiring intensification of systemic 
immunosuppressive therapy will be emolled and randomized in a 2:1 ratio to receive 
intravitreal   LFG316 
Corporate Confidential Information 
Only one eye (designated as the study eye) will be dosed per patient. 
Throughout the study, the fellow eye (non-sh1dy eye) should be examined and treated at the 
investigator's discretion (with the exceptions listed in Table 5-1); this study places no 
restrictions on topical/periocular/intravitreal therapy of the fellow eye. If systemic 
immunosuppressive therapy is required to treat either eye, patient will be placed on 
conventional therapy. 
Low-molecular-weight non-steroidal immunosuppressive medications are allowed up to the 
baseline day as long as the dose has not changed in the 3 weeks prior to baseline, except for 
c01ticoste roid doses for which may change. At baseline, the patient's non-steroidal systemic 
immunosuppression will be discontinued.  If  patients  are  also  receiving  systemic 
c01ticoste roids, a rapid tapering schedule will be initiated in conjunction with their first dose 
ofLFG316 per the tables in Section 5.5.9. 
Efficacy assessments (visual acuity and eye exams) will be conducted by a clinician masked 
to treatment condition. The patient will be instrncted not to divulge his or her treatment 
condition to this examiner. 
Patients randomized to LFG316, will receive  three successive int:rav i treal  doses on Days 1, 
29, and 57. First dose (Day 1) may occur within 14 days of Screening. After the first dose, 
safety, efficacy, and PK assessments will occur at 7 scheduled visits over a 12-week period. 
Corporate Confidential Information 
 
However, patients can 
attend for unscheduledvisits as needed and as determined by the investigator. Patients will be 
monitored for safety and ocular assessments obtained throughout treatment and follow-up 
periods. Patient eligibility will be assessed as outlinedin Figure 3-1 below. 


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A summa1y of the study visits is shown in Table 3-1 below. 
 
Table 3-1 
Overall study scheme 
C01porate Confid ential Information 
 
Screening 
Period 
TreooientPeriod 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Day 
-14 to -1 
1 
2 
8 
1 5 
29 
43 
57
LFG316 5 mg 
Intravitreal 
administration 
(n=16) 
X 
X 
X 
Corporate Confidential Information 
 
 
Corporate Confidential Information 
 
 
 
During the screening period (Day -14 to Day -1), eligibility will be verified though applicable 
ophthalmic/medical histmy, ocular evaluations, vital signs, safety laboratory tests, 
electrocardiogram, and pregnancy test. 
Ocular assessments include: 
• 
Best corrected visual acuity (ETDRS) 
• 
Intraocular pressure (IOP) 
• 
Slit lamp biomicroscopy 
• 
Dilated ophthalmoscopy 
• 
Standardized vitreous haze score (Nussenblatt et al 1985) 
• 
Color fundus photos 
• 
Spectral domain optical coherence tomography (sd-OCT): Study eye unless othe1w ise 
indicated. 


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• 
Anterior chamber cells 
• 
Chorioretinal lesions(absent/present per investigator) 
• 
Vasculitis (absent or present per Investigator) 
• 
Presence of chorioretinal infiltrates due to uveitis 
• 
Macular edema due to uveitis(absent or present per Investigator) 
If either eye would qualify as the study eye, one eye will be selected as the study eye during 
the screening period based on the following criteria 
• 
Higher vitreous haze score; 
• 
If not detennined by vitreous haze score, then by lower visual acuity; 
• 
If not detennined by visual acuity, investigatorpreference. 
At Baseline, vital signs will be checked and compared to eligibility criteria. 
Corporate Confidential Information 
 
 
 
 
 
 
 
In preparation of the LFG316 IVT injection, personnel from the study clinic should follow the 
LFG316 preparation  and instruction manuals.  These are provided separately. 
Patients randomized to LFG316, will receive c ..,..-c-s IVT dose of LFG316. Postdose safety 
assessments and ocular examination will occur after the IVT injection. PK/PD blood 
collection will occur prior to dosing. 
Corporate Confidential Information 
 
Patients will return for scheduled follow-up visits (see Section 3.1), where ocular exams and 
safety assessments will take place. Safety laborato1y studies and ECG will be done at the 
specified times throughout the trial and at the end-of-studyvisit. 
For assessment details, refer to the Assessment schedule. 
 
3.2 
Rationale of study design 
This is a randomized, prospecitve, proof-of-concept study of intravitreal LFG3l 6 in patients 
with active NIU who require intensification of systemic immunosuppressive therapy to 
manage their disease. 
This population has been selected as they may benefit from local anti-CS therapy such as 
LFG316 and reflect a future patient populationfor which this compound may be developed. 
Eligible patients who present with a flare and who are on systemic corticosteroids or non- 
steroid immunosuppressants will have their therapy tapered or stopped, respectively, at the 
time 
of 
intravitreal 
LFG3l6 
administration. 
This 
discontinuation 
of 
systemic 
immunosuppressive therapy will allow for a true assessment of local LFG3l 6 activity in 


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controlling the inflammation associated with NIU. Patients who do not respond to IVT 
therapy can be rescued by the investigator at any time and must be discontinued per protocol 
if their condition worsens or if they lose vision. Corporate Confide ntial Information 
 
 
 
 
 
Patients will be monitored for safety and ocular assessments 
obtained throughout treatment and follow-up periods. 
Corporate Confidential Information 
 
 
 
 
 
 
 
 
Women  of  child-bea1in g potential  (WOCBP)  will  be  included  because  women  are  equally 
affected by NIU and the disease is most prevalent in patients aged  20 to 50 years,  however 
they need to have effective contraception as explained on Section 4.1. 
3.3 
Rationale of dose/regimen, duration of treatment 
Corporate Confidential Information 
The treatment duration of 85 days was 
chosen as the period beyond which lack of response would be confidently  interpreted as lack of 
efficacy; it is based on clinician estimates of the time course of NIU response  to conventional 
therapies. Assessing the p1ima1y endpoint at Day 85 allows assessment of treatment effect after 
the patients have received the full benefit of a course ofLFG316 (3 doses). 
The treatment interval is based on comparison to the pha1macodynamics of other intravitreal 
monoclonal antibodies such as ranibizumab and bevacizumab. Siinilar to other intravitreal 
medications, the appropriate dose and interval will be dete1mined empirica lly in Phase II/III. 
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3.4 
Rationale for choice of comparator 
Not applicable. 
 
3.5 
Risk/ Benefit for this study 
Should int:ravitreal LFG316 be effective in NIU, patients may experience reduced intraocular 
inflammation and improved vision. 
To  date, LFG316 has been administered  to 153 patients via IVT injection,  90 of whom  have 
received  month-ly 
ea.,,,,,,, L FG316 
injections  (See  Section 1.1.1.6)  for  up   to  18   months with 
good safety and  tolerability.   This  includes  the administration of  over 2000 IVT  injections. 
No dmg related toxicity was observed in trials with LFG316 at single doses of up t-o 
with repeat dosing of intravit:real L FG3 l 6 at c_,,.c-o, 
""""'"'and 
IVT administration of LFG3l 6 has been shown to result in relatively low levels of sernm 
antibody concentration and no measurable  suppression of   semm  complement   activity 
(as measured  by the Wieslab assay) 
Corporate Confidential Information 
 
Thus, no systemic complement suppression is suspected in the present 
study with IVT administration. 
However, local immunosuppression could in the01y increase the eye ' s suscept ibility to 
infection, including endophthalmitis. Across all ongoing clinical trials with LFG316, the 
incidence of endophthalmitis (0.09%) has been similar to the background rate of 0.03% to 
0.13% per injection in the general population. With respect to endophthalmitis, the protocol 
uses cmTent best practices to reduce endophthalmitis rates. 
The reportedAEs and SAEs, including deaths, (See Section 1.1.1.6) are in agreement with those 
expected for the various patient populationsand IVT procedures employed in the administration 
of LFG316. Per the Reference Safety inf01mation (See investigator brochure) the expected 
adverse events considered 'Ve1y Common' include conjunctival haemon hage, vitreous floaters, 
vitreous detachment, and increased lacrimation. Events considered 'Common' include 
Endophthalmitis and Increased intraocular pressure. The assignment of 'common' for 
endophthalmitis is based on 2 cases of endophthalmitis observed in 153 patients. Both cases 


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were due to a common skin pathogen (staph. Epidennidis). Overall, these events are most likely 
associated with the injection procedure and not a specific chug-related toxicity. To monitor 
patients for these and other unexpected adverse events a comprehensive panel of ocular safety 
assessments based on the Phase I and Phase II studies with LFG3l 6 as well as that for other of 
intravitreal medications will be conducted on all patients emolled. The study also includes 
systemic safety assessments (serum chemistries, hematology, and electrocardiogram) at 
Screening and end-of-study to fmther profile any systemic changes that could be associated 
with the patient's disease or trnatment with LFG316. 
All IVT injections cany a risk of endophthalmitis, retinal detachment, vitreous or retinal 
hemonhage, cataract, elevated intraocular pressure, and ocular inflammation. LFG316 itself 
could cause, in theo1y, adverse effects such as increased risk of endophthalmitis, cataract, 
elevated intraocular pressure, ocular inflanunation, and retinal toxicity. Patients with NIU are 
at inherent risk for some of these complications. LFG3l 6 could cause existing NIU to worsen. 
Each of the above outcomes would be apparent on eye exam, and most would cause 
symptoms that would prompt the patient to seek evaluation. 
As with any antibody, LFG3 l 6 may cany the risk of hypersensitiivty and patients should be 
monitored and managed per local center practice. LFG3l 6 may elicit immunogenicity and the 
fonnation of anti-LFG316 antibodies; this has not been detected in any LFG316 trials to date. 
Regarding women of childbearing potential (WOCBP): to participate in this study, these 
patients must use effective contraception. Treatment of NIU often requires systemic 
immunosuppressive  therapy with   medications   in   Pregnancy   Categories   D   and   X 
(e.g., mycophenolic acid). By comparison for C5 inhibition with LFG316:  inborn deficiency 
of CS target in mice, inborn deficiency in human offspring, and haploinsufficiency in human 
mothers and fathers have not been associated with reproductive or embryofetal toxicity 
(Rosenfeldet al 1976; Haeney et al 1980; Cesbron et al 1985; Sanal et al 1992; Delgado-
Ce1viiio et al 2005;  Lopez-Lera et al 2009; Zerzri et al 2010). Case se1ies on the use of 
another anti-CS monoclonal antibody, eculizumab, during any or all trimesters of pregnancy 
have not identified any bi1th defects (Danilov et al 2010). For reasons mentioned above, no 
systemic effect on the complement cascade is expected. 
Overall, patients with NIU are expected to derive a benefit from participating in this trial with 
LFG3l 6. In the event activity of LFG3l 6 is not sufficient to control the inflammato1ydisease 
in this patient population, rescue therapy will be implemented per protocol or at the discretion 
of the investigator to minimize the risk to patient's vision. 
 
3.6 
Purpose and timing of interim analyses/design adaptations 
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4 
Population 
The investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria. No additional exclusions should be applied by the investigator, in 
order that the study population will be representative of all eligible subjects. 
Subject selection is to be established by checking through all inclusion/exclusion criteria at 
screening and study baseline. A relevant record (e.g., checklist) must be stored with the source 
documentation at the study site. 
Replacement subjects will be emolled to replace subjects who discontinue  the  study  for 
reasons other than safety, e.g., useof systemic immunosuppressive therapy to rescue fellow eye. 
Deviation from any ently criterion excludes a subject from emollment into the study. It is 
expected that approximately 24 patients with NIU requiring intensification of systemic 
immunosuppressive therapy will be emolled in the study. 
 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study must fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is perf01med. 
2. Male or female patients 18 years or older. 
3. Active NIU, in at least one eye, as defined below, in patients requiring intensification of 
systemic immunosuppressive therapy: 
• 
Viti·eous haze of at least 1+ at screening on the scale of Nussenblatt et al 1985, or 
• 
Chorioretinal lesions due to uveitis (chorioretinal lesions due to infectious uveitis are 
excluded) 
• 
Patients who present with a flare and who are at the time of the emollment on systemic 
c01ticoste roid or non-steroidal immunosuppressantswill have their therapy tapered or 
stopped, respectively, at the time of intravitreal LFG316 administration. 
4. ETDRS visual acuity of 20 letters (20/400) or better in the study eye. 
5. Women of child-bearing potential (WOCBP), defmed as all women physiologically 
capable of becoming pregnant, unless they are using effective methods of contraception 
during dosing of study treatment and 7 weeks (5 times the te1mi nal half-life) of LFG316. 
Effective contraception methods include: 
• 
Total abstinence (when this is in line with the prefened and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothe1m al, post-ovulation 
methods) and withdrawal are not acceptable methods of conti·aception 
• 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confomed by follow up h01mone level assessment 
• 
Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male pa1tn er should be the sole pa1tner for that subject 


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• 
Banier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spennicidal foam/gel/film/cream/ vaginal 
supposito1y 
• 
Use of oral, injected or implanted ho1monal methods of contraception or other fo1ms 
of ho1mona l contraception that have comparable efficacy (failure rate <l %, ) 
example ho1mone vaginal ling or t1ansde1mal ho1mone contraception 
• 
Placement of an intrauterine device (IUD) or intrauterine system (IDS) 
for 
• 
In case of use of oral contraception women should have been stabile on the same pill 
for a minimum of 3 months before taking study treatment. 
6. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
4.2 
Exclusion criteria 
Patient s fulfilling any of the following criteria are not eligible for inclusion in this study: 
Clinically   significant  abno1mality   in   screening  laborato1y   results   or   electrocardiogram 
(see below for definition on the te1m "clinicall y significant " . 
1. Uveitis that is so severe that, in the investigator's judgment, it is too Iisky to test an 
experimental drng. 
2. Bilateral uveitis for which, in the opinion of the investigator, systemic immunosuppressive 
therapy is required to manage the inflammation in the fellow eye; use of local therapy in 
the fellow eye is acceptable and not an explicit exclusion (See Section 5.5.7 for 
acceptable concomitant treatments). 
3. Histo1y of retinal detachment 
4. In the study eye, cataract expected to interfere with study conduct or require surgery 
during the study. 
5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the te1mination of gestation, confiimed by a positive hCG 
laboratory test (>5 mIU/ml). 
6. Histmy of hypersensitivity to any monoclonal antibody (mAb). 
7. Histo1y of infectious uveitis or endophthalmitis in either eye 
8. Anticipated need for intraocular surge1y during the study period 
9. Pa1ticipation in another interventional clinical study within 12 weeks prior to the sta1t of 
stud y treatment. 
10. Any medical, psychiatric, or substance-usecondition likely to interfere with the patient's 
pa1ticipation in the study, or likely to cause se1ious adverse events during the study. 
11. Uveitis with an underlying diagnosis that is uncertain and which would reasonably include 
a diseasefor which immunosuppression would be contraindicated (e.g., when the diagnosis 
of ocular lymphoma, histoplasmosis, toxoplasmosi,setc., are a reasonable possibility) or for 
which immunosuppressionis not proven to be beneficial (e.g., acute zonal occult outer 
retinopathy, progressive outer retinal necrosis, acute retinal necrosis syndrome, etc.). 
12. Fo1ms of uveit is that may spontaneously resolve such as multiple evanescent white dot 
syndrome (MEWDS). 


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13. Cunent use of or likely need for systemic medications known to be toxic to the lens, 
retina, or optic ne1ve (e.g., deferoxamin e, chloroquine, ethambutol, etc.). 
14. Change in low-molecular-weight immunosuppressive medications during the 3 weeks 
prior to baseline; this does not apply to co1ticosteroid doses. 
15. Patient is taking co11icosteroids or another systemic immunosuppressive medication for 
any extraocular disease or concunent medical condition unrelated to uveiti s (e.g., 
multiple sclerosis, organ transplantation, moderate or severe asthma, autoimmune disease, 
etc.) and the tapering or discontinuation of the immunosuppression, including 
c011icosteroids would not be safe because of the risk of exacerbation of the extraocular 
condition; the patient would be excluded. 
16. Any systemic immunosuppressive biologic agent given via intravitreal, intravenous or 
subcutaneous route such as: 
• 
Infliximab, daclizumab, etanercept, adalimumab, etc. within 4 months prior to Day 1 
• 
Depleting antibodies, e.g., rituximab and alemtuzumab, are excluded for 12 months 
prior to Day 1 
17. Periocular or intra-vitrealm u gs (e.g., cmticosteroids) administered to the study eye within 
three months prior to Day 1. 
18. Presence of ocular opacities that, in the opinion of the investigator, preclude imaging 
and/or reasonable vitreous haze scoring 
19. Chronic hypotony (IOP < 6 mmHg) in either eye 
20. Ozurdex®  (dexame   tha sone   intra  v itreal  implant) administered in the study eye during the 6 
months prior to Day 1 
21. Retise111®  (fluocinolone 
acetonide intravitreal implant) administered to the study eye 
within the 3 years prior to Day 1. 
22. Topical ocular steroid therapy greater than the equivalent of prednisolone acetate 1% 
eve1y hour while awake within 1 week of Day 1. 
23. Uncontrolled glaucoma or ocular hype11ension in either eye, defined as an intraocular 
pressure (IOP) >30 mmHg while on relevant therapy 
24. Ocular surgery in the study eye within the last 4 months except for a diagnostic vitreous or 
aqueous tap with a small-gaugeneedle. 
25. Laser photocoagulation in the study eye within 3 months prior to Day 1. 
No additional exclusions may be applied by the investigator, in order to ensure that the sh1dy 
population will be representative of all eligible patients. 
 
4.2.1 
Interpretation of laboratory and electrocardiogram results 
Any of the following results in isolation need not be considered clinically significant: low or 
moderately elevated sernm cholesterol or triglycerides; moderately low sernm creatinine; 
moderately elevated sernm glucose in a patient known to have diabetes mellitus; or urine 
white cells or positive leukocyte esterase in an patient without genitourinary symptoms. In the 
setting of a n01mal white blood count, mild anomalies in the leukocyte differential will not be 
considered clinically significant. On electrocardiogram, stable sinus bradycardia will not be 
considered clinically significant. 


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• 
• 
CarparnCoaM. 
• 
• 
• 
• 
CmpamoCca5dcmtwI 
 
5 
Treatment 
5.1 
lnvestigational treatment 
The LFG3 l 6 solution for inject ion is a liquid solution at a concentration of Capon,,°"'"""'""- 
The vials contam 
of active mgred1ent which conesponds to a volume of 
The LFG316 solution for injection is also be manufactured and packaged by Nova1tis and 
supplied to the investigator in bulk in an open label fashion. Both f01mulations are cons idered 
equivalent. 
Medications used as a part for IVT injection procedure need to be recorded in the appropriate 
concunent medication eCRF page. 
5.1.1 
Bio-batch Retention samples 
Not applicable. 
 
5.2 
Treatment arms 
Study patients will be randomized in 2:1 ratio to receive; 
• 
LFG3l 6 (n=16) administered intravitreally or 
Corpora te Confidential Information 
 
5.3 
Treatment assignment 
All study patients will be randomized to either receive c..,...,.~ of LFG316 administered 
intravitreally or coipora1e Confidential Information according to  treatment  assignment.  The randomization numbers 
will be generated using the following procedure to ensure that treatment assignment is 
unbiased and concealed from masked evaluator(s). A  randomization  list  will  be produced 
by, or under the responsibility of Nova1tis Drug Supply Management using a validated system 
that automates the random assignment of treatment aims to randomization numbers in the 
specified ratio. The randomization scheme for patients will be reviewed and approved by a 
member of the randomization office. 
 
5.4 
Treatment masking 
The investigator, patients, and  Nova1tis  will  not  be  masked  to  treatment  condition. 
An evaluator at each site will be masked to treatment condition. The patient will be instructed 
not to divulge his or her treatment assignment to this evaluator. 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Screening number 
Eac h patient screened is assigned a unique screening number. The screening number is a 
combination of the center number that is provided by Novaliis and a three digit number 
sta1ting with 001 for each subject which is assigned by the Investigator. Therefore, if  the 
center number is 1 (any leading O' s in the center number are dropped) the screening numbers 


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will be assigned such as 1001, 1002, 1003, etc. in ascending order. If the center number is 
2 (or 0002), the screeningnumbers will be 2001, 2002, 2003, etc. in an ascending order. 
 
Treatment number 
If the patient is deemed eligible for emollment into the study and will commence the dosing 
period,  site  study  personnel  will  contact  Nova1tis  clinical  trial  leader  or  designee and  a 
treatment number will be assigned for this patient. 
Once assigned to a patient, a treatment number will not be reused. 
There should be a source document maintained at the site which links the screening number to 
the treatment assignment number (once assigned). 
Treatment numbers will be assigned in ascending, sequential order to eligible patients in 
accordance with entry into the study. The u-eatment number becomes the definitive patient 
number as soon as a patient receives the first dose of the respective study treatment. 
The investigator will enter the u-eatment number on the eCRF. 
Patients will be assigned a u-eatment number beginning with 5001 up to 5072. If a patient 
discontinues prior to completingthe trial, they may be replaced. The replacementpatient will 
be assigned a randomization number c01Tesponding to the original patient number and 
treatment (e.g., we will replace patient 5003 with 6003). 
 
5.5.2 
Dispensing the study treatment 
Patients will receive active LFG316 or Coiporateconfidentialinformation according to their assigned 
treatment. LFG316 will be administered in the clinic according to the injection manual. 
Dispensing of 
Corporate ConfidentialInformation 
5.5.3 
Supply, storage and tracking of study treatment 
LFG316 must be received at the study site by a designated person, handled and stored safely 
and properly, and kept in a secured location to which only the Investigator and designated 
staff have access. Upon receipt, the study drugs should be stored according to the instructions 
specified on the drng labels. 
Storage conditions must be adequately monitored and appropriate temperature/humidity logs 
maintained as sourcedata. LFG316 solutionshouldbe storedin a refrigerator at 2 to 8°C. 
LFG316 Solution for Injectionshouldbe administered immediately and should not be used 
after 4 hours of initial opening at room temperature. 
Any waste material (such as syringes and needles) should be disposed of in accordance with 
local requiremenst. The Investigator must maintain an accurate record of the shipment, 
expiration date, and dispensing of study mug in a mug accountability ledger. Drug 
accountability will be noted by the Monitor during site visits and/or at the completion of the 
trial. 


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The following investigation site-provided products should be stored according to the 
manufacturers' package inse1ts: 
• 
ProparacaineHCl 0.5% ophthalmic solution 
• 
Lidocaine2% solution 
• 
Povidone-iodine5% solution 
• 
Approved ophthalmic topical fluoroquinolone 
To the extent possible, same batches/lots of the above mentioned investigation site-provided 
products should be used in the cmTent study. Batch numbers and/or lot numbers should also 
be recorded in a dtug accountability ledger. Note: site standard of care may require use of 
other products than those listed above-in this case the same requirements for storage and 
accountability apply. 
All dmg supplies are to be used only for this protocol and not for any other purpose. 
Unless specifically instructed by Novaitis, the Investigator must not destr·oy any dtug labels, 
or any pa1tly used or unused dt11g supply. 
At the conclusion of the study, and during the course of the study, the Investigator will 
provide a copy of the dtug accountability ledgerto the Monitor. 
Only after receiving a written authorization by Nova1its, the Investigator/designee will send 
all the unused and pa1tly used dtug supplies as well as the empty containers to the address 
provided at the time of authorization for destru ction. 
 
5.5.4 
Instructions for prescribing and taking of study treatment 
Please refer to the manual provided separately, for detailed instru ction on the use of LFG316. 
Procedures and required material related to IVT injection and preparation ai·e detailed in a 
separate manual. 
For the usage of each vial of LFG316 the study personnel should record in the somce 
document the time when the solution is withdrawn in to the injection syringe. 
For each patient the total dose injected (in mg), volume injected and the injection time need to 
be recorded in the somce document and on the Dosage Administr·ation Record eCRF page. 
LFG316 may be prepared by qualified site personnel but the inu-avitreal injection must be 
administered by a qualifiedophthalmologist 
 
5.5.5 
Permitted dose adjustment 
No dose adjustment is pe1mitted. 


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5.5.6 
Rescue 
 
5.5.6.1 
Rescue of study eye 
For any patients who meet the following criteria in the study eye, the study mug will be 
discontinued, and conventional therapy instituted: 
• 
Loss of >10 letters in best conected visual acuity (BCVA) at any visit, as compared to 
baseline that in the opinion of the investigator is due to worsening of uveitis. 
• 
Active vitritis, anterior chamber inflammation, or chorioretinitis 28 ± 3 days after their last 
dose that, in the opinion of the investigator, is significantly worse as compared to the 
previous visit and requires alternate therapy 
• 
Unilateral flare in fellow / non-study eye which does not respond to local treatment 
(including ozurdex® implant) or bilateral flare in both eyes which require the 
intensification of systemic immunosuppressive therapy. 
Patients who are rescued will be asked to attend the per protocol visit schedule for the 
remainder of the trial in order to be followed up for safety. 
Corporate Confidential Information 
 
 
 
 
 
 
 
 
 
 
5.5.6.2 
Rescue of fellow eye 
The investigator will care for the fellow eye at his or her discretion. There are no restrictions 
on topical, periocular, or intravitreal therapy in the fellow eye other than those noted in 
Section 5.5.7; Table 5-1. 
NOTE: If during the trial, a patient requires systemic immunosuppressive therapy for  the 
fellow eye, investigational therapy for the study eye should be stopped and conventional 
therapy instituted. The patient should continue in the study  for  assessment purposes.  
Patients who require systemic immunosuppressive therapy may be replaced to maintain 
adequate study power if the treatment was implemented for the sole purpose of treating the 
fellow eye. 


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5.5.6.3 
Recommended treatment of adverse events 
Ocular adverse events should be treated according to the type of adverse event. For clinically 
significant acute elevation of intraocular pressure (IOP) following LFG316injection, anterior 
chamber paracentesis should be perfo1med and normalization of IOP verified. For sub-acute 
or persistent elevation in IOP, aqueous suppressants may be indicated. Iritis or vitritis should 
be treated in accordance with pe1mitted medications (see below). Endophthalmitis should be 
treated with vitreous paracentesis and culture and/or vitrectomy, as indicated, plus appropriate 
IVT antibiotics per local practice. 
NOTE: In case of an adverse event attributed to IVT LFG316, the investigatormay wish to 
remove the LFG316 by pars plana vitrectomy. 
With any biologic treatment, systemic hypersensitivity reactions are theoretically possible. 
These can manifest with itching, flushing, headache, nausea/voiniting, hypotension, urticaria, 
bronchospasm, or angioedema. Assess and treat for anaphylaxis if indicated, and initiate 
suppmtive  care.  Fluids, vasopressors,  cmticoste roids,  antihistamines,  bronchodliators,  and 
oxygen should be on hand. 
Patients may remain in the study even after receiving treatment for adverse events. 
Medication used to treat AEs must be recorded on the Concoinitant medications/Significant 
non-drng therapies eCRF page after the sta1t of study drng. 
 
5.5.7 
Concomitant, permitted, and prohibited treatments 
Pe1mitted and concomitant therapies are listed in Table 5-1. Concomitant therapies should be 
entered on the appropriated CRF. 


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Table 5-1 
Permitted and concomitant therapies 
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Arm: 
LFG316 treatment arm 
 
 
Eye: 
Complement inhibitor (other 
than LFG316) 
Antibody (other than LFG316) 
lntraocular surgery 
Ocular laser 
Study eye 
Prohibited 
 
Prohibited 
Prohibited 
Prohibited 
Fellow eye 
Prohibited 
 
Prohibited 
Prohibit ed 
Prohibit ed 
Systemic steroid or IMT already 
in use at screening 
 
New systemic steroids or IMT 
lntravitreal medication (other 
than LFG316) 
Periocular/intravitreal steroids 
New topical steroid or anti- 
inflammatory 
Cycoplegic or !OP-lowering 
eyedrops 
Topical/local anesthetics and 
antibiotics used for intravitreal 
administration 
Incidental medications not 
prohibited above 
IMT = lmmuno-Modulatory Therapy 
Pe rmitted up to base line 
Will be titrated / stopped per protocol 
May not be increased in dose or frequency 
Prohibited 
Prohibited 
Permitted 
 
Prohibited 
Permitted 
Prohibited 
Permitted 
 
Permitted 
Permitted 
 
Permitted 
Permitted 
 
 
Permitted 
Permitted 
 
5.5.8 Prohibited treatment 
Prohibited treatments are listed above in Table 5-1. If a patient 1s deemed to reqmre a 
prohibited treatment, he or she should be withdrawn from the study. 
 
5.5.9 Tapering schedule for oral corticosteroids 
If a patient is receiving oral corticosteroids, one of the following schedules will be used for 
tapering the dose. The selection of the reduction schedule will be based on the prednisone 
dose the patient was receiving during the week prior to baseline. 
1. For patients on up to 100 mg of prednisone-equivalent during the week prior to Day 1, the 
cmticosteroid dose should be tapered according to the following scheme (with the exact 
doses detennined by rounding to the nearest 5 mg): week 1, 85% of the baseline dose; 
week 2, 67%; week 3; 50%, week 4, 33%; week 5, 17%; week 6, 8%; weeks 7, 0%. 
Examples of tapering schemes in Table 5-2 are provided for baseline prednisone doses in 
the range 10 to 100 mg/day. During this schedule, when the patient' s prednisone 
equivalent is 20 mg/day or below, the dose should be taken in the morning af ter waking up 
to reduce suppression of the pituita1y and adrenal glands. 
2. For patients who previously had uveitis that was controlled with a systemic immuno- 
suppressive drng or regimen that was discontinued and whose uveitis has flared and in 
whom the resumption of prednisone is not considered the appropriate systemic 
immunosuppressive therapy by the investigator, no prednisone will be given. 


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Table 5-2 
Prednisone tapering schedule (100 to 10 mg/day prior to 
Day 1 of study) 
Dose (mg/day) prior 
100 
90 
80 
70 
60 
50 
40 
30 
20 
15 
10 
to Day 1 
 
Week 
Approx.% 
Actual Daily Doses (mg) 
  
of baseline 
 
1 
83% 
85 
75 
65 
60 
50 
40 
35 
25 
15 
15 
10 
2 
67 % 
65 
60 
50 
45 
40 
35 
25 
20 
15 
10 
5 
3 
50% 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
5 
4 
3%3 
30 
30 
25 
20 
20 
15 
15 
10 
5 
5 
5 
5 
17% 
20 
15 
10 
10 
10 
10 
5 
5 
5 
0 
0 
6 
8% 
10 
5 
5 
5 
5 
5 
5 
0 
0 
0 
0 
7 
0% 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
T he ora l predni sone do se ma y be tapered more rapidly than specified by the appropriate 
schedule above in the following situations: 
• the patient's uveitis is subsiding rapidly and the investigator feels it is safe to accelerate 
the reduction in prednisone or prednisolone dose or 
• the investigator feels the prednisone or prednisolone must be tapered more rapidly because 
of co1ticosteroid-relatedside effects. 
If a patient 's uveitis is not, in the investigator's opinion, improving rapidly enough to safely 
continue the steroid taper, the investigator may maintain the steroid dose for 1-2 additional 
weeks, after which the patient will resume tapering as per the weekly schedules above. This is 
not considered a rescue. 
5.5.1o 
Discontinuation of study treatment and premature subject withdrawal 
Study stopping criteria 
If any of the following criteria is met, study enrollment and dmg administration will stop: 
• 
Two or more incidents of Serious Adverse Events that are, in the opinion of the 
investigator, related to LFG3l 6 treatment and not to the injection procedure. 
• 
The aggregate frequency, severity, and/or dmg relatedness of adverse events merit such. 
• 
The Sponsor requests it. 
If diug administration is stopped, subjects already enrolled may remain in the study for 
observation only. 


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Individual patient withdrawal 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make eve1y eff01i to 
dete1mine the prima1y reason for a subject's premature withdrawal from the study and record 
this info1mation on the Study Completion eCRF. 
The subject should be withdrawn from the trial under the following circumstances (but not 
limited to): 
• 
Withdrawalof info1med consent 
• 
New on set of healthy issues 
• 
Pregnancy 
• 
Any other protocol deviation that results in a significant risk to the subject' s safety 
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
document the steps taken to contact the subject, e.g., dates of telephone  calls,  registered 
letters. 
 
5.5.11 
Emergency unblinding of treatment assignment 
Not applicable. Both patient and investigator are aware of treatment assignment. 
 
5.5.12 
Study completion and post-study treatment 
Eac h patient will be required to complete the study in its entirety, and thereafter no further 
study treatment will be made available to them. The study will complete when the last subject 
completes his/her Study Completion visit, and any repeat assessments associated  with  this visit 
have been documented and followed-up appropriately by the fuvestigator. 
 
5.5.12.1 Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessa1y , 
study patients should be seen as soon as possible and treated as described in Section 5.5.10 for 
a prematurely withdrawn subject. The investigator may be info1med of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject's interests. The investigator will be responsible for info1ming IRBs and/or ECs of the 
early te1m ination of the trial. 


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6 
Visit schedule and assessments 
The timing of assessments required during the study is delineated in the Assessment schedule. 
All data obtained from these assessments must be suppo1ted in the subject' s source 
documentation. Source documentation must be available for all data  collected  during  the 
study and a source documentation verification list provided. 
Should it become necessaiy to repeat an evaluation, the results of the repeat evaluation should 
be captured. 
Patients should be seen for all visits on the designated day with an allowed "visit window" as 
indicated in the Assessment schedule, or as close to it as possible. 
Patients emolledColj)OteraCo  ufitlentiallnfonnationwho discontinue LFG3l 6 treatment prior to Day 85 should 
attend all remaining study visits in accordance with the protocol 
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All baseline assessments must be completed prior to LFG316 administration. 
Minor deviations for the following post-dose assessment times (~10-15 minutes) during 
baseline/Day 1 visit ai·e acceptable based on logistical and operational considerations: 
• 
Vitals signs and body measurements during Baseline/Day 1 visit 
• 
Ocular assessments during Baseline/Day1 visit 
• 
4 hours Post-injection PK/PD blood collection (if applicable) 
There is no strict requirement on the time of day when patients need to return for their 
outpatient follow up visits. 
 
6.1 
Dietary, fluid and other restrictions 
None. 
 
6.2 
Patient demographics/other baseline characteristics 
Demographics 
Date of birth, sex, race, and predominant ethnicity will be collected. 
 
Relevant medical history/ Current medical conditions 
Relevant medical histo1y and cmTent med ica l condit ions will be recorded on the in the eCRF 
until the sta1t of the study drng. 
Histo1y of surgical sterilization and postmenopausal status needs to be captured under relevant 
medical histo1y page in the eCRF. Any event or change in the subject's condition or health 
status occmTing prior to the initial study drng administration will be reported in the Relevant 
medical hist01y/Cun ent med ical cond itions sect ion of the eCRF . 


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Ocular and uveitis history 
Past or concmTent ocular histo1y and histo1y of uveitis diagnosis, progression, and treatments 
will be captured in the eCRF. 
 
Smoking history 
Smoking histo1ywill be recorded in the eCRF. 
 
6.3 
Treatment exposure and compliance 
Patient compliance, based on the completion of the IVT injection, will be evaluated by the 
study investigator. 
 
Drug administration record 
All doses prescribed and dispensed to the subject must be recorded on the Dosage 
Administration Record. 
Date and time of dose administration, including the staii time of the IVT injection, will be 
recorded in the Dosage administration record section of the eCRFs. 
 
Study completion information 
Infmmation on the date the subject last received the study drug, the subject completion or 
discontinuation of the study and the reason for discontinuation of the study will be recorded 
on the Study Completion eCRF page. 
Study Completion evaluations must also be perfo1med when a subject prematmely withdraws 
from the study for whatever reason. 
 
Comments 
All comments related to study conduct will be added to the eCRF. 


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6.4 
Efficacy / Pharmacodynamic assessment 
6.4.1 
Vitreous haze 
Vitreous haze in the study eye will be measmed by the Nussenblatt scale, as described below. 
 
Table 6-1 
Vitreous haze scoring 
Grade O 
No haze 
 
Trace 
Slight blurring of optic disc margin 
Grade 1+ 
Slightly blurred optic nerve and vessels 
Grade 2+ 
Moderately blurred optic nerve and vessels 
Grade 3+ 
Optic nerve head border blurry but visible 
Grade 4+ 
Optic nerve head obscured 
 
6.4.2 
Anterior Chamber cells 
Anter ior chamber cells will be scored as per SUN cliteria (Jabs et al 2005) described below: 
 
Table 6-2 
Anterior chamber cell grading 
Grade Description 
Aqueous Cells 
 
0 
1 cell 
 
0.5 
1-5 cells 
1 
6-15 cells 
2 
16-25 cells 
3 
26-50 cells 
4 
> 50 cells 
6.4.3 
Chorioretinal lesions 
Chorioretinal lesions will be assessed as present or absent by the investigator 
 
 
Corporate Confidential Information 
 
 
 
 
6.4.6 
Visual acuity 
Visual acuity in the study eye will be measured as described in Section 6.5.9.2 this protocol. 
 
6.4.7 
Optical coherence tomography(sd-OCT) 
Spectral domain optical coherence tomography will be performed on both eyes for each 
patient according to the Assessment schedule. sd-OCT images will be transferred according to 
the imaging manual or as directed by the sponsor. 


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6.4.8 
Total cs 
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6.4.8.1 
Total CS sample collection and processing 
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6.4.8.2 
Total CS analytical method 
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6.5 
Safety 
6.5.1 
Physical examination 
Physical examination may be perfo1med by the investigatoror by the patient' s prima1y care 
provider, if properly source-documented. A physical exam perfo1med within 4 weeks of the 
appointeddate will suffice, unless the patient' s medical histo1y has changed in the interim. 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, hea1,t abdomen, back, lymph nodes, 
extremities, vascular system and neurological system. If indicated based on medical hist01y 
and/or symptoms, rectal, external genitalia, breast, and/or pelvic exams may be perfo1med. 
lnfo1mation for all physical examinations must be included in the source documentaiton at 
the study site and will not be recorded the eCRF. Significant findings that are present prior 


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to the sta1tof study drng must be included in the Relevant Medical Hist01y /Cun-ent Medical 
Conditions screen on the subject's eCRF. Significant findings made after the start of study 
diug which meet the definition of an Adverse Event must be recorded on the Adverse Event 
screen of the subject's eCRF. 
 
6.5.2 
Vital signs 
For the pmpose of this study, vital signs will include blood pressure and pulse measurements, 
and otic or oral body temperature. Systolic and diastolic blood pressure and pulse rate will be 
assessed after the subjecthas rested quietly in the sitting position for at least 3 minutes. 
 
6.5.3 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. 
 
6.5.4 
Laboratory evaluations 
In the case where a laborat01y assessment that is listed in the inclusion/exclusion criteria is 
considered a clinically significant abnormality at screening, the assessment may be repeated 
once (for the pmpose of inclusion), and in any case, prior to emollment, to rnle out laborat01y 
en-or. If the repeat value is still a clinically significant abno1mality, the subject should be 
excluded from the study. 
In the case where a laborat01y range is not specified by the protocol, but is outside the 
reference range for the center at screening, a decision regarding whether the result is of 
clinical significanceor not shall be made by the Investigator and shall be based, in pa1,t upon 
the nature and degree of the obse1ved abn01mality. The assessment may be repeated once 
(for the purpose of inclusion) and in any case, prior to emollment/randomization,to rnle out 
laboratoryen-or. 
In all cases, the Investigator must document in the source documents, the clinical 
considerations (i.e., result was/was not clinically significant and/or medically relevant) in 
allowing or disallowing the subjectto continue in the study. 
Clinically relevant deviations of laborato1ytest results occun-ing during or at completion of 
the study must be repo1ted and discussed with Nova1t is personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandat01y until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted. 
 
6.5.4.1 
Hematology 
Hemoglobin, hematocrit, RBC, WBC count with differential (monocytes, eosinophils, 
basophils, neutrophisl, lymphocytes) as percentage or as absolute value (depending on the 
standard rep01ting procedure of the central or local lab), and platelet count. 


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6.5.4.2 
Clinical chemistry 
Albumin,   alkaline   phosphatase,   total   bilirnbin,   bicarbonate/CO2,     calcium,   cholesterol, 
chloride, creatinine, CK, y-GT, glucose, LDH, inorganic phosphorus, lipase, amylase, 
magnesium, potassium, total protein, AST, ALT, sodium, triglycerides,BUN and uric acid. 
If the total bilirnbin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirnbin should be differenitated. 
 
6.5.4.3 
Urinalysis 
A midstrean1 urine san1ple (approximately 30 mL) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments. 
A semi-quantitative "dipstick" evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirnbin, ketones, leukocytes and blood. 
If the dipstick result is positive for protein leucocytes and/or blood, the sample will be sent for 
microscopic analysis of WBC, RBC and casts. 
 
6.5.5 
Electrocardiogram (ECG) 
ECGs will be collected at the pre-specified times. Standard 12-lead ECGs will be perfonned. 
Data will include the following: time of ECG, heart rate, PR interval, RR  interval,  QT 
interv al (unconected)and QRS duration. OriginalECG tracings, appropriatelysigned, will be 
archived at study site. This assessment will be evaluated by a central laboratory , but the 
investigator will be responsible for determ ining eligibility based on the ECG. 
 
6.5.6 
Pregnancy 
Pregnancy tests are required of 
all 
female 
patients 
regardless 
of 
reported 
reproducitve/menopausal status. 
Sernm pregnancy tests will be perfo1med at screening; at all other times urine pregnancy tests 
may be used. A female patient in this study may not receive LFG316 until the screening 
pregnancy test is dete1mi ned to be negative. 
If   a  urine  pregnancy test  is  performed and  is  found  to  be positive,  se1um 
-hCG will be 
perf01med. If serum -hCG is positive, the patient must be discontinued from the trial. 
 
6.5.7 
Meal Record 
Not applicable. 
 
6.5.8 
Chest X-ray 
Not applicable. 


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6.5.9 
Ocular assessments 
 
6.5.9.1 
Post-injection safety assessment 
Following IVT injection of LFG316, perfusion of the central retinal arte1y should be 
verified by indirect ophthalmoscopy; in case of non-perfusion, treat with anterior chamber 
paracentesis. No1malization of intraocular pressure should be verified within 30 minutes of 
the injection. Intraocular pressureshould be re-measured again at 60 minutes post-injection if 
the pressure is elevated > 10 mmHg above baseline or above 30 mmHg when measured at 
30 minutes post-injectio.n 
 
6.5.9.2 
Best corrected visual acuity 
ETDRS best-con ected visual acuity will be obtained in each eye separately under ce1iified 
ETDRS cond itions. This assessment is to be perfo1med prior to pupil dilation. The number of 
letters read con ectly (for each eye) will be recorded in the appropriate eCRF page. 
 
6.5.9.3 
Slit lamp biomicroscopy 
Slit lamp exam of the adnexae, conjunctiva/sclera, cornea, anterior chamber, iris, and lens will 
be obtained on both eye for each patient according to the Assessment schedule. Attention 
should be directed to the presence of any anterior chamber cell or flare. Results from the slit 
lamp biomicroscopyexam (for each eye) will be recorded in the appropriate eCRF page. 
 
6.5.9.4 
Anterior Chamber cells assessment 
Anterior chamber cell score will be evaluated by slit lamp biomicroscopy. The anterior 
chamber cells score will be dete1mined according to the SUN criteria (Jabb et al 2005) as 
described in Table 6-1. 
 
6.5.9.5 
Dilated ophthalmoscopy 
Dilated exam of the vitreous, optic disc, retinal vessels, macula, and retinal periphe1ywill be 
obtained on both eye for each patient according to the Assessment schedule. Dilated 
ophthalmoscopy should be perf01med right after LFG316 IVT injection. Immediate anterior 
chamber paracentesis should be performed if central retinal arte1y is not perfused. 
 
6.5.9.6 
Vitreous haze assessment 
Vitreous haze will be evaluated with an indirect ophthalmoscope and a hand-held 20-diopter 
lens. Haze is defined as a reduction in the clarity of fundus details seen through the vitreous; 
the degree of haze will be quantified by the examiner comparing the view to standard NEI 
photographs (Nussenblatt et al 1985). The standard photographs provide a grading scale with 
photographsof fundi with vitreous haze grades " O" (ze ro), "trace"(which counts as 0.5+), 1+, 
2+, 3+, and 4+. If the amount of vitreous haze appears to fall between two integer grades, the 
value would be recorded as halfway between the grades. For example, if the haze was 
interm ediate  between  that in  the photographs of  grades  1+  and 2, +  the value  would  be 
recorded as 1.5+. The "trace" photographs conespond to 0.5+, so there is no inte1mediate 
value allowed between the grade O and trace, nor between trace and grade 1+. In this protocol, 
the words "step" and "grade" are used synonymously. One step or grade means a change of 


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one full unit except for the "trace" grade. For example, a change from grade 2+ to grade 1+ 
would count as an improvementof one grade (one step), as would a change from grade 2.5+ 
to grade 1.5+. However, a change from grade 1+ to O wo uld count as two grades or two steps, 
since it would include the "trace" grade. A change from 1.5+ to "trace" would count as a 
change of one grade. 
Color fundus photography 
Color fundus photography will be perfo1med on the designated eye(s) for each patient 
according to the Assessment schedule and the imaging manual. Color fundus photos will be 
evaluated according to AREDS scale. Color fundusphotoswill be transfened according to the 
imaging manual provided. 
 
6.6 
Pharmacokinetics 
6.6.1 
PK Blood Collection and Processing 
All blood samples will be taken by either direct venipuncture or an indwelling cannula. For a 
detailed sampling schedule please refer to the Assessment schedule and Section 13-Appendix 1. 
Corporate Confidential Information 
 
 
 
 
 
 
 
 
 
 
For all pa1ticipating patients, the date and exact time of each blood draw must be recorded 
on the PK Blood Collection page in the eCRF. Sampling problems will be noted in the 
Comments section of the PK Blood Collection page eCRF page. 
 
6.6.2 
Urine Collection and processing 
Not applicable. 
 
6.6.3 
Pharmacokinetic analytical method(s) 
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6.7 
Other assessments 
6.7.1 
Health-related quality of Life 
Not applicable. 
 
 
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7 
Safety monitoring 
7.1 
Adverse events 
An adverse event is the appearance or worsening of any undesirable  sign, symptom,  
or medical condition occm1ing after starting the study drng even if the event is not 
considered to be related to study mug. Study mug includes the investigational drng under 
evaluation and the comparator drng or placebo that is given dming any phase of the study. 
Medical conditions/diseases present before starting study drng are only considered adverse 
events if they worsen after starting studym ug. Abnmmal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, or ar·e cons idered 
clinically significant, or require therapy. 
The occunence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detectedwhen they are volunteered 
by the subject during or between visits or through physical examination, laborato1ytest, or 


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other assessments. All adverse events must be recorded on the Adverse Events eCRF with the 
following info1mation: 
1. the severity grade (mild, moderate, or severe) 
2. its relationshipto the study drng(s) (suspected/not suspected) 
3. its duration (sta1t and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
An SAE is defined as an event which: 
• 
is fatal or life-threatening 
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly/birthdefect 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• 
routine treatmentor monitoring of the studied indication,not associatedwith any 
deterioration in condition 
• 
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the sta1t of study drng 
• 
treatment on an emergencyoutpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• social reasons and respite care in the absence of any deterioration in the patient's 
general condition 
• 
is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomeslisted above 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
If an adverse event involves an eye, the affected eye(s) must be specified. 
All  adverse  events  should  be  treated  appropriately.  Treatment   may  include  one  or  more 
of the following: no action taken (i.e., fu1ther obse1vation only); study drng dosage 
adjusted/temporarily intenupted; study drng perm anen tly discontinued due to this  adverse 
event; conc01nitant medication given; non-mug therapy given; patient hospitalized/patient' s 
hospitalization prolonged.The action taken to treat the adverse event should  be recorded on  
the Adverse Event eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be pe1manent, and assessment should be made at each visit (or more frequently, if 
necessa1y)of any changes in severity, the suspected relationship to the study drng, the 
inte1ventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational mug can be 
found in the Investigator Brochure (IB) or will be communicated between 1B updates in the 
fmm of Investigator Notifications. This inf01mation will be included in the patient infmmed 
consent and should be discussed with the patient during the study as needed. 


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7.2 
Serious adverse event reporting 
To ensure subject safety, eve1y SAE, regardless of suspected causality, occmTing after the 
subject has provided info1med consent and until 30 days after the subject has stopped study 
pa1ticipation (defined as time of last dose of study mug taken or last visit whichever is later) 
must be repmted to Novartis within 24 hours of learning of its occunence. 
Any SAEs experienced after this 30-day period should only be reported to Novaitis if 
the investigator suspects a causal relationship to the study mug. RecmTent episo des, 
complications, or progression of the initial SAE must be repmted as follow-upto the original 
episode, regai·dless of when the event occurs. This repo1tmust be submittedwithin 24 hours 
of the investigator receiving the follow-up info1mation. An SAE that is considered completely 
umelated to a previously reported one should be repo1ted separately as a new event. 
Info1mation about all SAEs is collected and recorded on the Serious Adverse Event Report 
Fmm. The investigator must assess the relationship of any SAE to study mug, complete the 
SAE Report Form in English, and send the completed, signed fo1m by fax within 24 hours to 
the local Novaitis Drug Safety and Epidemiology Depa1tment. The telephone and telecopy 
number of the contact persons in the local depaitment of Clinical Safety and Epidemiology, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Repo1t Fo1m and the fax confirmation sheet must be kept with the case repo1t 
fo1m documentation at the study site. 
Follow-up information is sent to the same person to whom the original SAE Repmt Form was 
sent, using a new SAE Report Fo1m stating that this is a follow-up to the previously repo1ted 
SAE and giving the date of the original repo1t.  The  follow -up  info1mation should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the subjectcontinued or withdrew from study pa1itcipation. 
If the SAE is not previously documented in the Investigator's Brochure or Package Inse1t 
(new occun ence) and is thought to be related to the Novaitis study drug, a Drug Safety and 
Epidemiology Depa1tment associate may urgently require fu11her info1m ation from the 
investigator for Health Authority repo1ting. Nova1t is may need to issue an Investigator 
Notification(IN) to info1m all investigators invo lved in any study with the same mug that this 
SAE has been repmted. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and repo1ted to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulato1y requirements in 
pa1itcipatingcountries. 
 
7.3 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on study drug must be repo1ted to 
Novaitis within 24 hours of leaining of its occmTence. The pregnancy should be followed up 
to dete1mine outcome, including spontaneous or volunta1yte1mination, details of the birth, 
and the presence or absence of any bilt h defects, congenital abno1malities, or maternal and/or 
newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and repmted by the 
investigator to the local Novaitis Thug Safety and EpidemiologyDepartment. Pregnancy follow-up 
should be recorded on the san1e fo1m and should include an assessment of the possible 


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relationship to the Novartis study drng of any pregnancyoutcome. Any SAE experienced during 
pregnancy must be repo1ted on the SAE Rep01t Fo1m. 
Pre gnancy outcomes are not required for the female partners of the male patients who took 
study drng in this study. 
7.4 
Data Monitoring Committee 
Not applicable. 
 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator' s meeting, a Novartis 
representative will review the protocol and eCRFs with the investigators and their  staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entri es on the eCRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of emollment, and to ensure that study mug is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. 
The investigator must maintain  source  documents  for each subject in  the study,  consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and 
medical inf01mation, laborat01y data , elecu·ocardiog rams, and the results  of any other tests 
or assessments. All information on eCRFs must be u·aceable to these source document s in the 
subject' s file. The investigator must also keep the original informed consent fo1m signed by 
the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confilm 
their consistency with the eCRF enu·ies. Nova1tis monitoring standards require  full 
verification for the presence of inf01med consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and the recording of data that will be used for all primary  
and safety variables. Additional checks of the consistency of the source data with the eCRFs 
are perf01med accord ing to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
 
8.2 
Data collection 
Designated inve stigator staff will enter the data required by the protocol into the 
Electronic Case Report Fo1ms using fully validated software that confo1ms to 21 CFR Pait 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate e1Tor me ssages , allo w the data to be confirmed or co1Tected before 
u·ansfer of the data to the CRO working on behalf of Novartis. The Investigator must 
certify that the data entered into the Electronic Case Report F01ms are complete and accurate. 
After database lock, the investigator will receive a CD-ROM or paper copies of the subject 
data for archiving at the investigational site. 


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8.3 
Database management and quality control 
The data management vendor and Novartis staff will review the data entered into the 
eCRFs by investigational staff for completeness and accmacy and instruct  the  site 
personnel to make any required con ections or additions. Obvious enors are conected by 
Cmed data manager. Queriesare sent to the investigational site using an electJ.·onic data que1y. 
Designated investigator site staff is required to respond to the que1y and confiim or conect the 
data. If the electronic que1ysystem is not used, a paper Data Que1yF01m will be faxed to the 
site. Site personnel will complete and sign the faxed copy and fax it back to Novaitis staff 
who will make the c01Tection to the database. The signed copy of the Data Que1y F01m is kept 
at the investigator site. 
Concomitant medications entered into the database will be coded using the WHO Drng 
Reference List, which employs the Anatomical TherapeuticChemical classification system. 
Medical hist01y/cmTent medical conditions and adverse events will be coded using the 
Medical dictiona1yfor regulatoryactivities (MedDRA) tenninology. 
Throughout the  study,  the  occmTence  of  any  protocol  deviations  will  be  detennined. 
After these actions have been completed and the database has been declared  to  be complete 
and accmate, it will be locked and made available for data analysis. Any changes to  the 
database after that time can only be made by joint written agreement between the Global Head 
of Clinical Info1mation Sciences and the Clinical Franchise Head. 
 
 
Corporate Confidential Information 
 
 
 
 
 
 
 
9 
Data analysis 
9.1 
Analysis sets 
All patients who received study dmg will be included in the safety analysis set. 
All patients in the safety analysis set with evaluable PK data and with no major protocol 
deviations that have an impact on PK data will be included in the PK analysis set. 
Corporate Confidential Information 


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9.2 
Subject demographics and other baseline characteristics 
All data for background and demographic variables will be listed by treatment group and 
patients. For these parameters summary statistics will  be  provided  by  treatment  group 
(i.e., each LFG316 treatment group). 
Corporate Confidential Information 
 
Relevant medical hist01y, cmTent medical conditions, results of laboratory screens, drug  tests 
and any other relevant information will be listedby treatment group and patients. 
 
9.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
Study drug administration (including date, time of injection) will be listed by treatment and 
patients. 
 
9.4 
Analysis of the primary variable(s) 
The primary objective of the study is to assess the effect of IVT LFG3l 6 on Day 85 response 
rate in patients with active NIU requiring intensification of systemic immunosuppressive 
therapy. The analysis of safety data is described in Section 9.5.2. Additionalanalysis of ocular 
safety is described in Section 9.5.8. 
 
9.4.1 
Response rate 
The primary endpoint is the response rate (proportion of patients that respond in the study eye) 
and the remission (complete response)rate at Day 85. The analysis of responserate at Day 85 
will be caITied out on the PD analysis set. Patients will be analyzed as treated. The 90% 
confidence interv als for the proportion of responders in the LFG3l 6 CorporateC onfidential Information 
as well as the 90% confidence interval for the difference in response rates 
will be reported. T he response rates at other time points (e.g., at Days 15, 29, 57) will be 
analyzed similarly. 
Corporate Confidential Information 
 
 
 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy / Pharmacodynamics 
Summary statistics for the secondary endpoints and their changes from baseline will be 
provided  by  treatment   group and visit/time. Corporate Confidential Information 
 
A longitudinal analysis of the secondary PD endpoints may be performed if deemed relevant. 
Graphical displays of mean time profiles may be constructed as appropriate. 


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9.5.2 
Safety 
 
Adverse events 
All infmm ation obtained on adverse events will be listed by treatment group and subject. 
Time since stait of IVT injection will be indicated in the listing. 
The number and percentage of subjectswith adverse events will be listed by treatment group, 
body system and prefen ed term. Ocular adverse events will be tabulated and summarized 
by study eye vs. fellow (non-study) eye. A subject with multiple adverse events within a 
body system or prefened term is only counted once towards the total of this body system or 
prefened term 
Corpora te Co nfidential Information 
 
Concomitant medications I Significant non-drug therapies 
All concomitant therapies will be listed by treatment group and patients. 
 
9.5.3 
Health-related quality of Life 
Not applicable. 
 
9.5.4 
Pharmacokinetics 
Corporate Confidential Information 
 
9.5.5 
Pharmacogenetics I pharmacogenomics 
Corporate Confidential Information 


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9.5.6 
Other assessments 
 
 
Corporate Confidential Information 
Corporate Confidential Information 
 
 
9.5.7 
PK/PD 
Not applicable. 
 
9.5.8 
Ocular assessments 
Corporate Confidential Information 
 
Ocular assessments will be listed by treatment group and patients. 
Summa1y statistics of ocular assessments will be provided by treatment group and visit/time 
point. 
 
 
 
 
 
 
 
 
 
 
 
 
9.7 
Power for analysis of key secondary variables 
Not applicable . 
 
9.8 
Interim analyses 
Corporate Confidential Information 


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10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and repo1ted in accordance with 
the ICH Haimonized Tripa1tite Guidelines for Good Clinical Practice, with applicable local 
regulations(including EuropeanDirective 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
 
10.2 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation),IRB/IEC-approvedinfo1med consent , or, if incapable of doing 
so, after such consent has been provided by a legallyacceptable representative of the patient. 
In cases where the patient' s representative gives consent, the subject should be info1med 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicateassent by personally signing and dating the written info1med 
consent document or a separate assent f01m. Info1med consent must be obtained before 
conducting any study-specific procedures (i.e., all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. 
Nova1tis will provide to investigators in a separate document a proposed info1medconsent 
fo1m that complies with the ICH GCP guideline and regulato1y requirements and is 
considered appropriate for this study. Any changes to the proposed consent f01m suggestedby 
the investigator must be agreed to by Novaitis before sublnission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novaitis monitor after IRB/IEC approval. 
Corporate Confidential Information 
 
 
 
 
In the event that Nova1t is wants to perforn1 testing on the samples that  ai·e not  described in 
this protocol, additional Institutional Review Board and/or ethics comlnittee approval will be 
obtained. 
 
10.3 
Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed info1med consent fo1m must be reviewed and approved by a 
properly constituted Institutional Review Board (IRB) before study stait. A signed and dated 
statement that the protocol and info1med consent have been approved by the IRB must be 
given to Novartis before study initiation. Prior to study stait, the investigator is required to 
sign a protocol signature page confiiming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 


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protocol and to give access to all relevant data and records to Nova1its monitors, auditors, 
Nova1tis Clinical QualityAssmance representatives, designatedagents of Nova1t is, IRBs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigatormust inform Nova1tis immediateyl 
been made. 
 
10.4 
Publication of study protocol and results 
that this request has 
Upon study completion and finalization of the study repo1t the results of this trial may be 
submittedfor publication and/or posted in a publicly accessible  database  of  clinical trial 
results. 
 
11 
Protocol adherence 
Investigators asce1tain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Nova1tis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as no authorized deviations are pennitted. 
If the investigator feels a protocol deviation would improve the conduct of the study this 
must be considered a protocol amendment, and unless such an amendment is agreed upon 
by Novartis and approved by the IRB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by Nova1tis, Health Authorities where required,  and  the  IRB. 
Only amendments that are required for subject safety may be implemented prior to IRB 
approval. Notwithstanding the need for approval of f01mal protocol an1endments, 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, Novartis should be notified of this action and the IRB at the study site should be 
inf01med within 10 working days. 


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12 
References 
Ava ilable upon request. 
Bhavsar AR, Stockdale CR, Feni s FL 3rd, et al (2012) Diabetic Retinopathy Clinical 
Research Network. Update on risk of endophthalmitis after intravit:rea l dtug injections and 
potential impact of elimination of topical antibiotics. Arch Ophthalmiol. 130(6):809-10. 
Cesbron JY, Maillet F, Valance J, et al (1985) Deficit homozygote en CS revele par une 
meningite pmulente a Ne i sser ia m eni n g itidi s . P resse Me d ; 14: 2287 - 89 . 
Co pl a nd D A , Hu ssa in K , B aa las u b ramanian S, et al (2010) Systemic and local anti-CS 
therapy reduces the disease severity in experimental autoimmune uveoretinitis, Clin Exp  hnm 
159:3, 303- 314. 
Danilov AV, Brodsky RA, Craigo S, et al (2010) Managing a pregnant patient with 
paroxysmal nocturnal hemoglobinuria in the era of eculizumab. Molecular Immunol; 
42:105-11. 
Delgado-Cervifto E, Fontan G, L6pez-Trascasa M (2005) CS complement deficiency in a 
Spanish family: molecular characterization of the double mutation responsible for the defect. 
Mol. hnmunol. 42; 105-11. 
Haeney MR, Thompson RA, Faulkner J, et al (1980) RecmTent bacte rial meningitis in patients 
with genetic effects of terminal complement components. Clin Exp hnmunol 40; 16-24. 
Hazirolan D, Pleyer U (2013) Think global - act local: intravit:real dtug delive1y systems in 
chronic noninfectious uveitis. Ophthalmic Res; 49(2):59-65. 
Jabs DA, Nussenblatt RB, Rosenbaum JT (2005); Standardization of uveitis nomenclature for 
reporting clinical data. Results of the First International Workshop. Standardization of Uveitis 
Nomenclature (SUN) Working Group. Am J Ophthalmol; 140(3):509-16. 
Jabs DA (2008) Epidemiology of Uveitis. Ophthalmic Epidemiology 15:283-284. 
Jha P, Bora PS, Bora NS (2010) Role of Complement in Ocular Immune Response, 
Immunology, Inflammation and Diseases of the Eye, Academic Press, 2011 pp 160-164. 
Lopez-Lera A, Gan ido S, de la Cruz RM, et al (2009) Molecular characterization of three new 
mutations causing CS deficiency in two non-related families. Mol Immunol; 46:2340-7. 
Miserocchi E, Fogliato G, Modorati G, et al (2013) Review on the worldwide 
epidemiology of uveitis, Eur J Ophthalmol 2013; 23 (5): 705-717. 
Nentwich MM, Yactayo-Miranda Y, Schwarzbach F, et al. (2014) Endophthalmitis after 
intravitreal injectionL decreasing incidence and clinical outcome-8-year results from a 
tertia1y ophthalmic refe1rnl center. Retina;34(5):943-50. 
Ng TK, Chen LJ, Liu DT, et al (2008) Multiple gene polymmphisms in the complement factor 
h gene are associated with exudative age-related macular degeneration in Chinese. Invest 
Ophthalmol Vis Sci. 49(8):3312-7. 
Nussenblatt RB, Palestine AG, Chan C-C, et al (1985) Standardization of vitreal 
inflammato1y activity in inte1mediate and posterior uveitis. Ophthalmol; 92:467-71. 


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Pan J, Kapur M, McCallum R (2014) Noninfectious Immune-Mediated Uveitis and Ocular 
Inflammation, Cur Allergy Asth Rep, 14(1):409 
Rosenfeld SI, Kelly ME, Leddy JP (1976) Heredit:aiy deficiency of the fifth component of 
complement in man: I. clinical, immunochemica,l and family studies. J Clin Invest; 57:1626-1634. 
Sanal 6, Loos M, Ersoy F, et al (1992) Complement component deficiencies and infection: 
CS, C8 and C3 deficiencies in three families. Eur J Pediatr 151; 676-9. 
Wakefield D, Chang JH (2005) Epidemiology of uveitis. Int Ophthalmol Clin 45:1-13. 
Yang MM, Lai TY, Tam PO, et al (2011) CFH 184G as a genetic risk marker for anterior 
uveitis in Chinese female, Mol Vis. 2011;17:2655-64. 
Yang MM, Lai TY, Tam PO, et al (2012) Complement factor Hand interleukin gene 
polymorphisms in patients with non-infectious inte1mediate and poster ior uveitis . Mol Vis. 
18:1865-72 
Zerzri Y, Kallel-Sellami M, Abdelmalek R, et al (2010) Hereditaiy complement C5 
deficiency: study of 3 Tunisian adult cases and literature review. Tunis Med. 88(4); 269-76. 


 
 
 
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13 
Appendix 1: Blood collection log: blood sampling schedule for safety, PG, PK, PD, and 
immunogenicity 
 
StudyPhase 
Visit No 
Visit 
Window 
(Days) 
Time 
point 
Safety; 
Biochem 
and 
hematology 
PK Bloo
Sample
PK Col no. 
PK Sample 
no. 
lmmu noge 
nicity;Anti- 
l FG316 
Immunoge nicit 
y Anti-l FG316 
sample # 
PD Blood
Sample 
Total CS 
PD Blood;
Total CS
Sample # 
Pham,aco 
gene ic 
Sample # 
Pharmacogenetic 
Sample 
ml 
ml 
ml 
ml 
ml 
Screening (Day-14 to -1) 
1 
15 
10 
9999 
Day1 
2 
pre-dose 
5 
1 
10 
5 
101 
5 
201 
Day2 
3 
5 
1 
11 
5 
202 
Day8 
4 
Day15 
5 
+/- 1 
5 
1 
12 
5 
203 
Day29 
6 
+/-3 
pre-dose 
5 
2 
13 
5 
102 
5 
204 
Day43 
7 
+/-3 
5 
2 
14 
5 
205 
Day57 
8 
+/- 3 
pre-dose 
5 
3 
15 
5 
206 
Day85/EOS 
9/777 
+/- 3 
pre-dose 
15 
5 
4 
16 
5 
103 
5 
207 
PRN 
+/- 5 
pre-dose 
5 
5 
17 
5 
104 
5 
208 
Day169 
10 
+/- 5 
pre-dose 
5 
6 
18 
5 
105 
5 
209 
PRN 
+/- 5 
pre-dose 
5 
7 
19 
5 
106 
5 
210 
Day253) 
11 
+/- 5 
pre-dose 
5 
8 
20 
5 
107 
5 
211 
Day281/ EOES 
778 
+/- 5 
15 
5 
8 
21 
5 
108 
5 
212 
Total ml 
45 
60 
40 
60 
10 
Consolidated(approximate) 
total m l : 
215 
I 
I 
I 
I 


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14 
Appendix 2: Sample labeling and shipping information 
14.1 
Sample labeling 
The Samp le Numbers are reported in Section 13-Appendix 1. 
The subject ID, exact clock time of dosing, as well as actual sample collection date and time 
will be recorded using a 24-hour clock on the appropriate blood collection summa1ypage of 
the eCRFs. Sampling problems will be noted in the Notes field of the eCRFs. 
Examples of sample labels for different sample types are presented below. 
 
Sample labeling for serum PK sample 
The sample label is to include the following info1mation: 
Study Code: 
LFG3l 6A2204 
Subject Number: 
5101 
Sample Number: 
Sample l XX (sernm) (ex. 110 (se1um)) 
Vial indicator: 
Required Timepoint: 
And/ Or Study Day: 
Time: 
Date: 
A or B (because resulted se1um is to be split into 2 vials) 
ex. Pre-injection (or other predete1mined timepoints) 
ex. Day 1 
hh:mm (24 hours fo1mat) 
dd-Mmm-YY (ex. 18-Aug-l l) 
 
Sample labeling for serum PD samples (total CS assay) 
The sample label is to include the following info1mation: 
Study Code: 
LFG3l 6A2204 
Subject Number: 
5101 
Sample Number: 
Sample 2XX (sernm) (ex. 201 (se1um)) 
Vial indicator: 
A or B (because resulted sernm is to be split into 2 vials) 
Required Timepoint: ex. Pre-injection (or other predete1mined timepoints) 
And/ Or Study Day: 
ex. Day 1 
Time: 
hh:mm (24 hours format) 
Date: 
dd-Mmm-YY (ex. 18-Aug- l l ) 


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Sample labeling for serum immunogenicity samples 
The sample label is to include the following info1mation: 
Study Code: 
LFG316A2204 
Subject Number: 
5101 
Sample Number: 
Sample 1:XX (eg 101 serum) 
Vial indicator: 
A or B (because resulted setlllll is to be split into 2 vials) 
Required Timepoint: 
ex. Pre-injection (or other predete1mined timepoints) 
And/ Or Study Day: 
ex. Day 1 
Time: 
hh:mm (24 hours fo1mat) 
Date: 
dd-Mmm-YY (ex. 0 l -Oct-11) 
 
14.2 
Sample shipment instructions 
For each  shipment,  an  invent01y  of  the  samples should  accompany  the  shipment. 
This invent01y should include the study ID, subject ID, sample number, visit number, and 
scheduled time of collection. 
Clearly indicate any missing specimens. The original inventoy1 will be retained at the site in 
the Investigator's file. 
All samples will be kept at the temperature specified  up  to  and  during  the  shipment. 
Unless instructed othe1wise, the samples will be packed carefully with suitable packing 
material and d1y ice to keep them frozen. 
All shipments should be sent (Monday through Wednesday only) by a canier guaranteeing 
overnight delivery. The following items should be considered: 
• 
Advise the ca1Tier of the type of service desired, need for personalized door-to-door 
pickup, and delivey1 guaranteed within 24 hours. 
• 
Advise the can ier of the nature of the shipment' s contents (human biological specimens) 
and label the package accordingly. 
• 
Indicate Novaitis drug code and Study No. on the face of the parcel to be shipped. 
The parcel also must cany a "dangerous goods" label because of the dty ice 
(labels supplied by the courier). 
• 
The can ier must be asked to store the parcel(s) in a freezer if shipment is delayed and to 
replaceexhausted dty ice before transpo1t ation continues. 
• 
Shipping reservations should be made to allow delive1y to Novartis before 16:00 (4 pm) 
local time Monday to Thursday and before 11:00 (11 am) local time on Friday. 
Shipmentsshouldnot be sent between Thursday and Sunday, to prevent aITival over the 
weekend. 


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14.2.1 
Instructions for shipment of PK, PD, PG, and immunogenicity samples 
to the central lab 
All study samples (PK, PD, PG, and immunogenicity) will be first sent from the study clinics 
to the central lab for initial storage pending scheduled batch shipments to the appropriate 
analytical lab. Samples should be sent to the following address-unless othe1wise directed by 
Corporate Confidential Information 
 
 
For  each  shipment,  an  invento1y of  the  samples should  accompany   the   shipment. 
This invento1yshould include the study ID, subject ID, sample number, visit number, 
scheduled time of collection. 
Additional inf01mation will be provided by the central lab manual. 
Clearly indicate any Inissing specimens. The original invento1y will be retained at the site in 
the Investigator's file. 
All samples will be kept at the temperature specified up to and during  the  shipment. 
Samples have to be packed according to the ICAO/IATA-Packing-Instrnctionsin an insulated 
box. To guarantee that the samples remain deep frozen during transport, use about 10 kg of 
dry ice per box which will keep the samples frozen during the whole duration of the transp01t 
(air freight). One aliquot of samples will be shipped to the designated Laboratory. The 
remaining aliquots will be shipped to the same address after assurance that the first aliquots 
aITived in good condition. 
Please notif y the addressee above in advance of the shipment and indicate: 
• 
The time and date of shipping and approximate time of aITiva l, 
• 
To whom the shipment is addressed, the study number, the name of the caITier and the 
shipping fo1m number(or equivalentairbill number), 
• 
The sender's name, telephone number and alternative contact personnel, 
• 
The total number of samples, numberof matrices if applicable, and number of ca1tons and 
unit weight of each ca1ton. 
Also notify the Clinical Trial Leader at Nova1tis when a shipment has been scheduled. 
 
14.2.2 
Instructions for shipment of PK, PD, and immunogenicity samples 
from central lab to the bioanalyticallab 
All PK, PD, and immunogenicity specimens will be kept at the temperature specified in the 
PK, PD, and immunogenicity sample collection and processing sections untilshipment. 
Samples have to be packed according to the ICAO/IATA-Packing-Instrnctions in an insulated 
box. To guarantee that the samples remain deep frozen during transport, use about 10 kg of 
dry ice per box which will keep the samples frozen during the whole duration of the transpo1t 
(air freight). 
Please notify the analytical lab contact person in advance of the shipment. 


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Protocol No. CLFG316A2204 
 
 
A shipping log must be included with the shipment. Samples should be shipped with d1y ice 
(use about 10 kg of diy ice per box). 
Selection of the bioanalytical lab is ongoing and will be communicated to the central lab once 
it is finalized. 
Please notify the addressee in advance of the shipment and indicate: 
• 
Number of the airbill, 
• 
The time and date of shipping and approximate time of an ival, 
• 
Flight Number, 
• 
To whom the shipmentis addressed, the study number, canier and the shippingform 
number (or equivalent airbill number), 
• 
The sender's name, telephone number and alternative contact personnel, 
• 
The total number of ca1tons and unit weight of each ca1ton. 
Also notify the Clinical Trial Leader at Nova1tis when a shipmenthas been scheduled. 
The samples should be sent at the beginning of a week in order to anive not later than 
Thursday. 

SAP_000.pdf: 
Clinical Development
LFG316
CLFG316A2204
A randomized, active-controlled, open-label, multiple-dose, 
proof-of concept study of intravitreal LFG316 in patients 
with active non-infectious intermediate-, posterior-, or 
panuveitis requiring systemic immunosuppressive therapy
TSc RAP Module 3: Detailed Statistical Methodology
Author(s):
Document type:
RAP Module 3: Detailed Statistical Methodology
Document status:
Amendment 1/Final
Release date:
28-August-2017
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Data


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................2
1
Introduction to RAP documentation....................................................................................3
1.1
Scope........................................................................................................................3
1.2
Changes to RAP documentation (M3).....................................................................3
2
Study objectives and design ................................................................................................5
2.1
Study objectives.......................................................................................................5
2.2
Study design and treatment......................................................................................6
3
First interpretable results (FIR) ...........................................................................................8
4
Interim analyses...................................................................................................................8
5
Statistical methods: Analysis sets........................................................................................9
6
Statistical methods for Pharmacokinetic (PK) parameters................................................12
7
Statistical methods for Efficacy and Pharmacodynamic (PD) parameters........................12
7.1
Primary endpoint ...................................................................................................12
7.2
Secondary Efficacy and PD endpoints ..................................................................13
7.4
Handling of Missing values/censoring/discontinuations.......................................15
7.5
Supportive analyses ...............................................................................................15
8
Statistical methods for safety and tolerability data............................................................15
9
Statistical methods for Immunogenicity data....................................................................16
List of tables
Table 5-2
Protocol deviation codes and analysis sets (included as reference).............. 10
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1
Introduction to RAP documentation
1.1
Scope
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLFG316A2204”. 
Module 3 (M3) provides the description of the statistical methodology used to analyze the 
data, Module 7 (M7) details the presentation of the data, including shells of summary tables, 
figures and listings, and Module 8 (M8) contains programming specifications e.g. for derived 
variables and derived datasets, to support the creation of CSR outputs.
1.2
Changes to RAP documentation (M3)
Refer to corresponding guidances and NIBR RAP Addendum template for detailed 
information on the requirements of documenting changes to RAP documentation.
For the statistical methodology (M3), any major changes occurring before database lock to 
the statistical methodology should be reflected in the RAP M3 documentation via version 
control (new document version to be approved by the trial team as the original module.
Major changes include, but are not limited to, changes in protocol that affect study design and 
statistical methodology. 
Minor changes to the RAP M3 documentation can be captured e.g. by a study note to file / 
note in RAP Addendum or within the CSR itself.  Minor changes include, but are not limited 
to, change in statistical model.  Corrections of typographical errors or modification of spelling 
(from English to American, for example) do not need to be incorporated into the RAP M3 
documentation.
 
 
 
 
 
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2
Study objectives and design 
2.1
Study objectives
2.1.1 Primary objective(s)

To assess the effect of intravitreal LFG316 
 on the 
protocol-defined, Day 85 response rate in the study eye of patients who meet the 
inclusion criteria.
The above objective applies to the study eye only.
2.2.2 Secondary objective(s)

To assess the safety and tolerability of intravitreal LFG316 
 
in patients who meet the inclusion criteria. 
 
 

To assess the effect of intravitreal LFG316 
 on vitreous 
haze as measured on the Nussenblatt scale, ETDRS visual acuity, macular edema, 
presence or absence of chorioretinal lesions, and anterior chamber cells score in eyes 
with active NIU, in at least one eye, requiring intensification of systemic 
immunosuppressive therapy, and compared between Baseline and Days 2, 8, 15, 29, 
43, 57, and 85.
 
 

To evaluate the serum concentrations of total LFG316 and total C5 during the course 
of the study.
The above objectives apply to the study eye only.
 
 
 
 
 
 
 
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
 
 
2.2
Study design and treatment
This is a multi-center, randomized, active-controlled, open-label, proof-of-concept study. The 
study will be carried out at ocular inflammation specialty clinics in the US and UK. 
Approximately 24 patients with active NIU in at least one eye, requiring intensification of 
systemic immunosuppressive therapy will be enrolled and randomized in a 2:1 ratio to 
receive:

 LFG316 
 administered intravitreally (n=16) 
Only one eye (designated as the study eye) will be dosed per patient. If either eye would 
qualify as the study eye, one eye will be selected as the study eye during the screening period
based on the following criteria:
• Higher vitreous haze score
• If not determined by vitreous haze score, then by lower visual acuity
• If not determined by visual acuity, investigator preference.
Throughout the study, the fellow eye (i.e., non-study eye) should be examined and treated at 
the investigator’s discretion. Efficacy assessments (visual acuity and eye exams) will be 
conducted by a clinician masked to treatment condition.
For patients randomized to LFG316, three successive doses will be administered on Days 1 , 
29, and 57. First dose (Day 1) may occur within 0-14 days of Screening. After first dose, 
safety, efficacy, and PK assessments will occur at 6 scheduled visits over a 12-week period. 
 
 
 
 However, patients can attend for 
unscheduled visits as needed and as determined by the investigator. Patients will be monitored 
for safety and ocular assessments obtained throughout treatment and follow-up periods. 
Patient eligibility will be assessed as outlined in Figure 2-1 below. An overall study scheme is 
shown in Figure 2-2 below.
Ocular assessments include:

Best corrected visual acuity (ETDRS)

Intraocular pressure (IOP)

Slit lamp biomicroscopy

Dilated ophthalmoscopy

Standardized vitreous haze score (Nussenblatt et al 1985)

Color fundus photos*

Spectral domain optical coherence tomography (sd-OCT)*

Anterior chamber cells

Chorioretinal lesions (absent/present per PI investigator)

Vasculitis (absent or present per Investigator)
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5
Statistical methods: Analysis sets
Patients will be analyzed and reported based on the treatment received.
All patients who received study drug 
 will be 
included in the safety analysis set.
All patients in the safety analysis set with evaluable PK data and with no major protocol 
deviations that have an impact on PK data will be included in the PK analysis set.
All patients in the safety analysis set with evaluable PD data (Total C5) with no major 
protocol deviations that have an impact on PD data will be included in the PD analysis set.
All patients in the safety analysis set who receive any study treatment 
with evaluable efficacy data for at least one efficacy endpoint/s 
(ocular assessments) and with no major protocol deviations that have an impact on efficacy 
data will be included in the first efficacy (Efficacy 1) analysis set. For the Efficacy 1 analysis 
set, any patient who discontinues after receiving at least one dose of study drug will be 
included up to the time of discontinuation or until the time they received rescue medication.
All patients in the safety analysis set who receive any study treatment 
 with evaluable primary efficacy endpoint 
(response rate and remission rate on Day 85) and with no major protocol deviations that have 
an impact on the primary efficacy endpoint will be included in the second efficacy (Efficacy 
2) analysis set.
 
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Table 5-2
Protocol deviation codes and analysis sets (included as reference)
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from all (safety) analysis in case of these 
PDs: 
Exclude subject completely 
from all (safety) analysis 
sets
I01
ICF not obtained
Yes
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
I01
ICF not obtained
Yes
E07
Deviation from exclusion criterion 7 (V05)
Yes
E11
Deviation from exclusion criterion 11 11(V05)
Yes
Subjects are excluded from Efficacy 1 analysis in case of these 
PDs:
Exclude subject from 
Efficacy 1 analysis set
I01
ICF not obtained
Yes
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Category
Deviation code
Text description of deviation
Data exclusion
E07
Deviation from exclusion criterion 7 (V05)
Yes
E11
Deviation from exclusion criterion 11 11(V05)
Yes
Subjects are excluded from Efficacy 2 analysis in case of these 
PDs:
Exclude subject from 
Efficacy 2 analysis set
I01
ICF not obtained
Yes
I02
Deviation from inclusion criterion 2 (V05)
Yes
I03
Deviation from inclusion criterion 3 (V05)
Yes
I04
Deviation from inclusion criterion 4 (V05)
Yes
I10
Deviation from inclusion criterion 4 (V03-04) 
and 5 (V05)
Yes
E01
Deviation from exclusion criterion 1 (V05)
Yes
E02
Deviation from exclusion criterion 2 (V05)
Yes
E03
Deviation from exclusion criterion 3 (V05)
Yes
E04
Deviation from exclusion criterion 4 (V05)
Yes
E05
Deviation from exclusion criterion 5 (V05)
Yes
E06
Deviation from exclusion criterion 6 (V05)
Yes
E07
Deviation from exclusion criterion 7 (V05)
Yes
E08
Deviation from exclusion criterion 8 (V05)
Yes
E09
Deviation from exclusion criterion 9 (V05)
Yes
E11
Deviation from exclusion criterion 11(V05)
Yes
E12
Deviation from exclusion criterion 12 (V05)
Yes
E13
Deviation from exclusion criterion 13 (V05)
Yes
E14
Deviation from exclusion criterion  14 (V05)
Yes
E15
Deviation from exclusion criterion 15 (V05)
Yes
E16
Deviation from exclusion criterion 16 (V05)
Yes
E17
Deviation from exclusion criterion  17 (V05)
Yes
E20
Deviation from exclusion criterion 20 (V05)
Yes
E21
Deviation from exclusion criterion 21 (V05)
Yes
E22
Deviation from exclusion criterion 22 (V05)
Yes
E24
Deviation from exclusion criterion 24 (V05)
Yes
E25
Deviation from exclusion criterion 25 (V05)
Yes
M01
Use of prohibited medication during the study
Yes


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6
Statistical methods for Pharmacokinetic (PK) parameters
Summary statistics for total LFG316 may be analyzed on the PK analysis set.
Summary statistics of total LFG316 concentrations may be provided by visit/time. Summary 
statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), 
median, minimum, maximum, and the frequency (n, %) of concentrations below the LLOQ. A 
geometric mean will not be reported if the dataset includes zero values.
Total LFG316 concentrations may be expressed as μg/mL. All concentrations below the limit 
of quantification (LLOQ) or missing data may be labeled as such in the concentration data 
listings. Concentrations below the LLOQ may be treated as zero in summary statistics for 
concentration data only.
Arithmetic mean (SD) concentration-time plots as well as overlaying individual 
concentration-time profiles may be provided.
7
Statistical methods for Efficacy and Pharmacodynamic (PD) 
parameters
7.1
Primary endpoint
The primary endpoints are the response rate (proportion of patients that respond in the study 
eye) and the remission rate (complete response) at Day 85.
A response will be defined by any one of the following criteria in the study eye:

An improvement of 2 or more steps in vitreous haze, relative to baseline. For the 
purpose of “step” calculation, 0.5 shall count as one of the increments. Thus, 
improvement from a score of 2 to 0.5 or from 1 to 0 would constitute a 2-step 
improvement or,

An improvement of 10 or more letters in visual acuity, relative to baseline or,

An improvement of 2 or more steps in anterior chamber cells, relative to baseline

Resolution of chorioretinal lesions as determined by the investigator
Remission (complete response) will be defined as 

any patient who has a vitreous haze score of 0 or 0.5 in the study eye, who has an 
anterior chamber cell score of 0 and no chorioretinal lesions in the study eye and is off 
all immune modulatory therapy (systemic, corticosteroids and topical), without any 
worsening of uveitis during the trial.
The analysis of response rate and remission rate at Day 85 will be carried out on the efficacy
analysis sets (Efficacy 1 and Efficacy 2) , with the analysis on the Efficacy 1 analysis set 
being of primary interest.
The baseline value will be defined as Day 1 pre-dose value, or the screening values if the Day 
1 pre-dose value does not exist.


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The response rates and the 90% exact (Clopper-Pearson) confidence intervals in the LFG316 
group 
will be reported.
 
The response rates at other time points 
(Days 2, 8, 15, 29, 43, 57) will be reported and analyzed similarly.
Proportion of responders (90% CI) will be graphically presented at each time point, by 
treatment group using bar charts.
The same analysis will be performed for remission rates as well.
 
 
 
 
At Day 85, the null hypothesis that the response rate of the LFG316 arm (pLFG) is less than 
 
(60%):  H0: pLFG ≤ 0.60, will 
be tested against the alternative hypothesis: H1: pLFG >0.60. The exact (binomial) p-value will 
be reported.  Note that no decision should be made based on this p-value.
No multiplicity adjustments are required for the primary analysis.
Handling of missing values/censoring/discontinuations
If a subject had missing data for any of the parameters needed to derive the responder status, a 
subject was:

Considered as a responder if the subject met any of the responder criteria

Considered as missing if all the parameters for the responder criteria were missing

Considered as a non-responder, if the subject had at least one non-missing parameter 
needed for the responder criteria and had met no criteria to be considered a responder.
If a subject had missing data for any of the parameters needed to derive the remission status, a 
subject was:

Considered as a remission if the subject met all of the remission criteria.

Considered as a non-remission, if the subject did not meet at least one of the remission 
criteria.

Considered as missing, if the subject met all the available remission criteria but not all 
the remission criteria were available.
7.2
Secondary Efficacy and PD endpoints
7.2.1 Efficacy endpoints: Ocular assessments
All analyses in this section will be analyzed on the Efficacy 1 analysis set.
For vitreous haze score (VHS), the number and percentage of subjects will be listed by score 
(0, 0.5/Trace, 1+, 2+, 3+, 4+) for each visit/time and treatment group, separately for the study 
eye and the fellow eye. The number and percentage of subjects will also be listed by steps of 
improvement/worsening (change) from baseline in seven categories (“worsening of vitreous 
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haze score”, “no change”, and “1 – 5 steps of improvement”). The same analysis will be 
performed for anterior chamber cells score (ACCS) with the scores being 0, 0.5, 1, 2, 3, 4,
and the category of improvement/worsening (change) from baseline being “worsening of 
anterior chamber cells”, “no change”, and “1 – 5 steps of improvement”. Frequency tables and 
histograms for both of the original scores and steps of change will be provided for VHS and 
ACCS by eye (study and fellow), treatment group at each visit/time.
Visual acuity will be listed for each visit/time and treatment group, separately for the study 
eye and the fellow eye. Summary statistics will be provided for the raw and the change from 
baseline of best corrected visual acuity by visit/time and treatment group, separately for the 
study eye and fellow eye. Arithmetic mean (SE) will be plotted across time by treatment 
(overlaying) for study eyes and fellow eyes separately. Overlaying individual profiles will be 
plotted across time by treatment (separate) for study eyes and fellow eyes separately.
A longitudinal analysis of best corrected visual acuity will be performed for the study eye. 
Absolute change from baseline will be analyzed by a mixed model with repeated 
measurements. The independent variables will be treatment, time (categorical, i.e. visits until 
Day 85), and treatment-by-time interaction, with baseline and baseline-by-time interaction as
covariates, and subject as a random effect. Within treatment arm estimates and 90% 
confidence interval will be reported. A time plot for least square means and 90% CI by 
treatment (overlaying) will be provided.
Proportion of patients with presence or absence of macular edema, chorioretinal lesions, will 
be tabulated using frequency tables, and graphically represented using bar charts, at each visit, 
by eye (separate).
Percentage of patients that respond per response criterion (for criterion involving central 
retinal thickness, only if applicable) will be reported in each treatment group.
A separate set of summary tables will be produced for those subjects who participate in the 
LFG316 treatment extension, if deemed necessary.
7.2.2 PD endpoint: Total C5 Concentrations
Total C5 will be analyzed on the PD analysis set. Summary statistics of total C5 
concentrations will be provided by treatment and visit/time. Total C5 concentrations will be 
expressed as μg/mL. All concentrations below the limit of quantification (LLOQ) or missing 
data will be labeled as such in the concentration data listings. Concentrations below the 
LLOQ will be treated as zero in summary statistics for concentration data only.
Arithmetic mean (SD) concentration-time plots as well as overlaying individual 
concentration-time profiles will be provided.
 
 
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7.4
Handling of Missing values/censoring/discontinuations
Missing values will not be imputed, but treated as “missing at random” in the primary and 
secondary analyses.
 
8
Statistical methods for safety and tolerability data
All subjects in the safety analysis set will be included in the safety data analysis.
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment and subject. 
Summary statistics will be provided by treatment.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment and subject.
Adverse events
All information obtained on adverse events will be listed by treatment group and subject, 
separately for ocular and non-ocular adverse events. For ocular adverse events, the eye(s) 
involved (study/fellow/both eyes) will be reported in the listings. Time since start of IVT 
injection will be indicated in the listing.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system or preferred term will be only counted once towards the total of this 
body system or preferred term.
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Ocular adverse events will be tabulated and summarized separately for the study eye and for 
the fellow (non-study) eye. An adverse event reported in both eyes will be counted in both 
study and fellow eyes presentations.
 
 
Concomitant medications / Significant non-drug therapies
All concomitant therapies will be listed by treatment group and subject per visit. For systemic 
steroids doses of the therapy needs to be captured.
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/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit.
Standard clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit and abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit.
Special clinical laboratory evaluations
Not applicable.
Ocular assessments
Results from ocular assessments can be used for 
 primary safety analysis 
 
Ocular assessments will be listed by treatment group, and subject, with specification of the 
eye involved (study/fellow).
 
 
Results of other ocular assessments (Slit lamp biomicroscopy, Dilated ophthalmoscopy, Color 
fundus photography and sd-OCT ) will be listed and could be summarized if appropriate.
9
Statistical methods for Immunogenicity data
 
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