A Phase 2b Randomized, Double-masked, Controlled Trial to Establish the Safety and Efficacy of Zimura™ (Complement C5 Inhibitor) Compared to Sham in Subjects With Autosomal Recessive Stargardt Disease
Phase: PHASE2
Conditions: Stargardt's Macular Dystrophy
Sponsor: Astellas Pharma Global Development, Inc.

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A PHASE 2B RANDOMIZED, DOUBLE-MASKED, CONTROLLED TRIAL 
TO ESTABLISH THE SAFETY AND EFFICACY OF ZIMURA™ 
(COMPLEMENT C5 INHIBITOR) COMPARED TO SHAM IN SUBJECTS 
WITH AUTOSOMAL RECESSIVE STARGARDT DISEASE 
 
 
 
PROTOCOL NO: OPH2005 
Amendment C 
Version Date:  
21 Mar 2025 
 
 
SPONSOR: 
Astellas Pharma Global Development, Inc. 
Northbrook, IL 60062, US 
 
 
 
FOR MEDICAL EMERGENCIES, REFER TO THE “SAFETY CONTACT 
LIST” PROVIDED SEPARATELY 
 
 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND 
077902 
NCT 
NCT03364153 
EudraCT 
2017-004783-35 
 
 
                                                            Confidentiality Statement 
 
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information, which is the intellectual property of Astellas. By accepting or reviewing this document, you agree to 
hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s team 
who agrees to hold this information in confidence.   
 
 

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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Protocol Version 
Protocol Version Date 
Protocol Amendment C 
21 Mar 2025 
Protocol Amendment B 
06 Feb 2024 
Protocol Amendment A 
26 Jul 2021 
Original Protocol  
01 Nov 2017 
Amendment C [21 Mar 2025] 
This amendment is considered to be nonsubstantial based on the criteria set forth in 
Regulation (EU) No 536/2014 of the European Parliament.  
Overall Rationale for Amendment C:  
To align the endpoints throughout the protocol in the three sections where they are 
listed: Summary of Protocol Section: Synopsis, Trial Objectives: Section 5.2, Statistical 
Methods: Section 11.2. To clarify the trial imaging assessments collection timepoints 
and the timepoints that were analyzed by the independent reading center (RC). 
Additional administrative updates and clarifications were also made, prior to unmasking 
of the study. Refer to the table below for the description and brief rationale for each 
change. 
 

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Section # and Name 
Description of Change 
Brief Rationale 
• Section 2 Summary of 
Protocol OPH2005:  
Synopsis Table Endpoints  
• Section 5.2: Endpoints 
Adjusted wording of endpoint descriptions: 
• For applicable endpoints, revised 
description to delete “over 18 months”. 
• For endpoints of rate of change, revised 
description to use “through Month 18”.  
• For endpoints of change from baseline, 
revised description to use “at Month 18”. 
 
Secondary and supportive endpoints were 
split under separate headings. 
 
Removed “mean” from applicable endpoint 
descriptions.  
For clarity and consistency in endpoint 
presentation throughout the protocol. 
• Section 2 Summary of 
Protocol OPH2005:  
Synopsis Table Endpoints  
• Section 5.2: Endpoints 
Removed “at the position of maximum width 
of ellipsoid zone loss” from the applicable 
supportive endpoint. 
Following the internal sponsor review and 
discussions with the RC, it was decided that the 
secondary endpoint of outer nuclear layer (ONL) 
alignment will now be analyzed through the foveal 
center instead of at the position of maximum 
ellipsoid zone loss. Measuring the maximal ONL 
thickness through the fovea center in the same B-
scan is more accurate, as the position of the 
maximum width of the ellipsoid zone loss can vary 
over time. This variability can cause 
inconsistencies. Therefore, ONL measurements 
will be conducted through the foveal center to 
ensure consistency. 
• Section 2 Summary of 
Protocol OPH2005:  
Synopsis Table Endpoints  
• Section 5.2: Endpoints 
Removed secondary endpoint: 
Mean rate of change in the horizontal width of 
undetectable ellipsoid zone measured by a 
horizontal scan through the foveal center with 
SD-OCT over 18 months.  
The primary endpoint captures the overall 
ellipsoid zone area defect. Measuring the area is 
more effective than measuring the width, as 
ellipsoid zone width can vary between adjacent 
scans and with degeneration of ellipsoid zone. 
Measuring one scan can also yield variability; as 

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Section # and Name 
Description of Change 
Brief Rationale 
disease progresses, you may capture areas of 
degeneration of the ellipsoid zone versus areas of 
absent ellipsoid zone. 
Area measurement takes into account multiple 
scans, providing a more consistent assessment.  
The initial inclusion of this secondary endpoint 
was included as a potential practical clinical 
surrogate of the ellipsoid zone defect using one 
measurement (one number) versus area, which 
requires a calculation. 
Section 3: Schedule of 
Assessments 
 
Superscripted footnote #7 added to 
Microperimetry Testing row in the continued 
portion of the table. 
For consistency and clarity in presentation of this 
optional assessment. 
Section 7: Procedures 
Added text under section heading:  
Imaging assessments are collected at the 
timepoints specified in Section 10.2 “Trial 
Assessments”. The RC will analyze the data 
from three timepoints prior to database lock: 
Screening, Month 9 and Month 18. The 
additional imaging assessments collected at 
Month 3, Month 6, Month 12 and Month 15 
will be stored and made available if needed. 
To clarify which timepoints will be analyzed by the 
RC. 
 
Section 11.2: Endpoints 
Removed endpoint details from the section 
and added cross-reference to Section 5.2. 
For document conciseness.  
Section 11.3: Study Design 
Revised study design description as follows: 
This is a randomized, double masked, Sham 
controlled, Phase 2b trial that will obtain 
evidence regarding the effect of avacincaptad 
pegol on the mean rate of change in the area 
of ellipsoid zone defect (defined as ellipsoid 
zone attenuation in addition to total RPE 
loss) measured by en face SD-OCT over 
For consistency with the change to the description 
of the primary endpoint and to provide clarity and 
accuracy to the meaning of ellipsoid zone defect. 

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Section # and Name 
Description of Change 
Brief Rationale 
from Baseline through Month 18, when 
compared with Sham.    
Section 11.4.3: Statistical 
Analyses 
Revised primary endpoint analysis description 
as follows: 
Primary endpoint will be analyzed using a 
mixed model for repeated measures (MMRM) 
with all available data, using response 
variable of the area of ellipsoid zone defect 
measured by en face SD-OCT over time up to 
Month 18 including baseline and 
post-baseline assessments. The MMRM will 
be used to assess the difference between the 
treatment groups in terms of the rate of 
change (slope) ofin the area of ellipsoid zone 
defect from Baseline through Month 18 
over time of 18 months. For the model,The 
fixed effects will include treatment group 
(avacincaptad pegol or Sham), time, 
pooled geographic region (North America 
or Rest of World) and treatment by time 
interaction. 
• To clarify for readability. 
• To parsimoniously adjust for the randomization 
stratification factor “Site” in the analysis. 
Section 11.4.3: Statistical 
Analyses 
Revised efficacy analysis population as 
follows: 
The efficacy analysis will be conducted on all 
randomized and treated subjects according to 
the intention-to-treat principle. 
To clarify that all randomized patients, irrespective 
of whether they were treated with study drug, will 
be included in the analysis, following the intention-
to-treat principle. 
Entire document 
Administrative updates. 
To provide updated information and clarification 
throughout the protocol. 
 
 

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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS .................................................................................................................. 9 
2. 
SUMMARY OF PROTOCOL OPH2005 ......................................................................................................... 11 
3. 
SCHEDULE OF ASSESSMENTS .................................................................................................................... 13 
4. 
INTRODUCTION ........................................................................................................................................ 15 
4.1 
Stargardt Disease ..................................................................................................................................... 15 
4.2 
Stargardt Disease and Membrane Attack Complex (MAC) ....................................................................... 16 
4.3 
Avacincaptad Pegol .................................................................................................................................. 18 
4.4 
Trial Rationale .......................................................................................................................................... 19 
5. 
TRIAL OBJECTIVES .................................................................................................................................... 19 
5.1 
Objectives ................................................................................................................................................. 19 
5.2 
Endpoints .................................................................................................................................................. 20 
6. 
TRIAL DESIGN ...................................................................................................................................... 20 
7. 
PROCEDURES ...................................................................................................................................... 22 
7.1 
Procedures for Refraction and Vision Testing ........................................................................................... 22 
7.2 
Tonometry ................................................................................................................................................ 22 
7.3 
Ophthalmologic Examination ................................................................................................................... 22 
7.4 
Fundus Photography, Fluorescein Angiography, and Fundus Autofluorescence ...................................... 23 
7.5 
Spectral-Domain Optical Coherence Tomography (SD-OCT) .................................................................... 23 
7.6 
Retinal Sensitivity by Microperimetry ....................................................................................................... 23 
7.7 
Laboratory Tests ....................................................................................................................................... 24 
7.8 
Genetic Samples ....................................................................................................................................... 24 
7.9 
Vital Signs and Physical Examination ....................................................................................................... 25 
7.10 
12-Lead Electrocardiogram ...................................................................................................................... 25 
8. 
SUBJECT POPULATION .............................................................................................................................. 26 
8.1 
Sample Size ............................................................................................................................................... 26 
8.2 
Inclusion Criteria ....................................................................................................................................... 26 
8.3 
Exclusion Criteria ...................................................................................................................................... 27 
9. 
TRIAL MEDICATION .................................................................................................................................. 30 
9.1 
Avacincaptad Pegol .................................................................................................................................. 30 
9.2 
Dose and Administration .......................................................................................................................... 31 
9.3 
Previous or Concomitant Therapy ............................................................................................................ 33 

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10. 
TRIAL CONDUCT ....................................................................................................................................... 34 
10.1 
Subject Enrollment .................................................................................................................................... 34 
10.2 
Trial Assessments ...................................................................................................................................... 34 
10.3 
Withdrawal from Trial .............................................................................................................................. 49 
10.4 
Trial Discontinuation ................................................................................................................................. 50 
11. 
STATISTICAL METHODS ............................................................................................................................ 51 
11.1 
Interventions ............................................................................................................................................. 51 
11.2 
Endpoints .................................................................................................................................................. 51 
11.3 
Study Design ............................................................................................................................................. 51 
11.4 
Masking Procedure ................................................................................................................................... 53 
12. 
ADVERSE EVENTS ..................................................................................................................................... 55 
12.1 
Definition of Adverse Events ..................................................................................................................... 55 
12.2 
Assessment and Reporting of Adverse Events .......................................................................................... 55 
12.3 
Definition of Serious Adverse Events ........................................................................................................ 56 
12.4 
Assessment and Reporting of Serious Adverse Events .............................................................................. 58 
12.5 
Independent Data Safety Monitoring Committee .................................................................................... 58 
12.6 
Exposure in Utero ..................................................................................................................................... 59 
13. 
RESPONSIBILITIES ..................................................................................................................................... 60 
13.1 
Emergency Equipment .............................................................................................................................. 60 
13.2 
Case Report Forms and Trial Documentation ........................................................................................... 60 
13.3 
Drug Accountability/Storage Conditions .................................................................................................. 60 
13.4 
Protocol Compliance ................................................................................................................................. 61 
13.5 
Ethical Aspects .......................................................................................................................................... 61 
13.6 
Institutional Review Board (IRB) or Ethics Committee (EC) Approval and Informed Consent .................. 61 
13.7 
Clinical Trial Insurance .............................................................................................................................. 62 
13.8 
Trial Report and Publications .................................................................................................................... 62 
14. 
MONITORING ........................................................................................................................................... 62 
15. 
REFERENCES ............................................................................................................................................. 63 
16. 
SPONSOR SIGNATURE PAGE ..................................................................................................................... 67 
17. 
APPENDICES ............................................................................................................................................. 68 
17.1 
Method for Evaluating Anterior Chamber Inflammatory Activity ............................................................ 68 
17.2 
Method for Evaluating Vitreous Inflammatory Activity ............................................................................ 69 
17.3 
Procedures for Refraction and Vision Testing ........................................................................................... 70 

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17.4 
Intravitreal Administration Protocol ......................................................................................................... 81 
17.5 
NYHA Functional Classifications ............................................................................................................... 92 
 
 

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1. GLOSSARY OF ABBREVIATIONS 
 
A2E 
N-Retinylidene-N-Retinylethanolamine 
AAV 
Adeno Associated Virus 
ABC 
ATP-Binding Cassette 
AE 
Adverse Event 
atRal 
All-Trans-Retinal 
ALT 
Alanine Aminotransferase 
AMD 
Age-Related Macular Degeneration 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine Triphosphate 
BCVA 
Best corrected visual acuity 
Bsl 
Baseline 
BUN 
Blood Urea Nitrogen 
CFH 
Complement Factor H 
CLIA 
Clinical Laboratory Improvement Amendments 
CRF 
Case Report Form 
CRO     
Contract Research Organization 
CRRY 
Complement Receptor 1-Like Protein Y 
DDAF 
Definite Decrease in Autofluorescence 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EW 
Early Withdrawal 
FA 
Fluorescein Angiography 
FAF 
Fundus Autofluorescence 
FDA 
Food and Drug Administration 
FE 
Fellow Eye 
FP 
Color Fundus Photography 
GA 
Geographic Atrophy 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
HbA1c 
Hemoglobin A1c 
hERG 
Human Ether-a-go-go-Related Gene 
HRA 
High resolution angiography 
IB 
Investigator’s Brochure 
ICH     
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IFU 
Instructions for Use 
IND       
Investigational New Drug 
INN 
International non-proprietary name 

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IOP 
Intraocular Pressure 
IPCV 
Idiopathic Polypoidal Choroidal Vasculopathy 
IRB 
Institutional Review Board 
IRT 
Interactive Randomization Technology  
MAC 
Membrane Attack Complex 
MMRM 
Mixed model for repeated measures 
NLP 
No Light Perception 
NVAMD 
Neovascular Age-Related Macular Degeneration 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography 
OGTT 
Oral glucose tolerance test 
ONL 
Outer Nuclear Layer 
OU 
Both Eyes 
PEG 
Polyethylene Glycol 
RC 
Reading Center 
RNA 
Ribonucleic Acid 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
Scr 
Screening 
SD-OCT 
Spectral Domain-Optical Coherence Tomography 
SE 
Study Eye 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOP 
Standard operating procedure 
STGD 
Stargardt Disease 
STGD1 
Stargardt Disease 1 
WBC 
White Blood Cell 
 
 
 
 

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2. SUMMARY OF PROTOCOL OPH2005 
SYNOPSIS 
TITLE: 
A Phase 2b Randomized, Double-masked, Controlled Trial to 
Establish the Safety and Efficacy of Zimura™ (Complement C5 
Inhibitor) Compared to Sham in Subjects with Autosomal 
Recessive Stargardt Disease 
OBJECTIVES: 
The objectives of this study are to evaluate the safety and 
efficacy of avacincaptad pegol intravitreal injection compared to 
Sham in subjects with autosomal recessive Stargardt disease 1 
(STGD1).  
STUDY DESIGN: 
Subjects will be randomized in a 1:1 ratio to the following dose 
groups: 
• 
Avacincaptad pegol (Zimura™) 
• 
Sham  
Note: The international non-proprietary name [INN] of the 
investigational product, Zimura™, is avacincaptad pegol. 
All subjects will be treated as follows: 
Induction Phase: Administered on Day 1, Month 1, and Month 2 
in the following sequence, 14 days apart: 
• 
D0: Avacincaptad pegol 2 mg/eye or Sham 
• 
D14: Avacincaptad pegol 2 mg/eye or Sham 
Maintenance Phase: Administered monthly (Month 3 – Month 17): 
• 
Avacincaptad pegol 4 mg/eye (administered as two 
injections of avacincaptad pegol 2 mg) 
• 
Sham + Sham 
Monthly doses should be targeted for every 30 days from the last 
monthly visit and must be administered at least 21 days apart.  
There will be a final follow-up visit for all subjects at Month 18. 
ENDPOINTS: 
Primary Efficacy Endpoint 
• 
Rate of change in the area of ellipsoid zone defect 
measured by en face spectral domain-optical coherence 
tomography (SD-OCT) from Baseline through Month 18. 
Secondary Endpoints 
• 
Change in best corrected visual acuity (Early Treatment 
Diabetic Retinopathy Study [ETDRS] letters) from 
Baseline at Month 18. 
• 
Change in photopic and/or mesopic macular sensitivity 
measured by microperimetry (optional assessment) from 
Baseline at Month 18. 
Supportive Endpoints 
• 
Rate of change in the area of atrophic lesion (definite 
decrease in autofluorescence, DDAF) measured by 
fundus autofluorescence (FAF) from Baseline through 
Month 18.  
• 
Rate of change in the thickness of the outer nuclear layer 

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SYNOPSIS 
(ONL) measured by a horizontal scan through the foveal 
center using SD-OCT from Baseline through Month 18. 
• 
Time to persistent vision loss (defined as BCVA loss ≥ 10, 
15 or 20 letters from Baseline at two or more consecutive 
visits through Month 18). 
• 
Emergence of at least one new atrophic lesion (DDAF) 
measured by FAF through Month 18. 
Safety Endpoints: 
• 
Adverse events, vital signs, ophthalmic variables 
[ophthalmic examination, intraocular pressure (IOP), 
fluorescein angiogram (FA), FAF, SD-OCT, 
microperimetry], ECG and laboratory variables.   
PLANNED SAMPLE 
SIZE: 
Approximately 120 subjects will be enrolled in this study, 60 per 
dose group.   
SUBJECT SELECTION: 
Subjects of either gender, aged 18 – 60 years of age (inclusive), 
with the diagnosis of STGD1. 
TEST DRUG DOSAGE: 
Subjects randomized to avacincaptad pegol will receive 6 doses 
of avacincaptad pegol 2 mg and 15 doses of avacincaptad pegol 
4 mg. 
FORMULATION AND 
PRESENTATION: 
Formulation 
Avacincaptad pegol is formulated at a concentration of 20 mg/mL 
(oligonucleotide mass) in 10 mM phosphate buffered saline at pH 
6.8-7.8 as a sterile aqueous solution. The drug product is 
preservative-free and intended for intravitreal injection only. The 
drug product should not be used if cloudy or if particles are 
present.   
Presentation 
The clinical supply kits contain either an avacincaptad pegol 
standard 2R vial [Schott] or an empty 2R vial, along with BD 
syringe and BD filter needle.  
The drug product was originally presented in a USP Type I high 
recovery glass vial that contained a 0.5 mL v-shaped well sealed 
with FluoroTec®-coated, halobutyl rubber stoppers and red 
aluminum crimp seals.  In March 2023, the drug product was 
transitioned to presentation in a 2 mL (ISO 2R) Type I glass vial, 
stoppered with FluoroTec-coated, halobutyl rubber stopper, and 
sealed with aluminum crimp seals.  
Instructions for Use (IFU) are provided directly to the study site. 
Dosing Information  
The avacincaptad pegol 2 mg/eye dose will be administered in a 
total injection volume of 0.1 mL (100 µL).  Avacincaptad pegol 4 
mg/eye will be administered as two 0.1 mL (100 µL) injections. 
Comparator Sham Procedure 
To preserve the randomized treatment arm masking, subjects will 
have the sham procedure performed at study treatment visits. 

 
 
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4. INTRODUCTION  
4.1 
Stargardt Disease 
Stargardt disease (STGD) was first described by the German ophthalmologist Karl 
Stargardt in 1909 in seven patients from two families with visual loss (Stargardt, 1909; 
Fishman, 1976).  Patients presented with an atrophic lesion in the macula that was 
subsequently surrounded with white flecks in the first or second decade of life (Fishman, 
1976; Rotenstreich et al., 2003).  Although, Stargardt is the most common inherited 
macular dystrophy in both children and adults, it is a rare condition with an estimated 
incidence of 10-12.5 in 100,000 with no treatments approved by the Food and Drug 
Administration (FDA) in the United States or by the European Medicines Agency in 
Europe (Strauss et al., 2016).   
Stargardt disease is most commonly inherited in an autosomal recessive manner 
caused by mutations in the ABCA4 gene (Stargardt disease 1 [STGD1]; Allikmets et al., 
1997; Yi et al., 2012; Strom et al., 2012).  The ATP-binding cassette (ABC) transporters 
are the largest and most diverse membrane transport system and associated with many 
important biological processes as well as various severe pathological conditions 
(Higgins, 1992).  ABCA4, also known as ABCR, is a 250-kDa glycoprotein and a 
member of the ABCA subfamily of ABC.  During the visual cycle, in absence of 
adenosine triphosphate (ATP), ABCA4 binds with high affinity and clears N-retinylidene-
phosphatidylethanolamine (Beharry et al., 2004).  Adenosine triphosphate, converts the 
high affinity retinoid binding site to a low affinity site releasing the retinoid as part of the 
transport mechanism (Beharry et al., 2004).  Lacking ABCA4 causes the accumulation 
of retinaldehyde and N-retinylidene-phosphatidylethanolamine in the photoreceptor 
outer segments which in turn leads to the accumulation of N-retinylidene-N-
retinylethanolamine (A2E) bisretinoids in the retinal pigment epithelial (RPE) cells 
(Parish et al., 1998; Weng et al., 1999; Mata et al., 2000; Radu et al., 2008; Wu et al., 
2009; Sparrow et al., 2012).  The accumulation of bisretinoids in the RPE cells is toxic 
and potentially contributes to the pathogenesis of STGD1 (Sparrow et al., 2000; Schutt 
et al., 2000; Finnemann et al., 2002; Lenis et al., 2017).   
The seriousness of the disease and absence of treatment options for patients with 
STGD represents an area of urgent unmet medical need.   
 

 
 
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4.2 
Stargardt Disease and Membrane Attack Complex (MAC) 
Accumulation of bisretinoids leads to the activation of complement system and 
accumulation of membrane attack complex (MAC) in RPE cells, potentially contributing 
to their deterioration over time and resulting in photoreceptor loss and decrease in 
vision (Zhou et al., 2006; Zhou et al., 2009; Lenis et al., 2017).  Bisretinoids and C5b-9 
complex have a damaging effect on the RPE cell function by impacting both lysosomes 
and mitochondria inside the cells (Georgiannakis et al., 2015).   
Photo-oxidation of A2E in RPE cells activates the complement cascade in vitro and 
potentially could contribute to the chronic inflammatory process in the RPE-Bruchs 
membrane interface (Zhou et al., 2006; Zhou et al., 2009).  Bisretinoid pigments of 
lipofuscin other than A2E were also capable in activating the complement system in 
RPE cells (Zhou et al., 2009). 
Activation of complement cascade results in the formation of MAC.  In RPE cells MAC is 
cleared by endocytic pathway and lysosomal degradation (Georgiannakis et al., 2015).  
A2E accumulation leads to lysosomal dysfunction in RPE cells. This prevents the 
clearance of MAC and leads to its accumulation, inducing cellular distress (Schutt et al., 
2002, Bergmann et al., 2004, Georgiannakis et al., 2015).  These findings indicate that 
Bistretinoids/A2E not only activate the complement system but also prevent the 
clearance of MAC in RPE cells, creating a vicious cycle that makes RPE cells further 
susceptible to complement activation. 
The accumulation of MAC not only impacts lysosomes but also leads to mitochondrial 
perturbation in RPE cells (Georgiannakis et al., 2015).  MAC accumulation leads to a 
significant decrease in the quantitative number of mitochondria as a function of area 
and induces ultrastructural defects i.e. smaller size, rounder morphology, and fewer 
cristae.  These changes potentially have a deleterious impact on the energy production 
and subsequently the function of RPE cells.  In addition, the accumulation of A2E inside 
RPE cells also impacts mitochondria.  Mitochondria are significantly more sensitive to 
A2E when compared to lysosomes and their latency decreases at a lower concentration 
and a shorter period of time (Schutt et al., 2002).  Further, accumulation of MAC leads 
to the complete lysis and destruction of RPE cells in a concentration dependent manner 
(Li et al., 2010). 
Taken together, the accumulation of A2E and MAC synergistically damages both 
lysosomes and mitochondria inside the RPE cells, leading to their dysfunction. 

 
 
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In human RPE cell cultures, all-trans-retinal (atRal) sensitized RPE cells to complement 
mediated cell death.  The combined effect of atRal pre-treatment and complement 
activation was significantly greater than was expected from the additive effects of each 
independent treatment (Berchuck et al., 2013).  Incubation with anti-C5 antibody 
protected the RPE cells and prevented the combined atRal and complement mediate 
decrease in RPE cell viability (Berchuck et al., 2013).   
In the albino abca4-/- mice, an animal model for STGD1, the accumulation of lipofuscin 
fluorophores led to the activation of complement cascade with the deposition of 
complement proteins and MAC inside the RPE cells in vivo.  Further, the complement 
negative regulatory proteins were down regulated (Radu et al., 2011).  The complement 
receptor 1-like protein y (CRRY) is an important complement negative regulatory protein 
in mice and its downregulation leads to complement activation (Yang et al., 2009; Lenis 
et al., 2017).  Complement receptor 1-like protein Y prevents the generation of cytolytic 
MAC by inhibiting the cleavage of C3 and C5 complement components (Morgan, 2015).  
Complement receptor 1-like protein Y is down regulated in the albino abca4-/- mice.  The 
subretinal injection of recombinant adeno-associated virus containing the CRRY coding 
increased the expression of CRRY in the RPE cells of albino abca4−/− mice and 
significantly decreased the expression of complement factors in these cells (Lenis et al., 
2017).   
The down regulation of complement activation led to an approximately 2.5-fold 
decrease in the bisretinoid accumulation levels in mice that had received the CRRY 
when compared with the adeno-associated virus (AAV)-null virus.  Further, the RPE 
autofluorescence decreased in the AAV-CRRY injected abca4-/- mice with an 
approximately 30% decrease in the lipofuscin granules when compared with the 
AAV-null–injected albino abca4−/− mice.  Most unexpectedly, decreasing the 
complement activation lead to the rescue of the photoreceptors with an approximately 
30% increase in the number of photoreceptor nuclei in the transduced area (Lenis et al., 
2017).  These findings indicated that the inhibition of complement activation and MAC 
accumulation would lead to healthier RPE cells which in turn are better capable of 
processing the bisretinoids in STGD1 mice.   
These pre-clinical findings indicate that the activation of complement pathway and 
accumulation of MAC may play a significant role in the progression of STGD1 and their 
inhibition or modulation may decrease the accumulation of bisretinoids in RPE cells and 
potentially rescue the degeneration of photoreceptors in STGD1 patients.   

 
 
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4.3 
Avacincaptad Pegol 
4.3.1 Non-Clinical Pharmacodynamics 
Preclinical data demonstrating the complement C5 inhibitory properties of avacincaptad 
pegol are described in detail in the Investigator’s Brochure (IB).   
4.3.2 Non-Clinical Pharmacology of Avacincaptad Pegol 
Numerous nonclinical pharmacology studies were conducted with avacincaptad pegol, 
and, in some cases, with related anti-C5 aptamers.  Primary pharmacology studies 
included binding assays, complement activity inhibition, and radioligand binding.  Safety 
pharmacology studies included human ether-a-go-go-related gene (hERG) channel 
electrophysiology (in vitro), neurotoxicity in rats, and cardiovascular and respiratory 
safety in cynomolgus monkeys.   
The safety pharmacology studies did not reveal any effects on cardiovascular, 
respiratory, or neurologic function that would raise concerns for the intended ocular 
administration.   
Further information regarding the pharmacology of avacincaptad pegol is presented in 
detail in the IB.   
4.3.3 Toxicology  
Chronic intravitreal toxicity studies were conducted in rabbits and dogs with 10 doses of 
avacincaptad pegol given at 4-week intervals.  These studies included interim 
termination of animals after a single dose (i.e., within a few days and at 4 weeks after 
the first dose).  The full 9-month duration has been completed for both studies.   
Additional details of the results of these studies, as well as the results of the various 
intravenous toxicity studies that were previously conducted, can be found in the IB.   
4.3.4 Clinical Data  
Clinical trials investigating the safety, tolerability, and/or pharmacokinetic profile of 
intravitreal injections of avacincaptad pegol (alone or in combination with Lucentis®  
0.5 mg) have been conducted or are ongoing in subjects with neovascular age-related 
macular degeneration (NVAMD) (OPH2000, OPH2004, OPH2007), geographic atrophy 
(GA) secondary to dry AMD (OPH2001, OPH2003, ISEE2008 and ISEE2009), and 
idiopathic polypoidal choroidal vasculopathy (IPCV) (OPH2002). 
Additional details, including results of these studies, can be found in the IB.   

 
 
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4.4 
Trial Rationale 
The preclinical evidence indicates that bisretinoid accumulation inside RPE cells results 
in complement activation and MAC accumulation.  This further impairs the retinoid 
recycling capacity of RPE cells, causing more accumulation and cellular dysfunction.  
RPE cell dysfunction may lead to photoreceptor degeneration and potentially loss of 
vision (Travis et al., 2007; Lenis et al., 2017).  In human RPE cell cultures, incubation 
with anti-C5 antibody protected the RPE cells and prevented the atRal and complement 
mediate decrease in RPE cell viability (Berchuck et al., 2013).  Further, the inhibition of 
complement activation decreased the bisretinoid accumulation and photoreceptor 
degeneration in albino abca4−/− mice (Lenis et al., 2017).  Thus, molecules involved in 
inhibition or regulation of complement activation and MAC accumulation become prime 
targets for therapeutic intervention in STGD1.   
Avacincaptad pegol is FDA approved for the treatment of GA secondary to dry AMND 
and is currently being developed by Astellas for the treatment of STGD1.  Avacincaptad 
pegol is a PEGylated ribonucleic acid (RNA) aptamer.  Avacincaptad inhibits C5, a 
central component of the complement cascade, which plays multiple roles in innate 
immunity and inflammatory diseases.  Inhibition of this key step in the complement 
cascade at the level of C5 prevents the formation of key terminal fragments (C5a and 
C5b-9) regardless of which pathway (alternate, classical or lectin) induced their 
generation.  The C5a fragment is an important inflammatory activator inducing the 
recruitment and activation of phagocytes.  C5b is involved in the formation of MAC 
(C5b-9) which initiates cells lysis.  By inhibiting MAC formation therapeutic benefit may 
be achieved in STGD1. 
5. TRIAL OBJECTIVES  
5.1 
Objectives  
The objectives of this study are to evaluate the safety and efficacy of avacincaptad pegol 
intravitreal injection compared to Sham in subjects with autosomal recessive Stargardt 
disease 1 (STGD1).  

 
 
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5.2 
Endpoints  
Primary Efficacy Endpoint 
• Rate of change in the area of ellipsoid zone defect measured by en face spectral 
domain-optical coherence tomography (SD-OCT) from Baseline through 
Month 18. 
Secondary Endpoints 
• Change in best corrected visual acuity (Early Treatment Diabetic Retinopathy 
Study [ETDRS] letters) from Baseline at Month 18. 
• Change in photopic and/or mesopic macular sensitivity measured by 
microperimetry (optional assessment) from Baseline at Month 18. 
Supportive Endpoints 
• Rate of change in the area of atrophic lesion (definite decrease in 
autofluorescence, DDAF) measured by fundus autofluorescence (FAF) from 
Baseline through Month 18.  
• Rate of change in the thickness of the ONL measured by a horizontal scan 
through the foveal center using SD-OCT from Baseline through Month 18. 
• Time to persistent vision loss (defined as BCVA loss ≥ 10, 15 or 20 letters from 
Baseline at two or more consecutive visits through Month 18). 
• Emergence of at least one new atrophic lesion (DDAF) measured by FAF 
through Month 18. 
Safety Endpoints: 
• Adverse events, vital signs, ophthalmic variables [ophthalmic examination, 
intraocular pressure (IOP), fluorescein angiogram (FA), FAF, SD-OCT, 
microperimetry], ECG and laboratory variables.  
6. TRIAL DESIGN 
Subjects will be randomized in a 1:1 ratio to the following dose groups: 
• Avacincaptad pegol (Zimura™) 
• Sham  
Note:  The international non-proprietary name [INN] of the investigation product, Zimura™, 
is avacincaptad pegol. 

 
 
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All subjects will be treated as follows: 
Induction Phase: Administered on Day 1, Month 1, and Month 2 in the following 
sequence, 14 days apart: 
• D0: Avacincaptad pegol 2 mg/eye or Sham 
• D14: Avacincaptad pegol 2 mg/eye or Sham 
Maintenance Phase: Administered every month (Month 3 – Month 17): 
• Avacincaptad pegol 4 mg/eye (administered as two injections of avacincaptad 
pegol 2 mg) 
• Sham + Sham  
Monthly doses should be targeted for every 30 days from the last monthly visit and must 
be administered at least 21 days apart. 
There will be a final follow-up visit for all subjects at Month 18. 
 
 
 

 
 
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7. PROCEDURES 
Imaging assessments are collected at the timepoints specified in Section 10.2 “Trial 
Assessments”. The RC will analyze the data from three timepoints prior to database 
lock: Screening, Month 9 and Month 18. The additional imaging assessments collected 
at Month 3, Month 6, Month 12 and Month 15 will be stored and made available if needed. 
7.1 
Procedures for Refraction and Vision Testing  
Refraction and Vision Testing will be performed at all timepoints specified in 
Section 10.2 “Trial Assessments”. 
For ETDRS testing, retroilluminated modified Ferris-Bailey ETDRS (Early Treatment 
Diabetic Retinopathy Study) charts are used starting at 4 meters (see Appendix 17.3). 
When protocol refraction and best-corrected visual acuity measurement is required by 
the trial protocol, this will be performed only by certified visual acuity examiners.  The 
examiner will be supplied with the previous protocol refraction only.   
7.2 
Tonometry  
Tonometry will be performed at all timepoints specified Section 10.2 “Trial 
Assessments”.  On days when two injections are given, the second injection may not be 
administered until the IOP is ≤ 21 mmHg or within 5 mmHg of the pre-injection IOP, at 
which time the IOP is recorded.  After the second injection and also on days with only 
one injection, tonometry must be performed at least 30 minutes after the injection and 
IOP must return to < 30 mmHg before the subject leaves the clinic.  For the post-
injection tonometry, proper care should be taken to minimize the risk of contamination. 
Goldmann applanation tonometry must be performed at Screening, Pre-Injection 
(Day 1, Month 6, Month 9, Month 18) and Early Withdrawal.  Tono-Pen tonometry may 
be used at all other timepoints, but Goldmann applanation tonometry must be used to 
verify IOP for a post-injection reading of ≥ 30 mmHg occurring more than 30 minutes 
post-injection, or for a reading of ≥ 30 mmHg at any other time.   
7.3 
Ophthalmologic Examination 
The following examinations will be performed at all timepoints specified in Section 10.2 
“Trial Assessments”.   
• Inspection of the eyelids 
• Examination of the extra-ocular muscle movement  
• Inspection of the cornea 

 
 
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• Examination of the anterior chamber for inflammation (Appendix 17.1) 
• Examination of the pupils 
• Examination of the iris 
• Inspection of the lens 
• Inspection of the vitreous body (Appendix 17.2) 
• Inspection of the retina and optic disc 
7.4 
Fundus Photography, Fluorescein Angiography, and Fundus 
Autofluorescence 
Color stereoscopic fundus photography, fluorescein angiography (FA), and fundus 
autofluorescence (FAF) will be performed at all timepoints specified in Section 10.2 
“Trial Assessments”.  Heidelberg Spectralis® High Resolution Angiography (HRA) will 
be used for fundus autofluorescence.   
An image RC will be used for this study.  The RC will determine eligibility of all subjects 
prior to enrollment. Color fundus photos, FAs, and FAFs that are collected at protocol-
specified times must be sent to the RC as specified in the RC procedure manual.  The 
RC will provide instructions for the color fundus photographs as well as FA and FAF 
procedures.  
7.5 
Spectral-Domain Optical Coherence Tomography (SD-OCT) 
Spectral domain-optical coherence tomography will be performed at all timepoints 
specified in Section 10.2 “Trial Assessments”.  Heidelberg Spectralis® OCT is the 
preferred instrument.   
SD-OCTs that are collected at protocol-specified times must be sent to the RC as 
specified in the RC procedure manual.  The RC will provide instructions. 
7.6 
Retinal Sensitivity by Microperimetry 
Retinal sensitivity by microperimetry is an optional assessment to be performed if the 
site has the necessary equipment.  If performed, it will be done at all timepoints 
specified in Section 10.2 “Trial Assessments”.   
The Sponsor will provide the Principal Investigator with instructions for the 
microperimetry procedures.   

 
 
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7.7 
Laboratory Tests  
The following laboratory tests will be performed as specified in Section 10.2 “Trial 
Assessments”:   
• Hematology: hemoglobin, platelet count, white blood cell (WBC) and differential  
• Renal function: serum creatinine and blood urea nitrogen (BUN)  
• Hepatic function: serum bilirubin, alkaline phosphatase, gamma-glutamyl-
transferase (GGT), serum glutamic oxaloacetic transaminase (SGOT)/ aspartate 
aminotransferase (AST) and serum glutamic pyruvic transaminase (SGPT)/ 
alanine aminotransferase (ALT)  
• Electrolytes: sodium, potassium, chloride, bicarbonate, calcium and phosphate  
• Complete urinalysis (including specific gravity, protein, blood, etc.)  
• Serum pregnancy test (if of child-bearing potential)  
Additional urine or serum pregnancy testing may be performed during the course of the 
study at the discretion of the investigator, or in accordance with local requirements or 
regulations.   
If the Investigator judges a laboratory value outside of the normal range as clinically 
significant, the Investigator will repeat the laboratory determination as judged 
appropriate to ensure the validity of the abnormal result.  If any clinically significant 
abnormal results are noted, the tests are to be repeated until the results are normal, are 
no longer considered clinically significant by the investigator, or an explanation for the 
change is obtained.   
7.8 
Genetic Samples  
Genetic testing will be performed at Screening for ABCA4 gene mutations to verify 
eligibility for the study. Genetic testing done by a CLIA certified laboratory as part of the 
standard of care prior to informed consent is acceptable to satisfy Inclusion Criteria 
8.2.1.  
Genetic sampling for the Complement Factor H (CFH) gene may also be taken during 
the study, at any visit prior to or at the Month 18 visit. CFH testing performed by a CLIA 
certified laboratory prior to this study may also be acceptable (upon review). This 
sample would be collected only once during the course of this study.   
Analysis will be performed by a CLIA-certified laboratory. All supplies and instructions 
related to obtaining, processing, and shipping the sample will be provided by the 

 
 
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sponsor.  The deoxyribonucleic acid (DNA) samples will not be identified by subject 
number, date of birth, or initials.   
7.9 
Vital Signs and Physical Examination  
A physical examination will be performed at Screening and at the Investigators’ 
discretion thereafter.  Assessment of vital signs will be performed at all timepoints 
specified in Section 10.2 “Trial Assessments”.   
7.10 12-Lead Electrocardiogram 
A 12-lead ECG will be performed at all timepoints specified in Section 10.2 “Trial 
Assessments”.   
 
 

 
 
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8. SUBJECT POPULATION  
8.1 
Sample Size 
Approximately 120 subjects will be enrolled in this study.   
8.2 
Inclusion Criteria  
Subjects must meet the following criteria to be eligible to participate in this study.   
Ophthalmic Inclusion Criteria  
The following inclusion criteria apply to the study eye:   
8.2.1 At least two pathogenic mutations of ABCA4 gene confirmed by a CLIA-certified 
laboratory. 
8.2.2 Best corrected visual acuity in the study eye between 20/20 - 20/200 Snellen 
equivalent, inclusive. 
8.2.3 Presence of at least one identifiable location of at least 250 micrometers 
contiguous width of ellipsoid zone loss on SD-OCT within the total 9 ETDRS 
subfields.  
8.2.4 The total area of thinned layer(s) on OCT not extending beyond the outer ring of 
the total 9 ETDRS subfields (e.g., not extending beyond fields 5-9). 
8.2.5 Fundus autofluorescence may show heterogeneous signals (areas of increased 
and/or decreased autofluorescence) but no area of subfoveal definitely 
decreased autofluorescence (DDAF). 
8.2.6 Clear ocular media and adequate pupillary dilatation in both eyes (OU) to allow 
for all imaging procedures, including good quality stereoscopic fundus 
photography, fundus autofluorescence, and spectral domain ocular coherence 
tomography.   
8.2.7 Intraocular pressure of 21 mmHg or less in the study eye.   
General Inclusion Criteria  
8.2.8 Subjects of either gender aged between 18 and 60 years, inclusive.   
8.2.9 Women must be using two forms of effective contraception, be post-menopausal 
for at least 12 months prior to trial entry, or surgically sterile; if of child-bearing 
potential, a serum pregnancy test must be performed within 14 days prior to the 
first injection with a negative result.  The two forms of effective contraception 

 
 
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must be implemented during the trial and for at least 90 days following the last 
dose of test medication.  Male subjects should use a condom during the time of 
study drug exposure and for 90 days following last exposure of study drug. 
8.2.10 Provide written informed consent. 
8.2.11 Ability to return for all trial visits.   
8.3 
Exclusion Criteria  
Subjects will not be eligible for the trial if subjects cannot attend all of the trial required 
visits, or if any of the following criteria are present in the study eye or systematically:   
Ophthalmic Exclusion Criteria  
The following exclusion criteria apply to the SE unless otherwise noted:   
8.3.1 Macular atrophy secondary to any condition other than STGD1 in either eye 
(e.g., drug-induced).   
8.3.2 Any prior treatment for STGD1 including gene therapy, stem cell therapy or any 
prior intravitreal treatment for any indication in either eye.   
8.3.3 Participation in an interventional study of a vitamin A derivative ≤ 3 months prior 
to screening.   
8.3.4 Any ocular condition in the study eye that would progress during the course of 
the study that could affect central vision, microperimetry testing or otherwise be a 
confounding factor.   
8.3.5 Concomitant treatment with any ocular or systemic medication that is known to 
be toxic to the lens, retina or optic nerve.   
8.3.6 Presence of intraocular inflammation (≥ trace cell or flare), macular hole, 
pathologic myopia (spherical equivalent of -8 diopters or more negative, or axial 
length of 25 mm or more), epiretinal membrane, evidence of significant vitreo-
macular traction, vitreous hemorrhage or aphakia (pseudophakia with or without 
an intact capsule is not an exclusion criteria).   
8.3.7 Presence or history of idiopathic or autoimmune-associated uveitis in either eye.   
8.3.8 Significant media opacities, including cataract, which might interfere with visual 
acuity, assessment of toxicity, fundus photography or fundus autofluorescence.  
Subjects should not be entered if there is likelihood that they will require cataract 
surgery in the study eye during the study.   

 
 
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8.3.9 Any intraocular surgery or thermal laser within 3 months of trial entry.  Any prior 
thermal laser in the macular region, regardless of indication.   
8.3.10 Any ocular or periocular infection or ocular surface inflammation in the past 12 
weeks.   
8.3.11 History of any of the following procedures: Posterior vitrectomy, filtering surgery 
(e.g.  trabeculectomy), glaucoma drainage device, corneal transplant or retinal 
detachment.   
General Exclusion Criteria  
8.3.12 Any of the following underlying diseases including:   
• Diabetes mellitus (regardless of HbA1c level) 
• HbA1c value of ≥6.5%*: 
      If the HbA1c value is ≥ 6.5% and ≤ 6.9%, and the patient has no signs or 
symptoms of diabetes mellitus, has a normal creatinine, has no diabetic 
retinopathy and no glycosuria, then the patient may have an oral glucose 
tolerance test (OGTT) at the discretion of the investigator. If the 2-hour 
glucose value on OGTT is <200 mg/dL (<11.1mmol/L), then the patient may 
be enrolled.1 
•  History of other disease, metabolic dysfunction, physical examination finding 
or clinical laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug or that might 
affect interpretation of the results of the study or render the subject at high 
risk for treatment complications. 
• History or evidence of severe cardiac disease (e.g., New York Heart 
Association (NYHA) Functional Class III or IV - see Appendix 17.5), history or 
clinical evidence of unstable angina, acute coronary syndrome, myocardial 
infarction or revascularization within last 6 months, ventricular 
tachyarrhythmia requiring ongoing treatment.   
 
1 The OGTT will be performed at a local laboratory as follows: (1) A fasting baseline 
plasma glucose is drawn; (2) the subject is administered 75 gm oral dextrose; (3) a 2-
hour plasma glucose level is drawn.   
 

 
 
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• Subjects with a clinically significant laboratory value.  Laboratory tests may be 
repeated once before randomization.   
• Stroke within 12 months of trial entry.   
• Any major surgical procedure within one month of trial entry or anticipated 
during the trial which may interrupt trial participation.   
8.3.13 Previous therapeutic radiation in the region of the study eye.   
8.3.14 Any treatment with an investigational agent in the past 60 days for any condition.   
8.3.15 Women who are pregnant or nursing.   
8.3.16 Known serious allergies to the fluorescein dye used in angiography, povidone 
iodine, or to the components of the avacincaptad pegol formulation.   
8.3.17 History of systemic treatment with any complement inhibitor agent in the past or 
the likelihood of treatment with any systemic complement inhibitor agent during 
the study.   
 
 

 
 
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9. TRIAL MEDICATION 
9.1 
Avacincaptad Pegol  
Avacincaptad pegol is a PEGylated RNA aptamer consisting of a 13 kDa modified RNA 
aptamer that is conjugated at the 5’ terminus to a 43 kDa branched polyethylene glycol 
(PEG) moiety.  The aptamer portion of avacincaptad pegol (known as ARC672) is 
39 nucleotides in length and modified to a primary amine at the 5’ terminus to provide a 
reactive site for site specific conjugation (“PEGylation”).  The nucleotide composition 
consists of 2’-hydroxyl purines and modified 2’-fluorinated pyrimidines and 2’-methoxy 
purines.  The modified nucleotides minimize endonuclease digestion and contribute to 
activity.  The 3’ terminus is capped with an “inverted” 3’-3’ phosphodiester linkage to a 
deoxythymidine nucleotide to minimize 3’-exonuclease degradation.  PEGylation is 
employed because it confers delayed clearance in vivo without diminishing affinity or 
activity.  All concentrations and doses for avacincaptad pegol (1 µM = 13 µg/mL) are 
based on the mass of the aptamer, exclusive of the PEG mass.   
Avacincaptad pegol drug product is formulated at a concentration of 20 mg/mL 
(oligonucleotide mass) in 10 mM phosphate buffered saline as a sterile aqueous 
solution.   
The drug product was originally presented in a USP Type I high recovery glass vial that 
contained a 0.5 mL v-shaped well sealed with FluoroTec-coated, halobutyl rubber 
stoppers and red aluminum crimp seals.  In March 2023, the drug product was 
transitioned to presentation in a 2 mL (ISO 2R) Type I glass vial, stoppered with 
FluoroTec-coated halobutyl rubber stopper, and sealed with aluminum crimp seals. The 
product is preservative-free and intended for intravitreal injection only. The product 
should not be used if cloudy or if particles are present.   
The 2 mg/eye dose will be administered in a total injection volume of 0.1 mL (100 µL).  
The 4 mg/eye dose will be administered as two 0.1 mL (100 µL) injections of 
avacincaptad pegol 2 mg (see Section 17.4 Intravitreal Administration Protocol). 
 

 
 
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Active Ingredient: 
 
Avacincaptad pegol 
 
 
 
 
Excipients: 
Sodium Chloride 
 
Sodium Phosphate Monobasic, Monohydrate 
 
Sodium Phosphate Dibasic, Heptahydrate 
 
Nitrogen 
 
Water for injection  
 
9.2 
Dose and Administration 
9.2.1 Preparation 
Avacincaptad pegol will be injected without dilution.   
Avacincaptad pegol is supplied in a single-use vial. To prepare for injection, use the 
19-gauge filter needle (supplied by the sponsor) and a 1-mL Luer-LokTM sterile syringe 
(supplied by the sponsor) to withdraw all avacincaptad pegol content from the vial using 
aseptic technique.  Remove and discard the filter needle and replace it with the sterile 
30 gauge injection needle (supplied by the sponsor).  Expel any air bubbles and adjust 
the injection volume to 0.1 mL (100μL). 
Refer to the Instructions for Use (IFU). 
9.2.2 Treatment Regimen and Duration 
Subjects will be randomized in a 1:1 ratio to the following dose groups: 
• Avacincaptad pegol 
• Sham  
Interactive Randomization Technology (IRT) will be used to randomize study subjects 
and assign drug to study subjects. All subjects will be treated as follows: 
Induction Phase: Administered on Day 1, Month 1, and Month 2 in the following 
sequence, 14 days apart: 
• D0: Avacincaptad pegol 2 mg/eye or Sham 
• D14: Avacincaptad pegol 2 mg/eye or Sham 

 
 
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Maintenance Phase: Administered monthly (Month 3 – Month 17): 
• Avacincaptad pegol 4 mg/eye (administered as two injections of avacincaptad 
pegol 2 mg) 
• Sham + Sham 
Monthly doses should be targeted for every 30 days from the last monthly visit, and 
must be administered at least 21 days apart. 
There will be a final follow-up visit for all subjects at Month 18. 
9.2.3 Administration of Trial Drug 
The method for intravitreal administration of avacincaptad pegol is described in detail in 
Section 17.4.  
Subjects randomized to avacincaptad pegol will receive 6 doses of avacincaptad pegol 
2 mg and 15 doses of avacincaptad pegol 4 mg. The 2 mg/eye dose will be 
administered in a total injection volume of 0.1 mL (100 µL). Avacincaptad pegol 
4 mg/eye will be administered as two 0.1 mL (100 µL) injections of avacincaptad pegol. 
Intravitreal administration of avacincaptad pegol is contraindicated if active 
inflammation and/or suspected or active ocular or peri-ocular infection is present.  
If active inflammation and/or suspected or active ocular or peri-ocular infection is 
present, study drug  should not be administered and inflammation/infection should be 
treated at the discretion of the Investigator, according to standard-of-care.  Intravitreal 
administration of study drug  should only resume after treatment and full resolution of 
ocular inflammation and/or ocular or peri-ocular infection.   
9.2.4 Storage 
The investigator, or an approved representative (e.g., pharmacist), will ensure that all 
trial drugs are stored in a secured area, under labeled storage conditions and in 
accordance with applicable regulatory requirements.  Store trial drug under standard 
refrigeration conditions (2°C – 8°C; 36°F – 46°F); do not freeze.  Prior to use, allow the 
trial drug to reach room temperature (20°C – 25°C [68°F – 77°F]).  The unopened glass 
vial of trial drug may be kept at room temperature, 20°C – 25°C (68°F – 77°F), for up to 
24 hours. Ensure that the injection is given immediately after preparation of the dose. All 
study drug vials should be protected from light and stored in the original carton, as 
provided, until the time of use.   
 

 
 
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9.3 
Previous or Concomitant Therapy 
Any previous or concomitant treatment for Stargardt disease (systemically or in either 
eye) prior to Day 1 or during the study period is not permitted.   
Interventional treatment with a vitamin A derivative ≤ 3 months prior to Screening, any 
treatment with any investigational agent for any condition in the 60 days prior to 
Screening, or treatment with an investigational agent for any condition during the trial, is 
not permitted.   
9.3.1 Prohibited Medications 
Prior or concomitant treatment with any ocular or systemic medication that is known to 
be toxic to the lens, retina or optic nerve is not permitted.  These medications may 
include, but are not limited to amiodarone, deferoxamine, 
chloroquine/hydroxychloroquine sulfate (Plaquenil), tamoxifen, phenothiazines and 
ethambutol, and fingolomod (Gilenya). 
9.3.2 Concomitant Ocular Surgeries and Procedures 
For subjects requiring any ocular surgeries or procedures during the study period, the 
Investigator should consult with the study Sponsor prior to the surgery/procedure.  
 
 

 
 
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10. 
TRIAL CONDUCT 
10.1 Subject Enrollment 
Before recruitment of subjects into the trial, written Institutional Review Board (IRB) or 
Ethics Committee (EC) approval of the protocol and informed consent must be 
obtained. 
Subjects who meet the eligibility criteria and have provided written informed consent will 
be enrolled in the trial.  If any inclusion or exclusion criteria are not met, treatment with 
trial drug should not commence without prior written approval from Astellas or its 
designee.  
Written informed consent must be obtained before any of the Screening procedures 
listed below are performed.  However, if a routine office procedure (e.g., FA, OCT) has 
been previously performed independent of this clinical trial, and subsequently the 
subject provides informed consent for this study, these procedures performed prior to 
informed consent may be used as screening assessments for this study, provided the 
14-day period of screening evaluations is respected and provided the assessments are 
acceptable to the standards of the study.  An explanation of the trial and discussion of 
the possible risks and discomforts will be given by the investigator.   
For the Screening visit only, assessments can be broken into 2 days if necessary.  For 
all other visits, all assessments indicated must be performed on the same day.   
The RC will determine eligibility of all subjects prior to enrollment.  Only those subjects 
who fulfill all eligibility criteria will be entered into the trial.   
10.2 Trial Assessments 
The following dosing days apply to the Induction Phase. 
D0 
D0 = The first day of dosing at each monthly timepoint.   
D14 
D14 = The second day of dosing, 14 days after D0. 
The following evaluations, as outlined in the Study Assessments Chart (Section 3) will be 
performed on the days specified below:   
Note:  
• Concomitant medications should be assessed at every study visit.   
• Adverse events should be assessed starting at Day 1 after the first dose of 
trial drug.   

 
 
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10.2.1 Screening Assessments  
The following Screening evaluations, as outlined in the Study Assessments Chart (see 
Section 3) will be performed within 14 days prior to Day 1.   
• Informed consent 
• Medical history 
• Ophthalmologic history (OU) 
• Vital signs/Physical examination 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Ophthalmologic examination and Goldmann applanation tonometry (OU) 
• Color fundus photography (FP) (OU)  
• Fluorescein Angiography (FA) (OU, transit study eye) 
• Spectral Domain Optical Coherence Tomography (SD-OCT) (OU) 
• Fundus Autofluorescence (FAF) (OU) 
• Microperimetry testing (OU) (optional assessment) 
• Serum pregnancy test (if applicable) 
• Laboratory tests 
• Genetic sampling (if necessary to confirm eligibility) 
• 12-Lead ECG 
• Concomitant medication assessment 
10.2.2 Reconfirmation of Eligibility at Day 1 
To remain eligible for randomization on Day 1, the subject must continue to meet 
the inclusion criteria.  If the subject does not meet the inclusion criteria, the 
subject must NOT be randomized.   
 
10.2.3 Day 1 (D0 Visit) – Induction Phase 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Goldmann applanation tonometry and ophthalmologic examination (SE) 
• Randomization 

 
 
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Injection 
• 
Randomized Treatment  
Post-injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection, a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg before 
the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.4 Day 1 (D14 Visit ± 1 day) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Goldmann applanation tonometry and ophthalmologic examination (SE) 
Injection 
• 
Randomized Treatment  
Post-injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection, a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg before 
the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.5 Month 1 (± 7 days) (D0 Visit) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
Injection 
• 
Randomized Treatment  

 
 
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Post-injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection, a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg before 
the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.6 Month 1 (D14 Visit ± 1 day) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and ophthalmologic examination (SE) 
Injection 
• 
Randomized Treatment  
Post-injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection, a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg before 
the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.7 Month 2 (±7 days) (D0 Visit) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• Tonometry and Ophthalmologic Examination (SE) 
Injection 
• 
Randomized Treatment  

 
 
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Post-injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection, a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg before 
the subject leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.8 Month 2 (D14 Visit ± 1 day) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
Randomized Treatment  
Post-injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after injection to assure that the 
optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the injection, a 
full ophthalmologic exam must be performed and IOP must be < 30 mmHg before 
the subject leaves the clinic. 
3-Day Post-Injection Safety Check (±1 day) 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.9 Month 3 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
• 
Spectral Domain Optical Coherence Tomography (SD-OCT) (OU) 
• 
Fundus Autofluorescence (FAF) (OU) 

 
 
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Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within 
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.10 Month 4 Visit (± 7 days) – Maintenance Phase 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within 
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 

 
 
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• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.11 Month 5 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within 
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.12 Month 6 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Ophthalmologic examination and Goldmann applanation tonometry (OU) 
• 
Spectral Domain Optical Coherence Tomography (SD-OCT) (OU) 

 
 
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• 
Fundus Autofluorescence (FAF) (OU) 
• 
Vital signs 
• 
Serum pregnancy test (if applicable) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within 
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.13 Month 7 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within 
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  

 
 
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Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.14 Month 8 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within  
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to assure 
that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   

 
 
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10.2.15 Month 9 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Goldmann applanation tonometry and ophthalmologic examination (OU)  
• 
Color fundus photography (FP) (OU)  
• 
Fluorescein Angiography (FA) (OU, transit study eye) 
• 
Spectral Domain Optical Coherence Tomography (SD-OCT) (OU) 
• 
Fundus Autofluorescence (FAF) (OU) 
• 
Microperimetry testing (OU) (optional assessment) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within  
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic Exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.16 Month 10 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 

 
 
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Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within  
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.17 Month 11 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within  
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 

 
 
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• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.18 Month 12 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• 
Tonometry and ophthalmologic examination (OU) 
• 
Spectral Domain Optical Coherence Tomography (SD-OCT) (OU) 
• 
Fundus Autofluorescence (FAF) (OU) 
• 
Vital signs 
• 
Serum pregnancy test (if applicable) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within  
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 

 
 
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3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.19 Month 13 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within  
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.20 Month 14 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 

 
 
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• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within 
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.21 Month 15 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
• 
Spectral Domain Optical Coherence Tomography (SD-OCT) (OU) 
• 
Fundus Autofluorescence (FAF) (OU) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within  
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 

 
 
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3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.22 Month 16 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 
• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within  
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.23 Month 17 Visit (± 7 days) 
Pre-injection 
• 
Protocol refraction and visual acuity (4 meters) using ETDRS chart (SE) 
• 
Tonometry and ophthalmologic examination (SE) 
Injection 
• 
1st Injection - Randomized Treatment  
• Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the injection to 
assure that the optic nerve is perfused. 

 
 
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• Tonometry (SE) – After the injection, IOP must be ≤ 21 mmHg or within  
5 mmHg of pre-injection before the 2nd injection can be given.   
• 
2nd Injection - Randomized Treatment  
Post 2nd injection 
• 
Indirect Ophthalmoscopy (SE) – 1 to 2 minutes after the second injection to 
assure that the optic nerve is perfused. 
• 
Ophthalmologic exam/Tonometry (SE) – At least 30 minutes after the second 
injection, a full ophthalmologic exam must be performed and IOP must be  
< 30 mmHg before the subject leaves the clinic. 
3-Day Post-Injection Safety Check (± 1 day) 
• 
Telephone call to subject to ensure there are no signs or symptoms of retinal 
detachment or endophthalmitis.   
10.2.24 Month 18 Visit (± 7 days)/Early Withdrawal 
• Vital Signs 
• Protocol refraction and visual acuity (4 meters) using ETDRS chart (OU) 
• Tonometry and Ophthalmologic Examination (OU) 
• Color fundus photography (FP) (OU)  
• Fluorescein Angiography (FA) (OU, transit study eye) 
• Spectral Domain Optical Coherence Tomography (SD-OCT) (OU) 
• Fundus Autofluorescence (FAF) (OU) 
• Microperimetry Testing (OU) (optional assessment) 
• Serum pregnancy test (if applicable) 
• Laboratory Tests 
• 12-Lead ECG 
10.3 Withdrawal from Trial 
Subjects have the right to withdraw from the trial at any time for any reason.  The 
Investigator (after consultation with the Sponsor) or Sponsor also have the right to 
withdraw subjects from the trial in the event of concurrent illness, AEs, treatment-failure 
after a prescribed procedure, protocol violations, cure, administrative or other reasons.   
Final trial assessments as outlined in the Study Assessments Chart, Section 3, should 
be performed on all subjects who withdraw.  Subjects who withdraw due to an AEs 

 
 
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should be followed until resolution of the AEs, or an adequate explanation for the event 
is obtained.   
Subjects who withdraw for any reason should have assessments performed according 
to the Early Withdrawal schedule.  The subject must not receive an alternative treatment 
for Stargardt until he or she is withdrawn from the trial. If an alternative treatment for 
Stargardt is initiated before completing the study dosing, the subject will no longer be 
evaluated according to this protocol.   
10.4 Trial Discontinuation 
The reason for a subject discontinuing from the trial will be recorded in the case report 
form (CRF).  A discontinuation occurs when an enrolled subject ceases participation in 
the trial, regardless of the circumstances, prior to completion of the protocol.  The 
investigator must determine the primary reason for discontinuation.  A discontinuation 
must be reported immediately to the clinical monitor or his/her designated 
representative if it is due to a serious adverse reaction (SAE; see Section 12.3).  The 
final evaluation required by the protocol will be performed at the time of trial 
discontinuation.  The investigator will record the reason for trial discontinuation, provide 
or arrange for appropriate follow-up (if required) for such subjects, and document the 
course of the subject’s condition.   
Premature termination of this clinical trial may occur because of a regulatory authority 
decision, change in opinion of the IRB/EC, drug safety problems, or at the discretion of 
Astellas.   
The study will be considered completed when the last subject completes the final study 
visit.   
 
 

 
 
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11. 
STATISTICAL METHODS 
11.1 Interventions 
Subjects will be randomized in a 1:1 ratio to the following dose groups: 
• Avacincaptad pegol 
• Sham  
All subjects will be treated as follows: 
Induction Phase: Administered on Day 1, Month 1, and Month 2 in the following 
sequence, 14 days apart: 
• D0: Avacincaptad pegol 2 mg/eye or Sham 
• D14: Avacincaptad pegol 2 mg/eye or Sham 
Maintenance Phase: Administered every month (Months 3 – Month 17): 
• Avacincaptad pegol 4 mg/eye (administered as two injections of avacincaptad 
pegol 2 mg) 
• Sham + Sham  
There will be a final follow-up visit for all subjects at Month 18. 
11.2 Endpoints 
Refer to Section 5.2 for detailed study endpoints. 
11.3 Study Design 
This is a randomized, double masked, Sham controlled, Phase 2b trial that will obtain 
evidence regarding the effect of avacincaptad pegol on the rate of change in the area of 
ellipsoid zone defect (defined as ellipsoid zone attenuation in addition to total RPE loss) 
measured by en face SD-OCT from Baseline through Month 18, when compared with 
Sham.   
This Phase 2b trial will provide evidence suggesting that avacincaptad pegol:  
• Is not plausibly more efficacious than Sham; 
• Is plausibly more efficacious than Sham; or 
• Is more efficacious than Sham, with strength of evidence meeting the standard 
requirement of a 0.025 one-sided, false-positive error rate.   

 
 
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11.3.1 Determination of Sample Size and Statistical Rationale 
Approximately 120 subjects will be enrolled in this study.  This statistical rationale for 
the trial is based on the methodology presented in Fleming and Richardson (2004).  
Patients will be maintained on their randomized intervention (including those on the 
Sham control) for 18 months.   
The primary analysis of this Phase 2b trial for the comparison of avacincaptad pegol vs 
the Sham is formally based on a three-category decision guideline.  To be specific, if 
SDΔ is the standard deviation of the rate of change in the area of ellipsoid zone defect 
measured by en face SD-OCT over 18 months within each treatment group, the 
decision guideline for this trial is based on whether the difference between avacincaptad 
pegol and the Sham groups in the estimated mean rate of change in this area is less 
than 0.1843 SDΔ , is from 0.1843 SDΔ to 0.3577 SDΔ , or is at least 0.3577 SDΔ .   
Note that these categories should not be interpreted as providing strict decision rules 
but rather as guidelines that will be factored into a broader scientific assessment of the 
benefit to risk profile of avacincaptad pegol.  This broader assessment will include 
consideration of safety, of supportive efficacy endpoints, and of relevant information 
external to this trial.  Specifically, the decision guidelines for this trial are: 
1. If the difference between avacincaptad pegol and the Sham groups in the 
estimated mean rate of change in the area of ellipsoid zone defect measured by 
en face SD-OCT over 18 months is less than 0.1843 SDΔ , then avacincaptad 
pegol is not plausibly more efficacious than the Sham.  
2. If the difference between avacincaptad pegol and the Sham groups in the 
estimated mean rate of change in the area of ellipsoid zone defect measured by 
en face SD-OCT over 18 months is from 0.1843 SDΔ to 0.3577 SDΔ , then 
avacincaptad pegol is plausibly more efficacious than the Sham. 
3. If the difference between avacincaptad pegol and the Sham groups in the 
estimated mean rate of change in the area of ellipsoid zone defect measured by 
en face SD-OCT over 18 months is at least 0.3577 SDΔ , then this dose of 
avacincaptad pegol would be statistically significantly more effective than the 
Sham, with strength of evidence meeting the standard requirement of a 0.025 
one-sided, false positive error rate. 
The planned size of 120 subjects for this phase 2b trial was determined based on the 
number of subjects with STGD1 that could potentially be enrolled within a reasonable 

 
 
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period of time. Based on the actual recruitment rate during the trial, this number may be 
increased or decreased. As STGD1 is an orphan indication, there is no natural history 
data currently available regarding the standard deviation of rate of change in the area of 
ellipsoid zone defect over 18 months in the STGD1 patient population that we plan to 
enroll in this trial.  
11.3.2 Randomization Procedure 
Subjects will be centrally allocated to one of the two treatment groups by a dynamic 
minimization procedure. 
Randomization will occur with the use of an IRT system which will assign subjects to 
treatment in 1:1 ratio to avacincaptad pegol or Sham.   
11.4 Masking Procedure 
It is the responsibility of the Principal Investigator to ensure that the physician assessing 
AEs, the visual acuity examiner, all masked study personnel, and the subject remain 
masked to the subject’s treatment assignment.  Any unmasking should be documented 
and reported immediately to the Sponsor. 
11.4.1 Visual Acuity Assessments  
Refraction and visual acuity measurements will be performed for all subjects by a 
certified vision examiner.  Since this is a double-masked study, subjects and staff 
at the investigational site, particularly the visual acuity examiners, will be masked 
to study treatment.  All visual acuity assessments will be performed by the trial 
refractionist/ophthalmologist, who will be masked to the subject’s treatment as 
well as previous visual acuity assessments.  The trial refractionist/ophthalmologist 
will be supplied only with the subject’s most recent protocol refraction.   
11.4.2 Injections 
Each clinical site is required to have a minimum of 2 ophthalmologists – the unmasked 
injector and the masked assessor.  The unmasked injector will perform the 
avacincaptad pegol/Sham injection as well as the post-injection ophthalmic examination 
and tonometry measurements.  The unmasked injector and designated unmasked 
assistants (if needed) are not permitted to be involved in the conduct of the study in any 
other manner and are not to communicate with any other personnel or subjects 
regarding the treatment assignment.  Once the unmasked injector or unmasked 
assistant breaks the seal on the masked drug kit, no masked study personnel can be 
present until after the injections are complete and the drug kit and components (vial, 

 
 
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syringe, needles) have been disposed of by the unmasked injector/unmasked assistant; 
only the empty drug kit box and the tear-off part of the vial label are saved.  The masked 
assessor will perform all other physician assessments including the relationship of all 
AEs to study drug, including those noted by the unmasked injector.   
11.4.3 Statistical Analyses 
All statistical analyses will be conducted by the study Sponsor or under the authority of 
the study Sponsor. The Sponsor and the subjects will remain masked to treatments until 
the end of the study, except if safety considerations justify breaking the code for 
individual subjects. 
Primary endpoint will be analyzed using a mixed model for repeated measures (MMRM) 
with all available data, using response variable of the area of ellipsoid zone defect 
measured by en face SD-OCT over time up to Month 18 including baseline and 
post-baseline assessments. The MMRM will be used to assess the difference between 
the treatment groups in terms of the rate of change (slope) in the area of ellipsoid zone 
defect from Baseline through Month 18. The fixed effects will include treatment group 
(avacincaptad pegol or Sham), time, pooled geographic region (North America or Rest 
of World) and treatment by time interaction. Subject is the random effect with repeated 
measures.  
The efficacy analysis will be conducted on all randomized subjects according to the 
intention-to-treat principle.  
A Statistical Analysis Plan (SAP) will provide the details for the statistical analyses. 
11.4.4 Descriptive Statistics 
Descriptive statistics will be provided on demographic information, treatment 
administration, baseline characteristics, and protocol deviations, as well as for selected 
endpoints at relevant timepoints. 
11.4.5 Safety Analysis 
The safety analysis will be conducted on all subjects who had at least one 
administration of trial drug. 
Adverse events will be summarized using MedDRA terms. The incidence and severity 
of AEs will be listed and grouped by body system.  
All laboratory data will be listed and values falling outside normal ranges will be 
identified. Summary statistics (i.e., mean, median, standard deviation, minimum and 
maximum) will be presented for all continuous variables.  

 
 
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Summary statistics will be given on the number of subjects for whom the trial medication 
had to be permanently stopped.   
12. 
ADVERSE EVENTS 
12.1 Definition of Adverse Events 
An AE is defined as follows:  Any untoward medical occurrence in a patient or subject 
including unfavorable and unintended signs, symptoms or disease temporally 
associated with the use of a medicinal product and which does not necessarily have to 
have a causal relationship to this treatment.   
Adverse events include illnesses with onset during the trial, or exacerbations of pre-
existing illnesses.  Exacerbation of pre-existing illness is defined as a significant 
increase in the severity of the illness as compared to the start of the trial, and should be 
considered when a subject requires new or additional treatment for that illness.  Lack of 
or insufficient clinical response or efficacy should not be recorded as an AE.   
In addition, clinically significant changes in objective findings (e.g., laboratory, ECG, 
X-ray, physical examination) should also be considered as to whether they are AEs.  
The criteria for determining whether an objective finding should be reported as an AE 
are as follows:   
1. Associated with accompanying symptoms; and/or 
2. Requires medical/surgical intervention; and/or 
3. Leads to a change in trial dosing or discontinuation from the trial, significant 
additional concomitant drug treatment or other therapy; and/or 
4. Leads to any of the outcomes included in the definition of a SAE; and/or 
5. Is considered to be an AE by the investigator or Sponsor. 
Any abnormal test result that is determined to be an error does not require reporting as 
an AE.   
12.2 Assessment and Reporting of Adverse Events 
Adverse events will be recorded starting after the first dose of trial drug and 
continuing until 30 days after the last dose or until the last follow-up visit 
required by the protocol, whichever comes later.  An AE that is ongoing at the last 
follow up study visit is required to be followed up until the event resolves or stabilizes at 
a level acceptable to the investigator and/or Sponsor. If the subject still presents with 
any treatment-related toxicity, the follow-up period will be extended until return to 

 
 
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Baseline status or until the condition has stabilized.   
All AEs spontaneously reported, elicited or observed by the investigators will be 
recorded.  The events will be recorded in the source documents and onto the AE pages 
of the CRF, including date of onset and resolution, severity, relationship to trial 
treatment and determination of “serious”.   
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure 
was performed should be reported if it meets the definition of an AE.  For example, an 
acute appendicitis that begins during the AE reporting period should be reported as an 
AE and the resulting appendectomy should be recorded as treatment of the AE.   
The investigator will take all therapeutic measures necessary for resolution of the AE.  
Any medication necessary for treatment of the AE must be recorded in the subject’s 
source documents and on the appropriate pages of the subject’s CRF.   
To assist with grading of AE severity, the following definitions are provided: 
Mild 
= 
Aware of sign or symptom, but easily tolerated;  
Moderate 
= 
Discomfort enough to cause interference with usual activity; 
Severe 
= 
Incapacitating with inability to work or do usual activity; 
Adverse events are assessed as either related to the intravitreal injection procedure 
(eyelid speculum, anesthetic drops, mydriatic drops, antibiotic drops, povidone-iodine 
drops or flush, subconjunctival injection of anesthetic, intravitreal injection), termed 
“injection procedure-related”, or to avacincaptad pegol.   
The relationship to the intravitreal injection procedure or to study drug will be assessed 
using the following definitions: 
Not Related 
= 
There is not a reasonable possibility that the AE is related 
to the injection procedure or to the study drug. 
Related  
=  
There is a reasonable possibility that the AE is related to 
the injection procedure or to the study drug. 
 
12.3 Definition of Serious Adverse Events 
An SAE is any event that: 

 
 
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1. Results in death; 
2. Is life-threatening (immediate risk of death); 
3. Results in inpatient hospitalization or prolongation of existing hospitalization; 
4. Results in a persistent or significant disability/incapacity; or 
5. Results in congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient/subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.   
A life-threatening AE is any event that places the patient/subject at immediate risk of 
death from the reaction as it occurred; i.e., it does not include a reaction that, had it 
occurred in a more severe form, might have caused death.   
Disability is a substantial disruption of a person’s ability to conduct normal life functions. 
Hospitalization is defined as any formal inpatient admission (even if less than 24 hours).  
For chronic or long-term inpatients, inpatient admission also includes transfer within the 
hospital to an acute/intensive care inpatient unit (e.g., from the psychiatric wing to a 
medical floor, from a medical floor to the coronary care unit).   
• Inpatient admission does not include the following:   
o Emergency Room/Casualty Department visits 
o Outpatient/same-day/ambulatory procedures and observation/short-stay 
units 
o Hospice facilities and Respite care (e.g., caregiver relief) 
o Rehabilitation facilities, skilled nursing facilities, nursing homes, custodial 
care facilities 
• Inpatient admission in the absence of a precipitating, treatment-emergent, clinical 
AE may meet criteria for “seriousness” but is not an AE and thus is not subject to 
immediate reporting to the Sponsor.  For example:   
o Admission for treatment of a pre-existing condition not associated with the 

 
 
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development of a new AE or with a worsening of the pre-existing condition 
(e.g., for work-up of persistent pretreatment lab abnormality) 
o Social admission (e.g., subject has no place to sleep) 
o Optional admission not associated with a precipitating clinical AE (e.g., 
yearly physical, elective cosmetic surgery) 
12.4 Assessment and Reporting of Serious Adverse Events 
Serious adverse events will be recorded starting after the first dose of trial drug 
and continuing until 30 days after the last dose or until the last follow-up visit 
required by the protocol, whichever comes later.  Any SAE occurring at any other 
time after completion of the trial must be promptly reported if a causal relationship to 
trial drug is suspected.   
If a SAE occurs, the Sponsor is to be notified within 24 hours of awareness of the event 
by the investigator.  In particular, if the SAE is fatal or life-threatening, notification to the 
Sponsor must be made regardless of the extent of available AE information.  This 
timeframe also applies to additional new information (follow-up) on previously forwarded 
SAE reports. 
All SAEs must be reported to the  
Sponsor or Designee within 24 hours. 
Refer to the “Safety Contact List” provided separately 
 
12.5 Independent Data Safety Monitoring Committee 
An Independent Data Safety Monitoring Committee (DSMB), consisting of persons who 
are independent of the Sponsor, trial coordination center, data coordination center, 
regulatory agencies, IRB/EC and investigators, and who have no financial, scientific, or 
other conflict of interest with the clinical trial, will meet regularly to review aggregate and 
individual subject data related to safety, data integrity and overall conduct of the trial, 
and provide recommendations to continue, modify, or terminate the trial depending 
upon the analyses. The safety data provided to the committee will be prepared by an 
independent statistician.  For details, please refer to the Independent Data Safety 
Monitoring Committee (DSMB) Charter.  
The Sponsor will ensure the proper conduct of the study, collection of accurate and timely 
data, and promptly report potential safety concerns to the DSMB, and communicate with 

 
 
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regulatory authorities, IRB/EC, and investigators in a manner that maintains integrity of 
the data as necessary. 
12.6 Exposure in Utero 
Astellas Drug Safety or contract research organization (CRO) must be notified of any 
subject who becomes pregnant or their partner who becomes pregnant, while 
participating in a clinical trial.  The Investigator must immediately notify the Sponsor’s 
Medical Monitor of any pregnancy associated with study medication exposure (at least 
90 days after drug administration) and record the event using sponsor provided 
pregnancy report form.  Protocol-required procedures for study discontinuation must be 
performed on the subject unless contraindicated by pregnancy.  All pregnancies must 
be followed to conclusion to determine their outcome.  Infants should be followed for a 
minimum of 8 weeks, if the pregnant study subject or their pregnant partner provides 
consent for the follow-up and for access to the newborn’s data. 
 
 

 
 
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13. 
RESPONSIBILITIES 
13.1 Emergency Equipment 
All participating sites should have emergency resuscitation equipment available, 
including at a minimum, an Ambu bag, IV tubing, D5W IV fluid, oxygen, and epinephrine 
1:1000, and Diphenhydramine Hydrochloride (Benadryl).  It is each center’s 
responsibility to ensure that all equipment is within specifications for the duration of the 
trial.  Each center should have written policies regarding resuscitation procedures.   
13.2 Case Report Forms and Trial Documentation 
The investigator will complete the appropriate CRF pages promptly following completion 
of each procedure or evaluation. 
All data recorded on CRFs will be supported by source documents.  For certain trial 
parameters, with prior written agreement by the trial sponsor and monitor, the CRF may 
be used to record source data.   
All source documents will be made available to the Sponsor’s clinical monitors during 
scheduled monitoring visits, to auditors during any audits requested by Astellas, and to 
regulatory agencies during inspections.   
The investigator will maintain a Trial File containing all trial related documentation 
required by Good Clinical Practice (GCP).  This Trial File will be reviewed periodically 
for completeness by the Sponsor’s clinical monitors and must be made available to 
auditors and regulatory agencies.   
All CRFs and original source documents including ocular images should be stored for a 
minimum of two years after a marketing application has been approved, or two years 
after formal discontinuation of development of the investigational drug, or five years 
after completion of the trial, whichever is longer.  Documents should not be destroyed 
without the permission of Astellas.  In the event of the Principal Investigator leaving the 
clinical site, it is the Principal Investigator’s responsibility to notify Astellas in writing and 
to designate which trial material will be transferred at the clinical site.  
13.3 Drug Accountability/Storage Conditions 
The investigator is responsible for the accountability of all used and unused trial 
medication and for recording and documenting the drug storage temperature at arrival 
and throughout the trial.  Drug accountability records will be reviewed during monitoring 
visits.  Adequate drug accountability records include documentation of all trial drug 

 
 
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supplies received, dispensed to trial subjects, and returned to the Sponsor.  All drug 
documentation should be filed at the site and a copy sent to the Sponsor for archiving. 
At the end of the trial, all drug supplies and documentation will be reviewed and 
reconciled by the trial monitors.  The sites may destroy unused trial drug supplies when 
the trial is completed if they have an SOP to cover that activity. Otherwise the site may 
return the drug to a sponsor-contracted drug management facility for destruction.  If the 
drug is destroyed at the site, the drug destruction documentation must be sent to 
Astellas for archiving.   
13.4 Protocol Compliance 
Astellas will not compensate the Investigator for evaluation of cases in which the 
procedures and evaluations are conducted in a manner other than that specified by the 
protocol.   
13.5 Ethical Aspects 
Local Regulations/Declaration of Helsinki 
The investigator will ensure that this trial is conducted in full conformance with the 
principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, 
South Africa, and Scotland) and with the laws and regulations of the country in which 
the research is conducted, whichever affords the greater protection to the individual.  
The trial must fully adhere to the principles outlined in “Guideline for GCP” ICH Tripartite 
Guideline (May 9th 1997) and with local law if it affords greater protection to the subject.  
For studies conducted in the USA or under US Investigational New Drug (IND), the 
investigator will additionally ensure adherence to the basic principles of “GCP” as 
outlined in the current version of 21 CFR, subchapter D, part 312, “Responsibilities of 
Sponsors and Investigators”, part 50, “Protection of Human Subjects”, and part 56, 
“Institutional Review Boards”.   
13.6 Institutional Review Board (IRB) or Ethics Committee (EC) Approval 
and Informed Consent 
The investigator is responsible for obtaining approval of the trial protocol, informed 
consent, and any advertising used for subject recruitment from the appropriate IRB/EC 
prior to initiating the trial.  The investigator will forward the following documents prior to 
commencement of subject enrollment:    
• 
IRB/EC approval documentation 
• 
Approved trial subject informed consent 
• 
A list of IRB/EC members, or statement of compliance 

 
 
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Prior to enrollment, written informed consent must be obtained from each subject or 
his/her legally authorized representative.  The informed consent must contain all of the 
elements prescribed by the relevant regulatory authorities and must be appropriately 
signed, dated and witnessed.  Any changes by the Investigator or local IRB/EC to 
the sample consent provided by the Sponsor must be approved by the Sponsor 
before initiating enrollment.   
13.7 Clinical Trial Insurance 
Astellas has insurance coverage for medicine-induced injury and other liabilities 
incurred during clinical trials with its compounds.   
13.8 Trial Report and Publications 
The trial will be documented in a final report, which will contain appropriate statistical 
analysis and medical overview.  No individual site or investigator may publish or present 
any results from the trial until a joint, multi-center publication of the trial results is made 
by Sponsor in conjunction with various participating investigators and appropriate sites 
contributing data and comments.  Subsequently, individual investigators may request to 
publish or present results from the trial; however, approval will be at the sole discretion 
of the Sponsor.  Should the foregoing language be in conflict with the language 
addressing publication in the clinical trial agreement, the language in the clinical trial 
agreement will prevail.   
14. 
MONITORING 
The investigator will permit representatives of Astellas to review all CRFs, trial 
documentation, and subject medical records at regular intervals throughout the trial.  
These monitoring visits are for the purpose of verifying protocol compliance, subject 
safety, and the adequacy of data collected.   
 
 

 
 
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15. 
REFERENCES 
Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, 
Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis 
RA, Nathans J, Leppert M, Dean M, Lupski JR (1997).  A photoreceptor 
cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive 
Stargardt macular dystrophy.  Nat Genet. 15(3):236-46.   
Beharry S, Zhong M, Molday RS (2004).  N-retinylidene-phosphatidylethanolamine is 
the preferred retinoid substrate for the photoreceptor-specific ABC transporter 
ABCA4 (ABCR).  J Biol Chem. 279(52):53972-9.   
Berchuck JE, Yang P, Toimil, BA, Ma Z, Baciu P, Jaffe GJ (2013).  All-transretinal 
sensitizes human RPE cells to alternative complement pathway– induced cell 
death.  Invest Ophthalmol Vis Sci. 54:2669–2677.   
Bergmann M, Schutt F, Holz F, Kopitz J (2004).  Inhibition of the ATP-driven proton 
pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute 
to the pathogenesis of age-related macular degeneration.  FASEB J. 
18(3):562-4. 
Finnemann SC, Leung LW, Rodriguez-Boulan E (2002).  The lipofuscin component A2E 
selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by 
the retinal pigment epithelium.  Proc Natl Acad Sci USA 99:3842–3847.   
Fishman GA (1976).  Fundus Flavimaculatus, A Clinical Classification.  Arch 
Ophthalmol 94:2061-2067.   
Fleming TR, Richardson BA (2004). Some design issues in trials of microbicides for the 
prevention of HIV infection. The Journal of Infectious Diseases 190:666–74.  
Georgiannakis A, Burgoyne T, Lueck K, Futter C, Greenwood J, Moss S (2015).  Retinal 
Pigment Epithelial Cells Mitigate the Effects of Compliment Attach by 
Endocytosis of C5b-9. J Immunol. 195:3382-3389. 
Higgins CF (1992).  ABC transporters: from microorganisms to man.  Annu Rev Cell 
Biol. 8:67-113.   

 
 
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Lenis TL, Sarfare S, Jiang Z, Lloyd MB, Bok D, Radu RA (2017).  Complement 
modulation in the retinal pigment epithelium rescues photoreceptor degeneration 
in a mouse model of Stargardt disease.  Proc Natl Acad Sci USA. 114(15):3987-
3992.   
Li W, Chen S, Ma M, Qian J, Ma X (2010).  Complement 5b-9 complex-induced 
alterations in human RPE cells physiology. Med Sci Monit; 16(1): BR17-23. 
Mata NL, Weng J, Travis GH (2000).  Biosynthesis of a major lipofuscin fluorophore in 
mice and humans with ABCR-mediated retinal and macular degeneration.  Proc 
Natl Acad Sci USA 97:7154–7159.   
Morgan BP (2015).  The membrane attack complex as an inflammatory trigger. 
Immunobiology.  221(6):747-51.    
Parish CA, Hashimoto M, Nakanishi K, Dillon J, Sparrow J (1998).  Isolation and one 
step preparation of A2E and iso-A2E, fluorophores from human retinal pigment 
epithelium.  Proc Natl Acad Sci USA 95:14609–14613.   
Radu RA, Yuan Q, Hu J, Peng JH, Lloyd M, Nusinowitz S, Bok D, Travis GH (2008).  
Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model 
for ABCA4-mediated retinal dystrophies following vitamin A supplementation.  
Invest Ophthalmol Vis Sci 49:3821–3829.   
Radu RA, Hu J, Yuan Q, Welch DL, Makshanoff J, Lloyd M, McMullen S, Travis GH, 
Bok D (2011).  Complement system dysregulation and inflammation in the retinal 
pigment epithelium of a mouse model for Stargardt macular degeneration.  J Biol 
Chem. 286(21):18593-601.   
Rotenstreich Y, Fishman GA, Anderson RJ (2003).  Visual acuity loss and clinical 
observations in a large series of patients with Stargardt disease.  
Ophthalmology;110:1151–1158.   
Schutt F, Davies S, Kopitz J, Holz FG, Boulton ME (2000).  Photodamage to human 
RPE cells by A2-E, a retinoid component of lipofuscin.  Invest Ophthalmol Vis Sci 
41:2303–2308.   
Schutt F, Bergman M, Holz F, Kopitz J (2002).  Isolation of intact lysosomes from 
human RPE cells and effects of A-2.E on the integrity of the lysosomal and other 
cellular membranes. Arch Clin Exp Ophthalmol 240:938-988. 

 
 
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Sparrow JR, Nakanishi K, Parish CA (2000).  The lipofuscin fluorophore A2E mediates 
blue light-induced damage to retinal pigmented epithelial cells.  Invest 
Ophthalmol Vis Sci. 41(7):1981-9.   
Sparrow JR, Yamamoto K (2012).  The bisretinoids of RPE lipofuscin: A complex 
mixture.  Adv Exp Med Biol 723:761–767.   
Stargardt K (1909).  Uber familiare progressive degeneration in der makulagegend des 
auges. Graefes Arch Klin Ophthalmol  71:534-550.   
Strauss RW, Ho A, Muñoz B, Cideciyan AV, Sahel JA, Sunness JS, Birch DG, 
Bernstein PS, Michaelides M, Traboulsi EI, Zrenner E, Sadda S, Ervin AM, West 
S, Scholl HP; Progression of Stargardt Disease Study Group (2016).  The natural 
history of the progression of atrophy secondary to Stargardt disease (ProgStar) 
studies: design and baseline characteristics: ProgStar report no. 1.  
Ophthalmology;123:817-828. 
Strom SP, Gao YQ, Martinez A, Ortube C, Chen Z, Nelson SF, Nusinowitz S, Farber 
DB, Gorin MB (2012).  Molecular diagnosis of putative Stargardt Disease 
probands by exome sequencing.  BMC Med Genet. 3;13:67.   
Travis GH, Golczak M, Moise AR, Palczewski K (2007).  Diseases caused by defects in 
the visual cycle: retinoids as potential therapeutic agents.  Annu Rev Pharmacol 
Toxicol. 47:469-512.   
Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH (1999).  Insights into 
the function of Rim protein in photoreceptors and etiology of Stargardt’s disease 
from the phenotype in abcr knockout mice.  Cell 98:13–23.   
Wu Y, Fishkin NE, Pande A, Pande J, Sparrow JR (2009).  Novel lipofuscin bisretinoids 
prominent in human retina and in a model of recessive Stargardt disease.  J Biol 
Chem 284:20155–20166.   
Yang P, Tyrrell J, Han I, Jaffe GJ (2009).  Expression and modulation of RPE cell 
membrane complement regulatory proteins.  Invest Ophthalmol Vis Sci. 
50(7):3473-81.   
Yi J, Li S, Jia X, Xiao X, Wang P, Guo X, Zhang Q (2012).  Evaluation of the ELOVL4, 
PRPH2 and ABCA4 genes in patients with Stargardt macular degeneration.  Mol 
Med Rep. 6(5):1045-9.   

 
 
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Zhou J, Jang YP, Kim SR, Sparrow JR (2006).  Complement activation by 
photooxidation products of A2E, a lipofuscin constituent of the retinal pigment 
epithelium.  Proc Natl Acad Sci USA. 103(44):16182-7.   
Zhou J, Kim SR, Westlund BS, Sparrow JR (2009).  Complement activation by 
bisretinoid constituents of RPE lipofuscin.  Invest Ophthalmol Vis Sci. 
50(3):1392-9.   
 
 

 
 
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16. 
SPONSOR SIGNATURE PAGE 
Required sponsor signatures as required by ICH GCP 4.5.1 are located in the first 
attachment.   
Attachment 1  
Electronic Sponsor Signatures  
 
 
 
 

 
 
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17. 
APPENDICES 
17.1 Method for Evaluating Anterior Chamber Inflammatory Activity 
17.1.1 Examination 
1. The pupils will be maximally dilated. 
2. A slit-lamp biomicroscope will be used with a one by two mm2 beam at an angle of 
30-45°.  The number of cells within this wedge will be counted. 
3. The grade of anterior chamber inflammatory activity is determined. 
17.1.2 Standardized Description of Anterior Chamber Activity 
Anterior chamber activity will be graded on a scale of 0, trace, 1+, 2+, 3+, and 4+. 
The grading is as follows:   
0 
None 
Trace  
< 5 cells in wedge 
1+ 
5 - 10 cells in wedge 
2+  
11 - 20 cells in wedge 
3+  
21 - 50 cells in wedge 
4+  
> 50 cells in wedge 
 
Reference 
Hogan MJ, Kimura SJ, Thygeson P (1959).  Signs and symptoms of Uveitis.   
I.  Anterior uveitis.  Am J Ophthalmol; 47:155-170.   
 
 

 
 
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17.2 Method for Evaluating Vitreous Inflammatory Activity 
All subjects will have the standard fundus examination followed by evaluation for 
inflammatory activity in the vitreous.   
17.2.1 Marking  
The clarity of the optic nerve head, retinal vessels, and the nerve fiber layer are used as 
landmarks for the marking criteria.   
17.2.2 Examination  
1. The pupils will be maximally dilated. 
2. An indirect ophthalmoscope and a 20+ diopter aspheric lens will be used as the 
standard. 
3. Standard fundus examination is performed with the last view being over the disc 
and surrounding retina. 
4. Inflammatory activity is evaluated by the examiner by determining which 
standardized description most closely resembles the vitreal haze seen through 
the indirect ophthalmoscope. 
17.2.3 Standardized Description of Vitreous Inflammation 
Vitreous activity will be graded on a scale of 0, 1+, 2+, 3+, and 4+.   
The grading is as follows1:   
0 
No evident vitreal haze at all. 
1+  
Minimal haze.  Optic nerve head and retinal vessels are both clearly 
defined. 
2+  
Retinal vessels are visible, but not clearly defined. 
3+  
Optic nerve head is visible but the borders are blurry, and cannot see 
vessels. 
4+  
Optic nerve head is obscured. 
 
Reference 
Nussenblatt RB et al. (1985).  Standardization of Vitreal Inflammatory Activity in 
Intermediate and posterior Uveitis.  Ophthalmology 92:467-471.   
 

 
 
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17.3 Procedures for Refraction and Vision Testing 
Refraction and visual acuity measurements will be performed for all subjects by a 
certified vision examiner.  Another examiner should also be certified to serve as a 
back-up should the primary examiner be absent.  The name and certification number of 
the vision examiner should be documented in the subject’s source document at each 
visit.  Visual acuity examiners are “masked” to previous visual acuity testing results.  
Therefore, visual acuity examiners should not have access to the subject’s chart or 
previous visual acuity testing results.  The previous refraction should be made available.   
17.3.1 Refraction 
Refraction should be conducted prior to visual acuity testing to obtain best-corrected 
vision.   
17.3.2 Equipment 
Refraction equipment required includes: 
1. Retroilluminated light box and Charts R, 1 and 2 from Ferris-Bailey ETDRS distance 
visual acuity chart set 
2. Trial lens frames 
3. Trial lens set with plus or minus cylinder lenses 
4. Jackson cross-cylinders of 0.25, 0.5, and 1.00 diopters 
5. Pinhole occluder 
6. Tissues or eye pads and tape 
7. A 1 meter rigid measuring stick 
17.3.3 Beginning Approximate Refraction 
At the Screening visit, the subject’s beginning refraction is determined by one of the 
following methods:   
a)  If the subject’s visual acuity is 20/100 or better and the subject does not require 
glasses for distance vision, then the beginning approximate refraction should be no 
lens correction or plano.   
b)  If the subject’s visual acuity is 20/100 or better and the subject requires glasses for 
distance viewing, the glasses should be measured using a lensometer, and these 
measurements are used for the beginning refraction.   
c)  If the subject’s visual acuity is less than 20/100 with or without correction, then 
retinoscopy or autorefraction should be performed.   
d)  If the subject wears contact lenses for refraction, a notation should be made that the 
refraction was over contact lenses.  It is suggested that the subject wear the contact 
lenses for future examinations.  If the subject is not a regular contact lens wearer 

 
 
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and wore the lenses in by mistake, they should be removed and you should wait at 
least 30 minutes before beginning the refraction.  The subject should be reminded 
not to wear contact lenses at subsequent visits.   
 
Refractions are performed with either plus or minus cylinder power.  Whichever cylinder 
type is used at screening (minus or plus) must be used for all subsequent visits.  Best 
correction will be recorded on an examination form for each subject to be included in the 
source document.  At each follow-up visit, the results of the protocol refraction from the 
previous visit are used as the beginning approximate refraction.  If the previous 
refraction is not available for whatever reason, the procedure described immediately 
above should be used.  Note: The distance prescription worn in glasses should be used 
only as the starting point for the Screening Visit.  All subsequent visits should use the 
previous refraction as the starting point.   
 
The charts used for measuring distance visual acuity must NOT be used for refraction.  
Refraction for each eye should be performed at 4 meters unless the subject’s visual 
acuity measured at 4 meters on the refraction chart (Chart R) is worse than 20/160.  If 
visual acuity is worse than 20/160 the eye is refracted at 1.0 meter.  If during the 
refraction process at one meter, the subject is reading letters on the eighth line or lower, 
the refraction should continue at 4 meters.  Whenever a subject cannot read any letters 
on the top line of Chart R at 1.0 meter the vision should be checked with a pinhole to 
see whether reduced vision is due, at least in part, to a larger refractive error.  If there is 
no improvement with the pinhole, then the eye is exempt from refraction.   
 
Subjective refraction as described below should be performed for corrected aphakic 
subjects, including those with intraocular lenses.  For uncorrected aphakic subjects, a 
+10.00 diopter sphere should be added to the trial frame as the beginning approximate 
refraction.   
 

 
 
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17.3.4 Subjective Refraction 
Subjective refraction allows one to determine the best correction for a subject to perform 
the visual acuity tests at specified distances.  The “push plus” approach is used in this 
trial.  Add minus diopter spherical corrections only when the subject is able to read at 
least one more letter on a line or a letter on a smaller line.   
17.3.5 Procedure  
1. Measure the distance vision of each eye using Chart R while occluding the fellow 
eye (FE).  Subjects should be reminded to blink and encouraged to use eccentric 
fixation, or their side vision, when necessary.   
2. All vision testing must be done at 4 meters or 1 meter from Chart R, depending upon 
the visual acuity determined at 4 meters.  Distance for 4 meters is 13 feet and 
1.5 inches or 157.5 inches.  The one meter distance is 39 and 3/8 inches.   
3. All subjects should be seated for testing.  A rigid measuring device should be used 
to measure the distance from the subject to the chart at each visit if testing is done 
at 1 meter.  The distance is measured from the outer canthus to the center of the 
second letter (left eye) or fourth letter (right eye) of the third line of the chart.  If 
testing is done at 4 meters, clear and permanent floor markings should be used to 
mark the distance for consistency.   
4. Place and adjust the trial frame on the subject’s face so that the lens cells are 
parallel to the anterior plane of the orbits and centered in front of the pupils.  Adjust 
the lens cells for the proper distance from the cornea.   
5. Occlude the left eye by lightly patching with an eye pad or tissue and tape.   
a) Place the spherical lens correction in the compartment closest to the eye.   
b) The cylindrical lens correction, if present, is placed in the compartment in front of 
the spherical correction.  Adjust the axis.   
6. Spherical Correction: To determine the highest plus or least minus sphere, refract 
the right eye.  The following refraction steps are recommended for visual acuities 
of 20/10 to 20/80 with the beginning approximate refraction.  For visual acuities 
less than 20/80, refer to the refraction table for the appropriate sphere and 
cylinder powers and testing distance (See 17.3.10) and follow a similar 
procedure.  Note: Whenever visual acuity is improved to a higher range by improved 
correction, refraction should be performed with the smaller sphere and cylinder 
powers given for the better visual acuity level (See table at end of this appendix).   
a) Hold a +0.50 sphere in front of the subject’s right eye.  The subject should be 
looking at the smallest legible line on the visual acuity chart.  In these exact words, 
ask the subject, “Is this better, worse, or no change?” 

 
 
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b) If the subject responds that the vision is worse or blurred, remove the +0.50 sphere 
from in front of the trial frame, record the visual acuity to the nearest letter, and go 
to Step 6d.   
c) If the subject responds better or no change, remove the +0.50 sphere from in front 
of the trial frame and replace the spherical lens in the trial frame with a spherical 
lens that is one-half diopter more positive.  Continue this procedure by returning to 
Step 6a and repeating this process until a +0.50 makes the vision worse or blurred 
and then go to Step 6d.   
d) Hold a -0.50 sphere in front of the subject’s right eye.  In these exact words, ask 
the subject, “Is this better, worse or no change?”  If the subject replies “worse” or 
“no change”, go to Step 6f.  If they reply “better” go to step 6e.   
e)  Hold the -0.50 sphere in front of the eye.  If the subject responds that the vision is 
better, ask the subject to read the visual acuity chart.  Whenever the visual acuity 
is improved, even by one letter, you may increase the minus by 0.50 (or decrease 
the plus) and repeat Step 6d.  Whenever visual acuity is not improved, go to 
Step 6f.   
f) Remove the -0.50 sphere from in front of the eye and hold a +0.50 sphere in front 
of the right eye.  In these exact words, ask the subject, “Is this better, worse, or no 
change?”  If the subject responds that vision is better or unchanged, then return to 
Step 6c.  Otherwise, go to Step 7.  Spherical testing should always end with a plus 
lens.   
7. Cylinder Axis:  To determine and refine the cylinder axis for PLUS cylinder, proceed 
as follows (If negative cylinders are used, the appropriate technique using minus 
cylinders must be employed and minus cylinder must be used throughout the trial.):   
a) Have the subject look at a line, which is either one or two lines larger than the 
smallest line the subject is able to read.  Ask the subject to focus on a rounded 
letter such as “C”, “D”, or “O”.  The subject should focus on this same letter 
throughout this procedure.   
b) If a cylinder is present in the beginning approximate refraction, then go to Step 7c.  
Otherwise, follow one of the options listed below to determine the appropriate 
cylindrical correction.   
 

 
 
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Option 1: 
Place a +0.50 diopter cross-cylinder with the positive axis (white) first at 
90°, then at 180°, then 45°, and 135°.  If the subject says that vision is 
improved at any one of these axis positions, place a +0.50 cylindrical lens 
in the trial frame at the preferred axis and go to Step 7c.  If none of the 
positions are preferred, then proceed to Step 9.   
Option 2 (preferred):   
Place a +0.50 diopter cross-cylinder with the positive axis (white) first at 
90°, then compare this to no cylinder; repeat this procedure for 180°, then 
45°, and 135° always comparing to no cylinder after each axis position.  If 
the subject says that vision is improved at any one of the four axis 
positions, place a +0.50 cylindrical lens in the trial frame at the preferred 
axis.  If the subject prefers no cylinder at all four axis positions, then go to 
Step 9.   
c) Place the +0.25 diopter cross-cylinder (for visual acuity 20/10-20/80) first with the 
positive axis 45° to the right of the preferred cylinder axis (as determined above), 
and second with the positive axis 45° to the left of the preferred cylinder axis.  Ask 
the subject, “Which do you like better, position one or position two?”  Also, tell the 
subject that both positions may blur their vision.  The subject must choose the least 
blurred position, either one or two.  “Neither” is allowed only if both positions are 
equally blurred or equally good.   
d) If “neither” position is better and this was the first test of axis position, move the 
axis of the cylinder in the trial frame 15° to the right or left and return to Step 7c.  
Otherwise, proceed to Step 7e.   
e) When one position is preferred over another, move the cylinder to the preferred 
positive axis position in the step sizes noted below and return to Step 7c.  If no 
single position is better than another than go to Step 8.   

 
 
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CYLINDER REFINEMENT     - AXIS STEP SIZES 
Cylinder Power  
 
Axis Step Sizes 
< 1.00D 
 
15° 
1.00 - < 2.00D 
 
10° 
2.00 - < 3.00D 
 
5° 
3.00 - < 5.00D 
 
3° 
5.0  - < 8.00D 
 
2° 
 
8. Cylinder Power:  Cylinder power is refined by following the steps: 
a) Ask the subject to look at the smallest line that can be read on the visual acuity 
chart. 
b) Test the cylinder power by placing the 0.25 diopter cross-cylinder (for vision of 
20/10-20/80) first with the positive axis and second with the negative axis 
coincident with the cylinder axis.  Ask the subject, “Which is better, position one or 
position two?” Do not give the subject the choice of neither.   
c) If the subject prefers the negative (red) axis coincident with the cylinder axis, the 
total power of the correcting plus cylinder is reduced by 0.25 diopter.  Repeat the 
process until the subject cannot choose one of the cross cylinder positions over 
the other.  If the subject indicates a change that would introduce negative cylinder 
power, remove all cylinder power and continue testing for positive cylinder power 
at an axis 90°away from the previous axis.  Otherwise go to Step 8d.   
d) If the subject prefers the positive (white) axis coincident with the cylinder axis, 
increase the power of the cylinder by 0.25 diopters and return to Step 8b.  
Otherwise proceed to Step 8e. 
e) When the subject feels that both positions are equally bad or good, and the cylinder 
power in the trial frame has changed by more than 0.50 diopter, return to Step 7c 
and re-adjust the axis if necessary.  Otherwise, proceed to Step 9.   
Note: If the cylinder is changed by more than 0.50 diopter, the spherical equivalent 
should be maintained.  (For each 0.50 plus CX increase, add –0.25 to the sphere, 
for each 0.50 minus CX increase, add +0.25 to the sphere).   
9. Spherical Correction Refinement: Recheck the power of the sphere by adding 
+0.25 and -0.25 spheres and changing the spherical power by 0.25 diopter 
increments of the appropriate sign until the subject cannot detect any improvement 

 
 
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in vision.  As a reminder, spherical testing should always begin and end with a plus 
lens.   
10. Record the lens corrections obtained by subjective refraction for the right eye on the 
examination form in the section for visual acuity measurements as the corrections 
obtained by protocol refraction for the right eye.  If the corrective power was changed 
by more than 2 diopters from the starting refraction, confirm that the subject can read 
at least as well as the beginning approximate refraction.  If not, then begin again at 
Step 1 and repeat the process.   
11. Repeat the entire process (Steps 1-10) for the left eye and record the result on the 
examination form.   
17.3.6 Visual Acuity Testing 
Best-corrected visual acuity is measured at all trial visits using standard charts, lighting, 
and procedures.  Best correction is determined by careful refraction at that visit 
according to the standard protocol for Refraction as described in the previous section.   
17.3.7 Visual Acuity Charts 
Chart 1 is used for testing the visual acuity of the right eye; Chart 2 for testing the left 
eye; and Chart R for testing refraction only.  Subjects should not be allowed to see any 
of the charts before the examination.   
17.3.8 Visual Acuity Lane and Visual Acuity Box 
A distance of 4 meters is required between the subject’s eyes and the visual acuity 
chart.  With the box light off, not more than 15 foot-candles of light (161.4 Lux) should 
fall on the center of the chart.  To measure the amount of light, the room is set up for 
visual acuity testing, but with the box light off.  The light meter is placed at the fourth line 
from the top of the chart, with its back against the chart and the reading is taken.  If 
more than one lane is available for testing visual acuity, the visual acuity of an individual 
subject should be measured in the same lane at each visit, if possible.  If different lanes 
are used to test visual acuity, they must each meet the same standards.   
Retroilluminated ETDRS charts are used in this trial.  The illuminator box will be either 
wall-mounted or mounted on a stand manufactured by the Lighthouse Low Vision 
Services.  The light box should be mounted at a height such that top of third row letter is 
49 ± 2 inches from floor.   
The visual acuity light box is equipped with two General Electric Cool Daylight 20-watt 
fluorescent tubes and a ballast which partially covers the tubes.  Because the 
illumination of fluorescent tubes diminishes by 5 percent during the first 100 hours and 

 
 
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by another 5 percent during the next 2000 hours, new tubes should be kept on for 
4 days (96 hours) continuously, and should be replaced once a year.   
A sticker should be placed on the back of the light box, indicating the date on which the 
present tubes were installed.  A spare set of burned in bulbs should be available on site. 
Each tube is partly covered by a 14-inch fenestrated sleeve, which is open in the back.  
This serves as a baffle to reduce illumination.  Each sleeve should be centered on the 
tube with the opening towards the back.   
17.3.9 Corrected Visual Acuity Measures 
• As a reminder, Charts 1, 2, and R are used for testing the right eye, left eye, and 
refraction, respectively.  Subjects should not see the charts until the test begins. 
• All eyes must be tested at 4 meters first, even if the refraction was performed at 
1 meter.   
• The subject should be seated comfortably directly in front of the chart so that the 
eyes remain at the 4 meter distance.  Testing always begins with the right eye.  
Occlude the subject’s left eye.  A folded tissue or eye pad lightly taped over the 
eye behind the trial frame serves as an effective occluder that allows eccentric 
fixation without inadvertent use of the covered eye.  After testing the right eye, 
occlusion of the right eye should be done BEFORE Chart 2 is put up for testing 
the left eye.   
• The lens correction from the subjective refraction should be in the trial frame 
worn by the subject.   
• The subject is asked to read the letters slowly, approximately one letter per 
second.  The subject should be told that only one chance is given to read each 
letter on the chart.  If the subject is unsure about the identity of the letter, then the 
subject should be encouraged to guess.   
• The subject should begin by reading the top line of the chart and continue 
reading every letter on each smaller line, from left to right on each line.  The 
examiner circles every correct letter read and totals each line and the whole 
column (0 if no letters are correct) on the data collection form.  An X is put 
through letters read incorrectly.  Letters, for which no guess was attempted, are 
not circled.  When a subject reaches a level where he/she cannot guess, the 
examiner may stop the test provided that the subject has made errors on 

 
 
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previous guesses, which is a clear indication that the best visual acuity has been 
obtained.   
• When a subject cannot read at least 20 letters on the chart at 4.0 meters, the 
subject is tested at 1.0 meter.  The distance from the subject to the chart should 
be measured again using the rigid one meter stick.  The distance is measured 
from the outer canthus to the center of the fourth letter (right eye) or the second 
letter (left eye) of the third line of the chart.  The spherical correction in the trial 
frame should be changed by adding +0.75 to correct for the closer test distance.  
The subject may fixate eccentrically or turn or shake his/her head to improve 
visual acuity.  If this is done, the examiner must ensure that the FE remains 
occluded both centrally and peripherally and that the subject does not move 
forward in the chair.  Particular care should be taken to make sure the subject 
does not move forward when testing at 1 meter.  The subject should be reminded 
to blink.   
• The examiner should not tell the subject if a letter was identified correctly.  The 
subject may be encouraged by neutral comments, such as “good”, “next”, and 
“OK”.   
• The examiner should not stand close to the chart during testing.  Attention should 
be focused on the subject and the data collection form.  If the subject has 
difficulty locating the next line to read, the examiner may go up to the chart and 
point to the next line to be read, but then must move away from the chart.   
• When it is possible to measure the visual acuity of the eye at 4.0 meters (i.e.  
20 or more letters read at 4 meters), the visual acuity score for that eye is 
recorded as the number of letters correct plus 30.  The subject gets credit for the 
30 1M letters even though they did not have to read them.  Otherwise, the visual 
acuity score is the number of letters read correctly at 1.0 meter plus the number, 
if any, read at 4M.  If no letters are read correctly at either 4.0 meters or 1 meter, 
then the visual acuity score is recorded as 0.   
Testing for Count Fingers Vision, Hand Motion Vision and Light Perception/No 
Light Perception (NLP) Vision 
If the subject’s visual acuity is so poor that he/she cannot read any chart letters when 
tested at one meter then the subject’s ability to count fingers, detect hand motion, or 
have light perception should be evaluated.   
 

 
 
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Testing for Count Fingers Vision 
In testing for count fingers vision, the examiner’s hand holding 1, 2, or 5 fingers is held 
steady at a distance of two feet directly in front of the eye being examined.  The FE is 
completely occluded with a patch on the face.  A light should be shown directly on the 
hand from behind the subject.  The examiner’s fingers should be presented in random 
order and repeated 5 times.  Eccentric fixation, if present, should be encouraged.  If the 
subject correctly identifies three of the five presentations, then count fingers vision is 
noted.  If not, then the subject must be tested for hand motion vision. 
 
Testing for Hand Motion Vision 
The examiner’s hand with all fingers spread out should be extended two feet directly in 
front of the eye being examined.  The FE should be occluded with a patch on the 
subject’s face.  A light should be shone directly on the hand from behind the subject.  
The examiner’s hand should be moved in an up-and-down direction (vertically) or in a 
side-to-side direction (horizontally) at a constant speed of approximately one back and 
forth presentation per second.  The subject is instructed that the examiner’s hand will be 
presented and they will have to respond to the question: “What am I doing with my 
hand?” This should be repeated five times.  Three out of five correct responses indicate 
that hand motion vision is present.  If the subject does not correctly identify three of five 
presentations, then you must test for light perception.   
 
Testing for Light Perception/NLP Vision 
Light perception should be tested with an indirect ophthalmoscope in a darkened room.  
The indirect ophthalmoscope light should be in focus at 1 meter with the rheostat set at 
maximum voltage.  From that distance the beam should be directed in and out of the 
eye at least four times, and the subject should be asked to respond when he or she 
sees the light.  If the examiner is convinced that the subject perceives the light, vision 
should be recorded as “light perception”, if not, vision should be recorded as “no light 
perception (NLP)”.   
 

 
 
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17.3.10 
Refraction Sequence Chart 
Refraction Protocol Summary 
Vision with Best 
Correction (Refraction 
Distance) 
Sphere 
Cylinder 
 
Sphere Refinement 
 
 
Power 
(a) 
Increment 
Axis 
(b) 
Power 
(c) 
Increment 
Power 
(d) 
Increment 
20/10 - 20/80 
(4 meters) 
+.50 
-.50 
+.50 
-.50 
.25 
JCC 
.25 
JCC 
+.25 
-.25 
+.25 
-.25 
+.25 
-.25 
20/100 - 20/160 
(4 meters) 
+1.00 
-1.00 
+1.00 
-1.00 
.50 
JCC 
.50 
JCC 
+.50 
-.50 
+.50 
-.50 
+.50 
-.50 
20/200 - 20/400 
(1 meter) 
+2.00 
-2.00 
+2.00 
-2.00 
1.00 
JCC 
1.00 
JCC 
+1.00 
-1.00 
+1.00 
-1.00 
+1.00 
-1.00 
<20/400 
(1.0 meters) 
+2.00 
-2.00 
+2.00 
-2.00 
No cylinder test 
No refinement 
Sequence of Refraction: (a) - (d)  
 
 
 

 
 
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17.4 Intravitreal Administration Protocol 
This protocol applies to avacincaptad pegol and Sham injections. 
The injection volume for avacincaptad pegol 2 mg/eye is 0.10 mL (100 µL).   
The avacincaptad pegol and Sham injections must be performed by the unmasked 
ophthalmologist at the clinical site.   
Subjects will receive one or two intravitreal injections (including Sham) at each 
monthly visit.  Subjects will receive one of the following treatments at each injection 
visit: 
• Avacincaptad pegol 2 mg/eye 
• Avacincaptad pegol 4 mg/eye (administered as two injections of avacincaptad 
pegol 2 mg) 
• Sham 
• Sham + Sham 
Only an ophthalmologist who is experienced with intravitreous injections may 
perform the intravitreous injections. 
When there are two intravitreal injections to be administered on the same day, 
this intravitreous preparation and administration procedure MUST be followed 
for both injections, i.e., subjects MUST undergo a second preparation 
procedure and povidone-iodine (Betadine®) application prior to the second 
injection.  
In addition to the procedures outlined, any additional safety measures in adherence 
to specific institutional policies associated with intravitreal injections may be utilized. 
NOTE: Prior to the intravitreous injection, direct ocular massage using a sterile 
cotton-tip applicator at the intended site of injection may be utilized at the 
Investigator’s discretion.  However, a paracentesis MAY NOT be performed prior to 
injection of the intravitreous drug. 
NOTE: Pre-operative antibiotic drops are NOT required prior to the scheduled 
injection(s) of intravitreous drug. In addition, peri-operative and post-operative 
antibiotic drops are NOT required at the time of the procedure or after the procedure, 
respectively. However, if it is considered the standard of care at the individual 

 
 
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institution, appropriate broad spectrum topical antibiotics (topical ofloxacin, 
levofloxacin, or an antibiotic drop with comparable antimicrobial coverage) may be 
prescribed for subject use at the discretion of the investigator. 
NOTE: Intravitreal administration of avacincaptad pegol is contraindicated if 
active inflammation and/or suspected or active ocular or peri-ocular infection 
is present. 
NOTE: Clinically significant blepharitis should be treated and resolved prior to 
randomization. 
Before the Injection Day 
1) If pre-operative topical ofloxacin, levofloxacin, or an antibiotic drop with 
comparable antimicrobial coverage therapy is ordered by the investigator, the 
subject should be instructed to initiate the use of such antibiotic drops according 
to the regimen selected at the discretion of the investigator. The antibiotic drops 
should be provided to the subject with clear instructions of how to use them at 
the visit immediately prior to each planned injection. 
Preparation on the Day of the Injection 
2) Approximately one hour prior to injection, topical 1% tropicamide (e.g., Mydriacyl) 
and 2.5% phenylephrine (e.g., Neo-Synephrine) from new bottles should be 
applied topically to achieve adequate pupillary dilation.  If 2.5% phenylephrine is 
not available, another dilating drop may be used at the discretion of the 
investigator.  
3) Injection preparation (for the following, new povidone-iodine bottles must be used 
and cannot be shared between subjects):   
a. Apply single use topical anesthetic drop(s) to the eye. 
b. Apply 2-3 drops of povidone-iodine to the injection site.  
c. OPTIONAL:  Apply 2-3 drops of povidone-iodine to the lower 
fornix and/or use sterile cotton-tipped applicators soaked in 5% 
or 10% povidone-iodine to swab the upper and lower eyelid 
margins and the upper and lower eyelashes.   
4) Place a sterile eyelid speculum to stabilize the eyelids.   

 
 
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5) Consider additional anesthesia with the application of one or two cotton-tipped 
applicators soaked in topical anesthetic over the intended injection site for at 
least 30 seconds.  Subconjunctival anesthesia (0.5 mL of 2% xylocaine without 
epinephrine subconjunctivally at the intended injection site) can be used if the 
investigator believes that topical anesthetic is not sufficient to minimize 
discomfort.  Lidocaine gel is not recommended. 
6) Encourage the study participant to look superonasally (if injection site is 
inferotemporal) during the application of the povidone-iodine.  Apply one of the 
following to the conjunctiva directly over and surrounding the intended injection 
site: 
a. A cotton-tipped applicator soaked in 5% or 10% povidone-iodine. 
b. A 10% povidone-iodine swabstick. 
c. At least 1-3 drops of 5% povidone-iodine (at least enough to 
cover the intended injection site). 
7) Allow 30-60 seconds for the povidone-iodine to be in contact with the injection 
site before injection. 
NOTE: As indicated above, injection preparation must include the use 
of povidone-iodine either applied directly to the injection site using 
topical drops, a cotton-tipped applicator, or a swabstick. If a study 
participant experiences an adverse reaction to povidone-iodine, other 
approaches to limit the exposure of povidone-iodine may be permitted. 
However, a study participant may not receive a study intravitreal 
injection without use of povidone-iodine directly to the injection 
site just prior to the injection. 
8) Sterilized calipers should be used to measure the injection site. The entry site of 
the needle for the intravitreous injection should be 3.0-3.5 mm from the limbus in 
aphakic/pseudophakic subjects, and 3.5-4.0 mm in phakic subjects.  
NOTE: During the preparation and injection of the drug, 
investigators, ancillary staff and subjects should refrain from 
talking.  If talking becomes absolutely necessary, the investigator 

 
 
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should face away from the bare needle and the injection site to 
avoid contamination of the needle and injection site. Wearing a 
mask during the preparation and injection of the drug is optional. 
1st Injection (avacincaptad pegol 2 mg/eye or Sham) 
If the Subject is Randomized to Receive avacincaptad pegol 2mg (0.10 mL 
injection volume): 
a. Use sterile gloves during preparation and administration of the injectable 
drug. 
b. Using aseptic technique, 0.2 mL of the avacincaptad pegol injection vial 
contents are withdrawn through a 5-micron 19-gauge filter needle attached to 
a 1-mL sterile syringe (supplied).  Care should be taken to aim the filter 
needle toward the center of the vial.  The filter needle should be discarded 
after withdrawal of the vial contents and should not be used for intravitreal 
injection. The filter needle should be replaced with the sterile 30-gauge 
needle (supplied) for the intravitreal injection. The contents and any air 
bubbles should be expelled until the plunger tip is aligned with the line that 
marks 0.10 mL on the syringe for avacincaptad pegol 2mg. 
c. Insert the drug into the vitreous cavity pointing toward the optic nerve via the 
pars plana. Once the needle is in place, continuous pressure should be 
applied to the syringe for approximately 10 seconds to assure slow, even 
delivery of all drug. 
d. As the needle is withdrawn, a sterile cotton tip applicator should be rolled over 
the entry site to minimize the risk of drug reflux.  This should be held in place 
for a full 10 seconds. 
e. The eye can then be irrigated as per the typical practice pattern of the 
investigator to minimize irritation from the aseptic procedure. 
f. 
Two drops of single use antibiotic may be placed over the injection site at the 
end of the injection procedure at the discretion of the investigator.  This 
same antibiotic may then be used four times daily for 3 days following the 
injection at the discretion of the investigator. 

 
 
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g. One to two minutes following the intravitreal injection, subjects should be 
examined with indirect ophthalmoscopy to assure that the optic nerve is 
perfused, the retina is attached and there is no new intraocular hemorrhage. 
h. If a second injection is to be administered, the second injection may NOT 
be administered until the IOP is ≤ 21 mmHg or within 5 mmHg of the 
baseline IOP on the day of injection. If the IOP is not ≤ 21 mmHg or within 
5 mmHg of the baseline IOP, the IOP should continue to be monitored until it is  
≤ 21 mmHg or within 5 mmHg of the baseline IOP (record IOP at this time) 
before proceeding to the second injection.  
i. If there is no second injection, the IOP should be measured and recorded 
30 minutes after the intravitreal injection is administered. Monitor the IOP until it 
is below 30 mmHg; the subject should not be discharged until at least 30 minutes 
after the 1st injection and the IOP is below 30 mmHg or at a lower level as 
determined by the investigator.   
If the Subject is Randomized to Receive Sham: 
a. Use sterile gloves during preparation of the empty syringe and during the 
simulated injection. 
b. Use the sterile empty syringe without an attached needle. 
c. Use the blunt opening of the syringe barrel to indent the conjunctiva in the 
inferotemporal quadrant to simulate the pressure on the eyeball of an injection.   
Note: This procedure should be performed in a manner so that the subject 
is not aware that the syringe has no needle, and that the globe is not being 
penetrated (i.e. the subject should be instructed to look away).  
d. The eye can then be irrigated as per the typical practice pattern of the 
investigator to minimize irritation from the aseptic procedure. 
e. One to two minutes following the Sham injection, subjects should be examined 
with indirect ophthalmoscopy to assure that the optic nerve is perfused, the 
retina is attached and there is no new intraocular hemorrhage. 
f. If a second injection is to be administered, the second injection may NOT 
be administered until the IOP is ≤ 21 mmHg or within 5 mmHg of the 

 
 
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Baseline IOP on the day of injection. If the IOP is not ≤ 21 mmHg or within  
5 mmHg of the baseline IOP, the IOP should continue to be monitored until it is  
≤ 21 mmHg or within 5 mmHg of the baseline IOP (record IOP at this time) 
before proceeding to the second injection.  
g. If there is no second injection, the IOP should be measured and recorded 
30 minutes after the intravitreal injection is administered. Monitor the IOP until it 
is below 30 mmHg; the subject should not be discharged until at least 30 minutes 
after the 1st injection and the IOP is below 30 mmHg or at a lower level as 
determined by the investigator. 
2nd Injection (avacincaptad pegol 2 mg/eye or Sham) (if regimen includes a second 
injection) 
Prepare the eye for the 2nd injection.  Repeat the injection preparation steps 3) 
through 8) above.  For convenience, the steps are repeated here: 
3) Injection preparation (for the following, new povidone-iodine bottles must be used 
and cannot be shared between subjects):   
a. 
Apply single use topical anesthetic drop(s) to the eye. 
b. 
Apply 2-3 drops of povidone-iodine to the injection site.  
c. 
OPTIONAL:  Apply 2-3 drops of povidone-iodine to the lower fornix 
and/or use sterile cotton-tipped applicators soaked in 5% or 10% 
povidone-iodine to swab the upper and lower eyelid margins and the 
upper and lower eyelashes.   
4) Place a sterile eyelid speculum to stabilize the eyelids.   
5) Consider additional anesthesia with the application of one or two cotton-tipped 
applicators soaked in topical anesthetic over the intended injection site for at 
least 30 seconds.  Subconjunctival anesthesia (0.5 mL of 2% xylocaine without 
epinephrine subconjunctivally at the intended injection site) can be used if the 
investigator believes that topical anesthetic is not sufficient to minimize 
discomfort.  Lidocaine gel is not recommended.   
6) Encourage the study participant to look superonasally (if injection site is 
inferotemporal) during the application of the povidone-iodine.  Apply one of the 

 
 
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following to the conjunctiva directly over and surrounding the intended injection 
site: 
a. 
A cotton-tipped applicator soaked in 5% or 10% povidone-iodine. 
b. 
A 10% povidone-iodine swabstick. 
c. 
At least 1-3 drops of 5% povidone-iodine (at least enough to cover the 
intended injection site). 
7) Allow 30-60 seconds for the povidone-iodine to be in contact with the injection site 
before injection. 
NOTE: As indicated above, injection preparation must include the use 
of povidone-iodine either applied directly to the injection site using 
topical drops, a cotton-tipped applicator, or a swabstick. If a study 
participant experiences an adverse reaction to povidone-iodine, other 
approaches to limit the exposure of povidone-iodine may be permitted. 
However, a study participant may not receive a study intravitreal 
injection without use of povidone-iodine directly to the injection 
site just prior to the injection. 
8) Sterilized calipers should be used to measure the injection site. The entry site of 
the needle for the intravitreous injection should be 3.0-3.5 mm from the limbus in 
aphakic/pseudophakic subjects, and 3.5-4.0 mm in phakic subjects.  
NOTE:  During the preparation and injection of the drug, investigators, ancillary 
staff and subjects should refrain from talking.  If talking becomes absolutely 
necessary, the investigator should face away from the bare needle and the 
injection site to avoid contamination of the needle and injection site. Wearing a 
mask during the preparation and injection of the drug is optional. 
If the Subject is Randomized to Receive avacincaptad pegol 2 mg (0.10 mL 
injection volume): 
a. Use sterile gloves during preparation and administration of the injectable drug. 
b. Using aseptic technique, 0.2 mL of the avacincaptad pegol injection vial 
contents are withdrawn through a 5-micron 19-gauge filter needle attached to 

 
 
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a 1-mL sterile syringe (supplied).  Care should be taken to aim the filter needle 
toward the center of the vial.  The filter needle should be discarded after 
withdrawal of the vial contents and should not be used for intravitreal injection. 
The filter needle should be replaced with the sterile 30-gauge needle (supplied) 
for the intravitreal injection. The contents and any air bubbles should be 
expelled until the plunger tip is aligned with the line that marks 0.10 mL on the 
syringe. 
c. Insert the drug into the vitreous cavity pointing toward the optic nerve via the 
pars plana. Once the needle is in place, continuous pressure should be applied 
to the syringe for approximately 10 seconds to assure slow, even delivery of all 
drug. 
d. As the needle is withdrawn, a sterile cotton tip applicator should be rolled over 
the entry site to minimize the risk of drug reflux.  This should be held in place 
for a full 10 seconds. 
e. The eye can then be irrigated as per the typical practice pattern of the 
investigator to minimize irritation from the aseptic procedure. 
f. 
Two drops of single use antibiotic may be placed over the injection site at the 
end of the injection procedure at the discretion of the investigator.  This same 
antibiotic may then be used four times daily for 3 days following the injection 
at the discretion of the investigator. 
g. One to two minutes following the intravitreal injection, subjects should be 
examined with indirect ophthalmoscopy to assure that the optic nerve is 
perfused, the retina is attached and there is no new intraocular hemorrhage. 
h. The IOP should be measured and recorded 30 minutes after the 2nd injection is 
administered.  Monitor the IOP until it is below 30 mmHg; the subject should not 
be discharged until at least 30 minutes after the 2nd injection and the IOP is below 
30 mmHg or at a lower level as determined by the investigator. 
If the Subject is Randomized to Receive Sham: 
a. Use sterile gloves during preparation of the empty syringe and during the 
simulated injection. 

 
 
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b. Use the sterile empty syringe without an attached needle. 
c. Use the blunt opening of the syringe barrel to indent the conjunctiva in the 
inferotemporal quadrant to simulate the pressure on the eyeball of an injection.   
Note: This procedure should be performed in a manner so that the subject 
is not aware that the syringe has no needle, and that the globe is not being 
penetrated (i.e. the subject should be instructed to look away).  
d. The eye can then be irrigated as per the typical practice pattern of the 
investigator to minimize irritation from the aseptic procedure. 
e. One to two minutes following the Sham injection, subjects should be examined 
with indirect ophthalmoscopy to assure that the optic nerve is perfused, the 
retina is attached and there is no new intraocular hemorrhage. 
f. The IOP should be measured and recorded 30 minutes after the Sham injection is 
administered.  Monitor the IOP until it is below 30 mmHg; the subject should not 
be discharged until at least 30 minutes after the 2nd injection (Sham) and the IOP 
is below 30 mmHg or at a lower level as determined by the investigator. 
After All Injections (including Sham injections) 
1) One to two minutes following each intravitreal injection, subjects should be examined 
by ophthalmoscopy to verify reperfusion of the central retinal artery in the immediate 
post-injection period.  Verify that the retina is attached and that there is no new 
intraocular hemorrhage.  
2) After each intravitreal injection (including Sham), check the intraocular pressure 
(IOP) while maintaining a clean field. 
a. If a second injection is to be administered, monitor the IOP after the 1st 
injection until it is ≤ 21 mm Hg or within 5 mm Hg of the baseline IOP 
on the day of injection; record the IOP at this time. 

 
 
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b. The IOP should be measured and recorded 30 minutes after the last 
injection (whether it is the first or second injection).  Monitor the IOP until it 
is below 30 mmHg; the subject should not be discharged until at least  
30 minutes after the 2nd injection and the IOP is below 30 mmHg or at a 
lower level as determined by the investigator.   
c. If a Tono-Pen is used to check pressure, a clean Tono-Pen condom 
should be placed on the tip before taking each measurement. If 
applanation tonometry is used, the applanator tip should be swabbed 
with alcohol and let to dry before using it to measure IOP. Sterile 
fluorescein strips and single use proparacaine bottles should be used 
for all subjects.  “Fluoracaine” or other combination fluorescein sodium 
and proparacaine HCl mixtures should only be used if single use 
presentation is available, and then only if single use bottles are 
available.  Intraocular pressure may be lowered by pharmaceutical or 
surgical intervention, if required.  Treatment should be initiated 
whenever IOP is increased to the extent that the central retinal artery 
remains closed and the subject has NLP for more than 1-2 minutes or 
as per investigator judgment.  Transient graying or obscuration of vision 
following injection, however, is expected and should not be treated.  See 
below for additional information concerning paracentesis. 
3)  No special precautions are required before discharge of a subject who has had 
an uneventful recovery from the intravitreal injection(s), but subjects and/or 
caregivers should be educated to avoid rubbing the eye and to recognize the signs 
and symptoms of endophthalmitis, retinal detachment and intraocular hemorrhage, 
including eye pain or increased discomfort, increased redness of the eye 
(compared to immediately after injection), blurred or decreased vision, and 
increased ocular sensitivity to light.  Subjects should be informed that some 
blurring of vision is common post-injection, which is often described as seeing 
spots floating in the eye. Subjects who experience post-injection AEs that require 
additional 
monitoring 
should 
remain 
in 
the 
clinic 
for 
longer 
than  
30 minutes, and treated according to the investigator’s medical judgment.  
Instructions Regarding Paracentesis: 
Paracentesis should be used only in extreme circumstances when the degree of 

 
 
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pressure elevation poses an imminent and irreversible threat to vision.  In the rare 
situation when a paracentesis is warranted, the IOP should be recorded both before 
and after the procedure.  Apply single use topical anesthetic drop(s) to the eye. Use 
a new pair of sterile gloves. Place a sterile lid speculum to open the eye lids. Apply  
2-3 drops of povidone-iodine to the paracentesis site, and allow 30-60 seconds for the 
povidone-iodine to be in contact with the paracentesis site.  A 0.1 mL paracentesis is 
performed at the temporal limbus using a 27-gauge or 30-gauge needle by the 
investigator.  Antibiotic eye drops are applied per discretion of the investigator.  
Record pre- and post-paracentesis IOP measurements in the source document and 
on the appropriate CRF page. 
NOTE: A paracentesis MAY NOT be performed prior to injection of the intravitreous 
drug.