Conditions: Dry Age-related Macular Degeneration
Keywords: Dry age-related macular degeneration Geographic atrophy Retinal disease Eye disease Retinal degeneration Macular atrophy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 255
Healthy volunteers: no

Brief summary:
The purpose of this clinical study was to evaluate the safety and efficacy of two doses of GT005 administered as a single subretinal injection in subjects with geographic atrophy secondary to age-related macular degeneration (AMD).

Detailed description:
This was a Phase II, open-label, outcomes-assessor masked, multicenter, randomized, controlled study designed to evaluate the safety and efficacy of two doses of GT005 administered as a single-time subretinal injection in subjects with Geographic atrophy (GA) secondary to Age-related macular degeneration (AMD).

Approximately 250 subjects, across Stage 1 and Stage 2, were planned to be randomized to one of two doses of GT005 or the untreated control group.

Subjects entered the study had genotyping and serum Complement factor I (CFI) levels assessed either through participation in a previous Gyroscope sponsored study, or a Sponsor-approved laboratory during the HORIZON screening period. If both eyes are eligible; the eye with the worse visual acuity will be selected as the study eye. If subjects failed to meet the eligibility criteria for this study, they were classified as screen failures and could be considered for entry into another Novartis/Gyroscope sponsored study.

After providing the informed consent, subjects underwent ophthalmic and clinical assessments to determined eligibility for inclusion in the study.

Upon confirmation of eligibility, subjects were randomized to one of two dose groups (medium dose \[5E10 vg\] or high dose \[2E11 vg\]). Within each dose group, subjects were allocated to GT005, or untreated control based on a 2:1 ratio. The overall study population (N=approximately 250) aimed to include approximately 60% of subjects with foveal GA and 40% of subjects with non-foveal GA (extrafoveal lesions). The study eye was identified for all subjects.

Enrolment for HORIZON were composed of two stages. Stage 1 enrolled subjects with foveal or non-foveal GA until 180 subjects were randomized. Stage 2 enrolled subjects with nonfoveal GA. Subjects with a CFI rare variant associated with normal or low serum CFI were also allowed to be enrolled in Stage 2, irrespective of GA foveal involvement.

Subjects were stratified by GA lesion size on Fundus autofluorescence (FAF) (≤10 mm2 or \>10 mm2) and AMD genotype subgroup. Randomization of study eyes in the GA lesion size upper stratum of \>10 mm2 to 17.5 mm2 was capped at 20% of total subjects randomized in Stage 1 and Stage 2, respectively. In Stage 2, once enrolment capping at 20% based on upper GA lesion size was reached, eyes that fulfilled the cap criteria were no longer eligible, unless the subject had a CFI rare variant genotype (minor allele frequency ≤1%) previously associated with normal or low serum CFI or had an unreported CFI rare variant genotype (Group 1 and 5). A permuted-block method was used to obtain an approximately 2:1 ratio between GT005 and the untreated control groups for each dose group within each stratum.

Following randomization, the Investigator was informed of the subject's allocated treatment (GT005 or the untreated control group) and the study eye selected. To minimize bias during imaging grading, all imaging endpoint assessments and grading were performed at a Central reading centre (CRC). All imaging efficacy assessments were performed in a masked fashion. The Sponsor, subjects, investigators, and study personnel performing clinical assessments remained masked to the dose received for those allocated to GT005.

For each subject, the study comprised of a screening period lasting up to 8 weeks (or up to 12 weeks if agreed by the Sponsor Medical Monitor) followed by a 96-week study period. All subjects were assessed for the occurrence of AEs at each visit and underwent functional assessments, retinal imaging, and biological sampling as per the schedule of assessments.

This study was conducted in compliance with Independent ethics committees (IECs) / Institutional review boards (IRBs), informed consent regulations, the Declaration of Helsinki, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and the Food and Drug Administration (FDA), 21 Code of Federal Regulations (CFR) Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance for Industry: Computerised Systems Used in Clinical Trials.

On 24-Aug-2023, the decision was taken to terminate the study and the GT005 program. The decision was aligned with the recommendation of an independent Data monitoring committee (DMC), which concluded that futility criteria had been met for the HORIZON study (GT005-03) and the overall benefit-risk ratio did not support continuation of the current development program as planned. All GT005- treated subjects, who were willing to be transferred into the long-term safety follow-up study were enrolled in the ORACLE (CPPY988A12203B) study.

Arms:
arm 1: GT005 Medium dose \[5E10 vg\] arm 2: GT005 High dose \[2E11 vg\] arm 3: Untreated control

Interventions: intervention 1: GT005
Intervention descriptions: intervention 1: GT005 is a recombinant, non-replicating AAV2 expressing human complement factor I (CFI). GT005 was administered as a single time subretinal injection into the study eye of subjects allocated to one of the two GT005 doses.

Protocol document:
Prot_000.pdf: 
GYROSCOPE THERAPEUTICS 
PAGE 1 
PROTOCOL: GT005-03 (HORIZON): V5.0, 15 SEP 2022 
CONFIDENTIAL 
HORIZON: A PHASE II, OPEN-LABEL, OUTCOMES-ASSESSOR MASKED, 
MULTICENTRE, RANDOMISED, CONTROLLED STUDY TO EVALUATE THE 
SAFETY AND EFFICACY OF TWO DOSES OF GT005 ADMINISTERED AS A 
SINGLE SUBRETINAL INJECTION IN SUBJECTS WITH GEOGRAPHIC 
ATROPHY SECONDARY TO DRY AGE-RELATED MACULAR DEGENERATION 
STUDY PROTOCOL 
STUDY NUMBER:  
VERSION: 
DATE: 
SUPERSEDED 
VERSION/DATE: 
PRODUCT NAME/CODE: 
EudraCT NUMBER: 
SPONSOR 
GT005-03/ NCT04566445
5.0 
15 Sep 2022 
4.0/04 Jan 2022 
GT005 
A RECOMBINANT, NON-REPLICATING 
ADENO-ASSOCIATED VIRAL VECTOR 
SEROTYPE 2 (AAV2) EXPRESSING HUMAN 
COMPLEMENT FACTOR I 
2020-002431-30 
GYROSCOPE THERAPEUTICS 
ROLLING STOCK YARD, 
188 YORK WAY, 
LONDON, 
N7 9AS 
UNITED KINGDOM 
This protocol is the property of Gyroscope Therapeutics Ltd. The protocol and its contents are 
confidential. It must not be transmitted, copied or published, in whole or in part, without the 
prior written permission of Gyroscope Therapeutics.  


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PROTOCOL: GT005-03 (HORIZON): V5.0, 15 SEP 2022 
CONFIDENTIAL 
 
 
 
TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................... 6 
LIST OF FIGURES .................................................................................................................. 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 7 
PROTOCOL SIGNATURES .................................................................................................. 9 
AMENDMENT HISTORY .................................................................................................... 10 
COMPLIANCE STATEMENT ............................................................................................ 17 
PROTOCOL SYNOPSIS ....................................................................................................... 18 
1 
BACKGROUND INFORMATION ............................................................................. 32 
1.1 
Indication ....................................................................................................................... 32 
1.2 
Investigational Product ................................................................................................. 32 
1.3 
Findings from Pre-clinical Studies .............................................................................. 32 
1.4 
Clinical Studies .............................................................................................................. 34 
1.5 
Study Rationale ............................................................................................................. 34 
 
The Complement Cascade ........................................................................... 34 
 
Rare Variant Genetic Population ............................................................... 35 
 
Broad Genetic Population ........................................................................... 35 
 
Non-foveal GA ............................................................................................. 37 
 
Dose Rationale ............................................................................................. 37 
1.6 
Risk/Benefit Assessment ............................................................................................... 38 
 
Potential Risks ............................................................................................. 38 
 
Potential Benefits ........................................................................................ 41 
 
Risk Benefit Analysis................................................................................... 42 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................... 43 
3 
STUDY DESIGN ........................................................................................................... 45 
3.1 
Study Overview ............................................................................................................. 45 
3.2 
Dose Selection ................................................................................................................ 46 
3.3 
Data Monitoring Committee ........................................................................................ 46 
3.4 
Randomisation and Masking ....................................................................................... 47 
 
Masking ....................................................................................................... 47 
 
Randomisation/Stratification ...................................................................... 47 
 
Determination of Study Eye ........................................................................ 48 
 
Breaking the Randomisation Code ............................................................. 49 
3.5 
Duration of Subject Participation................................................................................ 49 
3.6 
Early Study Termination .............................................................................................. 49 
3.7 
End of Study Definition ................................................................................................ 49 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 50 
4.1 
Inclusion Criteria .......................................................................................................... 50 
4.2 
Exclusion Criteria ......................................................................................................... 51 
4.3 
Screen Failures and Replacements .............................................................................. 52 
4.4 
Randomisation Criteria ................................................................................................ 52 
4.5 
Contraception ................................................................................................................ 52 
4.6 
Discontinuation/Withdrawal Procedures.................................................................... 52 
4.7 
Lost to Follow-up........................................................................................................... 53 
4.8 
Long-term Follow-up .................................................................................................... 53 
5 
STUDY TREATMENT ................................................................................................ 54 


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PROTOCOL: GT005-03 (HORIZON): V5.0, 15 SEP 2022 
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5.1 
Acquisition and Accountability .................................................................................... 54 
5.2 
Formulation, Appearance, Packaging and Labelling ................................................ 54 
5.3 
Product Preparation, Storage, and Dispensing .......................................................... 54 
5.4 
Dosing and Administration .......................................................................................... 55 
5.5 
Measures to Minimise Bias: Randomisation and Masking ....................................... 55 
5.6 
Concomitant Medication/Therapy Rescue Medication ............................................. 56 
 
Required/Permitted Medication .................................................................. 56 
 
Prohibited Medication ................................................................................. 56 
5.7 
Treatment of Overdose of GT005 ................................................................................ 56 
5.8 
Administration Compliance ......................................................................................... 56 
6 
STUDY PROCEDURES ............................................................................................... 57 
6.1 
Study Visits .................................................................................................................... 57 
 
Screening (Visit 1: Local or Surgical) ........................................................ 57 
 
Randomisation (Telephone Call) ................................................................ 59 
 
Visit 2, Day 1 (Surgical Site) ....................................................................... 59 
 
Post-Surgery Day 2 (Surgical Site) ............................................................. 60 
 
Day 3 (Telephone Call) ............................................................................... 60 
 
Visit 3, Week 1 (Surgical Site) .................................................................... 61 
 
Week 2 (Telephone Call) ............................................................................. 61 
 
Visit 4, Week 5 (Local or Surgical Site for GT005 Subjects/Telephone 
Call for Untreated Control Subjects) .......................................................... 61 
 
Visit 5, Week 8 (Local or Surgical Site) ..................................................... 62 
 
Visit 6, Week 12 (Local or Surgical Site) ................................................... 62 
 
Visit 7, Week 24 (Local or Surgical Site) ................................................... 63 
 
Visit 8, Week 36 (Local or Surgical Site) ................................................... 64 
 
Visit 9, Week 48 (Local or Surgical Site) ................................................... 64 
 
Visit 10, Week 72 (Local or Surgical Site) ................................................. 65 
 
Visit 11, Week 96/End of Study and Early Termination Visit (Local or 
Surgical Site) ............................................................................................... 66 
 
Unscheduled Visit ........................................................................................ 66 
7 
STUDY ASSESSMENT ................................................................................................ 68 
7.1 
Demographic and Screening Assessments .................................................................. 68 
7.2 
Concomitant Medication and Corticosteroid Compliance ........................................ 69 
 
Concomitant Medication ............................................................................. 69 
69 
7.3 
Ophthalmic Assessments .............................................................................................. 69 
 
Ophthalmic Examination ............................................................................ 69 
 
Pre-surgical Ocular Safety Check .............................................................. 69 
 
Colour Fundus Photography ...................................................................... 69 
 
Fundus Autofluorescence ........................................................................... 69 
 
Optical Coherence Tomography (Macula or Bleb).................................... 70 
 
Optical Coherence Tomography A ............................................................. 70 
 
Fluorescein Angiography............................................................................ 70 
70 
 
Visual Acuity Check .................................................................................... 71 
 
Best Corrected Visual Acuity ...................................................................... 71 
 
Low Luminance Difference ........................................................................ 71 


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Reading Performance (MNRead) ............................................................... 71 
 
Visual Function Questionnaire (VFQ-25) ................................................. 71 
 
Functional Reading Independence Index .................................................. 71 
7.4 
Safety .............................................................................................................................. 72 
 
Vital Signs .................................................................................................... 72 
 
Adverse Events ............................................................................................. 72 
 
Pregnancy Test ............................................................................................ 72 
 
Laboratory Safety Tests ............................................................................... 72 
 
 73 
8 
ADVERSE EVENT REPORTING .............................................................................. 75 
8.1 
Definition of an Adverse Event .................................................................................... 75 
8.2 
Definition of Serious Adverse Event ............................................................................ 75 
8.3 
Adverse Events of Special Interest .............................................................................. 76 
8.4 
Classification of an Adverse Event .............................................................................. 76 
 
Severity Assessment ..................................................................................... 76 
 
Causality Assessment .................................................................................. 77 
 
Expectedness Assessment ............................................................................ 77 
 
Action Taken Regarding the Investigational Medicinal Product .............. 77 
 
Outcome ....................................................................................................... 77 
8.5 
Reporting Requirements .............................................................................................. 77 
 
Serious Adverse Events and Adverse Event of Special Interest ................ 77 
8.6 
Follow-up of Adverse Events........................................................................................ 78 
8.7 
Pregnancy....................................................................................................................... 79 
8.8 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events ....... 79 
8.9 
Reporting to Competent Authorities/Ethics Committees/Other Investigators ....... 80 
9 
STATISTICS METHODS ............................................................................................ 81 
9.1 
Sample Size Determination .......................................................................................... 81 
9.2 
Analysis Populations Definitions ................................................................................. 81 
9.3 
Significance Testing and Estimations .......................................................................... 81 
9.4 
Statistical/Analytical Methods ..................................................................................... 81 
 
Demographics and Baseline Characteristics.............................................. 81 
 
Efficacy Assessments ................................................................................... 81 
 
Safety Assessments ...................................................................................... 83 
 84 
9.5 
72-Week Readouts ......................................................................................................... 84 
9.6 
Data Monitoring Committee ........................................................................................ 84 
9.7 
Handling Missing Data ................................................................................................. 84 
10 
STUDY MANAGEMENT ............................................................................................ 85 
10.1 Monitoring Procedures ................................................................................................. 85 
10.2 Recording of Study Data .............................................................................................. 85 
10.3 Source Data Verification .............................................................................................. 85 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 86 
11.1 Inspections and Auditing Procedures.......................................................................... 86 
12 
DATA HANDLING AND RECORD KEEPING ....................................................... 87 
12.1 Data Quality ................................................................................................................... 87 
12.2 Data Management ......................................................................................................... 87 
12.3 Sponsor Discontinuation Criteria ................................................................................ 88 


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12.4 Subject and Data Confidentiality ................................................................................ 88 
12.5 Sample Preparation, Handling and Storage ............................................................... 88 
12.6 Record Archiving and Retention ................................................................................. 88 
13 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE ............................................................................................................... 89 
13.1 Institutional Review Board/Independent Ethics Committee Ethical Conduct of 
the Study ........................................................................................................................ 89 
13.2 Subject Information and Consent................................................................................ 89 
13.3 Reporting of Significant Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ........................................................................................................................ 90 
14 
ADMINISTRATION PROCEDURES ........................................................................ 91 
14.1 Regulatory Approval .................................................................................................... 91 
14.2 Publication Policy .......................................................................................................... 91 
14.3 Clinical Study Report ................................................................................................... 91 
14.4 Contractual and Financial Details ............................................................................... 91 
14.5 Insurance, Indemnity and Compensation ................................................................... 91 
15 
PROTOCOL AMENDMENTS.................................................................................... 93 
15.1 Protocol Amendments and Protocol Deviations ......................................................... 93 
15.2 Protocol Deviations and Exceptions ............................................................................ 93 
16 
REFERENCES .............................................................................................................. 94 
17 
APPENDICES ............................................................................................................... 97 
17.1 Age-Related Eye Disease Study Clinical Lens Grading System ............................... 97 
17.2 Reading performance (MNRead) .............................................................................. 101 
17.3 Visual Function Questionnaire (VFQ-25) ................................................................. 103 
17.4 Vitreous Haze Grading Scale ..................................................................................... 119 
20 
 
 
 


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LIST OF TABLES 
Table 1: Schedule of Assessments: Subjects Allocated to GT005 ...................................... 27 
Table 2: Schedule of Assessments: Subjects Allocated to Untreated Control .................. 30 
Table 3: Laboratory Parameters........................................................................................... 73 
Table 4: Intercurrent Events and Corresponding Primary Data Handling Strategies. .. 82 
 
LIST OF FIGURES 
Figure 1: Study Design1 .......................................................................................................... 21 
Figure 2: Dose-response Shapes of the Candidate Models ................................................. 83 
 
 


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CONFIDENTIAL 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition  
AAV 
Adeno-associated virus 
AAV2 
Adeno-associated virus serotype 2 
 
 
 
 
 
AE(s) 
Adverse event(s) 
AESI 
Adverse events of special interest 
AMD 
Age-related macular degeneration 
AREDS 
Age-related eye disease study 
ATA 
Anti-transgene antibodies 
BCVA 
Best corrected visual acuity 
BSS 
C3 
Balanced salt solution 
Complement component 3 
CFB / CFB 
Complement factor B (Gene / PROTEIN) 
CFH / CFH 
Complement factor H (Gene / PROTEIN) 
CFI / CFI 
Complement factor I (Gene / PROTEIN) 
CFP 
Colour fundus photography 
CFR 
Code of Federal Regulations 
CMO 
Cystoid macular oedema 
CNV 
Choroidal neovascular AMD 
CRC 
Central Reading Centre 
CRO 
Clinical Research Organisation 
CSR 
Clinical study report 
DBL 
Database lock 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EIU 
Exposure in utero 
EoS 
End of study 
ETDRS 
Early treatment diabetic retinopathy study scale 
FA 
Fluorescein angiography 
FAF 
Fundus autofluorescence 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FRI 
Functional reading independence 
GA 
Geographic atrophy 
GAT 
Goldmann applanation tonometry 
GCP 
Good Clinical Practice 
HEK 
Human embryonic kidney 
IB 
Investigator's Brochure 
ICF 
Informed Concent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 


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PROTOCOL: GT005-03 (HORIZON): V5.0, 15 SEP 2022 
CONFIDENTIAL 
 
 
 
 
Abbreviation 
Definition  
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ISC 
Independent Statistics Centre 
LLD 
Low luminance difference 
LLVA 
Low luminance visual acuity 
 
 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures analysis 
MNRead 
Minnesota low-vision reading (test) 
NA 
Not applicable 
OCT  
Optical coherence tomography  
OCT-A 
Optical coherence tomography-angiography 
OR 
Odds ratio 
PRL 
Preferred Retinal Locus 
PSA 
Prostate-specific antigen 
RPE 
Retinal pigment epithelium 
SAE(s) 
Serious adverse event(s) 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDV 
Source data verification 
SUSAR 
Suspected unexpected serious adverse reactions 
Tel 
Telephone 
V 
Visit 
VFQ 
Visual function questionnaire 
Vg 
Vector genomes 
 
 




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PROTOCOL: GT005-03 (HORIZON): V5.0, 15 SEP 2022 
CONFIDENTIAL 
 
 
 
 
AMENDMENT HISTORY 
Protocol Version 
Change 
Justification 
Version 1.0, 
04 May 2020 
(Initial) 
Not applicable (NA) 
NA 
Version 2.0, 
19 Nov 2020 
(Amendment 1) 
Study period extended to 
2 years with the addition of 
Weeks 72 and 96. 
• The study period has been extended to 2 years to 
enable the capture of longer term treatment effect 
and durability of outcomes. 
Revision of objectives to 
include the additional 
Week 72 and 96 timepoints 
The addition of secondary 
objective: The change from 
baseline to Week 72 and 
Week 96 in geographic 
atrophy (GA) area as 
measured by fundus 
autofluorescence (FAF). 
• Added due to extension of the study to 2 years. 
Reference to Dose 1 and 2 
removed to include vector 
genome along with mid and 
high doses added for 
clarification to sites. 
• Investigative sites involved across the clinical 
GT005 program are familiar with low 
, 
medium 
 and high doses 
) and therefore 
edits have been made.. 
Inclusion/Exclusion Criterion 
• 
Inclusion criterion 3 language has been clarified for 
requirement of age-related macular degeneration 
(AMD) in contralateral eye 
• 
Inclusion criterion 6 has been broadened to best 
corrected visual acuity (BCVA) of 24 letters (6/95 
and 20/320 Snellen acuity equivalent) to evaluate 
the treatment effect of subjects with worse-seeing 
vision. 
• 
Inclusion criterion 7a revised to to include an 
evidence-based approach to enrolment of subjects 
into the study. 
• 
Inclusion criterion 9 has been clarified to include 
further guidance relating to pregnancy testing. 
• 
Removal of exclusion criteria 1b as inclusion 
criteria confirms eligible variants and this text is not 
needed. 
• 
New exclusion criterion 5 has been added to 
provide clarification of prior intraocular surgery 
before screening. 
 
 
 
 
• 
Exclusion criterion 13 updated to broaden the 
malignancies/cancer types excluded from the study. 
Randomisation to 
either eye (if both 
eligible) removed 
• 
The eye with worse visual acuity will be selected, if 
both eyes are eligible to help safeguard vision in the 
better seeing eye. 
Corrected the 
imaging modality for 
retinal anatomical 
measures 
• 
Updated terminology to multimodal imaging as 
colour fundus photography (CFP) is not the only 
imaging modality used to measure retinal 
anatomical measurements 


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CONFIDENTIAL 
 
 
 
 
Protocol Version 
Change 
Justification 
Revised text for unused or 
expired GT005 product  
• Correction of discrepant text in the protocol. 
Removal of Preferred Retinal 
Locus (PRL) identification in 
the Schedule of assessments  
• The revised retinotomy location will not encroach 
on the PRL and therefore the requirement to identify 
the PRL has been removed. 
 
 
 
 
 
 
 
 
  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion of fluorescein 
angiography (FA) assessment 
• 
FA included as an assessment to verify subjects do 
not have choroidal neovascular AMD (CNV) at 
baseline or conversion to CNV during the study. 
• 
Addition that all potential FAs to be sent to CRC. 
Additional optical coherence 
tomography-angiography 
(OCT-A) 
• OCT-A additional imaging added, if required, for 
CNV conversion. 
Clarification of OCT 
modalities  
• The differing OCT modalities have been clarified: 
OCT-A (for monitoring CNV conversion), OCT 
macula 
provide clarity to 
investigational sites and to add further time points if 
required by the Investigator to detect any safety 
changes on the retina, i.e. conversion to CNV, any 
other safety-related changes. 
Genotyping Informed Consent 
Form (ICF) 
• Genotyping ICF included. 
Pre-surgical checks 
• Clarification 
of 
the 
pre-surgical 
ophthalmic 
examination. 
Volume of blood (annual) 
altered to account for the 
study extension to 2 years and 
inclusion of Week 72 and 96 
visits 
• Study extension as presented in the rationale above. 
Adverse event (AE) reporting 
language 
• Safety reporting requirements updated to collect all 
AEs from date of consent.  
Protocol deviations and 
exceptions 
• 
Clarification of handling of protocol deviations, in 
response to Medicines and Healthcare Producs 
Regulatory Agency grounds for non-acceptance. 
Throughout the protocol 
• Administrative 
inconsistences removed and 
language 
clarified. 
As 
these 
are 
minor revisions, they have not been summarised. 
Version 3.0, 
03 JUN 2021 
(Amendment 2) 
Inclusion/Exclusion Criterion 
• 
Inclusion critierion 6 and exclusion criterion 1 
altered to allow inclusion of patients with CNV/wet 
AMD in fellow eye. 




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PROTOCOL: GT005-03 (HORIZON): V5.0, 15 SEP 2022 
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Protocol Version 
Change 
Justification 
Study design Figure 1 
clarification  
• 
Clarified that enrolment at Stage 1 will be complete 
first before enrolling Stage 2 subjects. 
Randomisation of study eye 
• 
Provided clarification on the requirements for 
randomisation of the study eye in Stage 1 and 2. 
 
 
 
 
 
 
 
 
• 
Clarification that subjects who have foveal or non-
foveal GA with a CFI rare variant genotype 
associated with low or normal serum CFI may be 
enrolled in Stage 2. 
Increased total number of 
subjects  
• 
Emerging evidence has suggested that complement 
mediating therapies may have a greater effect in 
subjects 
with 
non-foveal 
(extrafoveal) 
GA, 
 
 
Number of investigative sites  
• 
Increased 
the 
number 
of 
global 
sites 
to 
approximately 90 to support Stage 2 recruitment in 
subjects with non-foveal GA. 
Clarification of bleb number 
• 
Correction of an inconsistency between the 
protocol and surgical manual to provide further 
clarity on the use of more than 1 bleb for the 
delivery of GT005. 
GT005 deferral guidance 
• 
Clarified that in the event GT005 dosing was 
deferred during surgery, the time from screening 
may be extended up to 16-weeks. 
• 
Clarified that if the time from screening is extended 
past 12 weeks, in case of GT005 deferral, FAFs 
should be repeated in addition to the standard 
ophthalmic exam, haematology/biochemistry and 
BCVA or low luminance visual acuity (LLVA). 
Rescreening guidance within 
8 weeks and outside of 
8 weeks 
• 
Provided clarification that if a subject is rescreened 
within the 8-week screening period, the site staff 
needs to repeat only the standard ophthalmic exam 
and visual acuity (BCVA and LLVA) assessment 
provided all other original results were acceptable. 
• 
Further, if a subject is rescreened outside of the 
8-week screening period, all screening assessments 
should be repeated except for genotyping and serum 
CFI. 
Additional safety assessment 
with FAF at Week 5 
• 
Included an additional safety assessment using FAF 
at Week 5, post GT005 delivery. 
Statistical analysis  
• 
Clarified when data readouts will be made during 
the study given the new increase in the number of 
subjects. 
Vital signs  
• 
Clarified that the blood pressure assessment may be 
performed in either arm in line with standard 
clinical practice. 


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Protocol Version 
Change 
Justification 
Throughout the protocol  
 
 
 
 
 
• 
Administrative 
inconsistences removed and 
language 
clarified. 
As 
these 
are 
minor revisions, they have not been summarised. 
Version 5.0, 
15 SEP 2022 
(Amendment 4.0) 
Updated primary endpoint 
read-out timepoint from 
Week 48 to Week 72 
• 
Updated the primary endpoint read-out to Week 72 
as this is considered the most appropriate timepoint 
to evaluate the treatment effect of GT005, since the 
clinical effect size is hypothesised to be linked to the 
exposure to higher CFI levels and thus may increase 
over time beyond Week 48, based upon preliminary 
data on expression kinetics of the CFI transgene 
product from our Phase I/II FOCUS study. 
Secondary endpoints 
 
 
 
• 
The study endpoints have been reviewed and the 
opportunity taken to rationalise the number of 
secondary endpoints currently listed. 
 
 
 
 
Updates to secondary and 
 endpoints to be 
reported ‘through Week 96. 
• 
Clarified the analysis timepoints for secondary and 
 endpoints. 
Updates to the Statistical 
Methods 
• 
Change in the primary endpoint timepoint to 
Week 72 from Week 48. 
• 
The following sections were expanded/added: 
Sample size determination, 
 
readout 
timing, 
analysis 
populations. 
More 
information and detail relating to the planned 
statistical analysis has been added to the protocol to 
provide evidence for the statistical integrity and 
robustness of the study design. 
• 
Removed height, weight and body mass index from 
the planned analyses in the demographics section 
under Section 9.0 Statistical Methods as they are 
not captured in the study database. 
Clarification under the 
Surgical Procedure of the 
synopsis and Section 5.4: 
Dosing and Administration 
• 
Subretinal GT005 dosing will occur across multiple 
administration blebs. The text regarding the 
subretinal bleb dosing procedure for GT005 was 
further clarified to better align with the Surgical 
Manual. 
Updated 7.4.2 Adverse Events 
and footnote 11 to clarify that 
any additional safety 
assessments may be collected 
to follow up on AEs 
(previously the text 
erroneously referenced 
imaging tests only)   
• 
In order to appropriately protect subjects’ safety in 
the study it was always intended for Investigators to 
have the ability to perform any additional safety 
tests at their clinical discretion to evaluate/monitor 
AEs. Accordingly, the text has been updated to 
reflect this original intent.  




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Protocol Version 
Change 
Justification 
Updates to Section 3.1 Study 
Overview, Section 3.4.1 
Masking, and Section 5.5 
Measures to Minimise Bias 
• 
Definitions of fully-masked and dose-masked to 
reflect the definition of masking in other clinical 
and regulatory documentation. No change in 
masking status for the study has been implemented. 
• 
Updated the text regarding 
 to reflect the 
multimodal assessment that is performed 
Administrative/formatting 
changes throughout 
• 
For general document improvement, providing 
further clarity where necessary and following input 
from sites/regulators and other stakeholders. 
ensuring 
consistency, 
addressing 
inadvertent 
formatting and typographical errors from the last 
version 
• 
Administrative 
inconsistences removed and 
language clarified.  
Abbreviations: AE=adverse event; AESI= adverse event of special interest; AMD=age-related macular 
degeneration; BCVA=best corrected visual acuity; CNV=choroidal neovascular AMD, CRC=central reading 
centre; FA=fluorescein angiography; FAF=fundus autofluorescence; GA=geographic atrophy; IB=Investigational 
Brochure; ICF=informed consent form; IMP=investigational medical product; LLVA= low luminance visual 
acuity; 
NA=not 
applicable; 
OCT=optical 
coherence 
tomography; 
OCT-A=optical 
coherence 
tomography-angiography; PRL=preferred retinal location; RPE=retinal pigment epithelium. 
 
 


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COMPLIANCE STATEMENT 
This study will be conducted in compliance with Independent Ethics Committees 
(IECs)/Institutional Review Boards (IRBs), informed consent regulations, the Declaration of 
Helsinki, ICH GCP Guidelines, and Food and Drug Administration (FDA), 21 Code of 
Federal Regulations (CFR) Part 11, Electronic Records, Electronic Signatures, and FDA, 
Guidance for Industry: Computerised systems used in clinical trials. In addition, this study 
will adhere to all local regulatory requirements.  
Any episode of noncompliance will be documented. 
 


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PROTOCOL SYNOPSIS 
SPONSOR:  
Gyroscope Therapeutics 
INVESTIGATIONAL MEDICINAL PRODUCT: 
GT005: A recombinant non-replicating adeno-associated viral vector derived from wild-type adeno-
associated virus serotype 2 (AAV2). The expression cassette contains deoxyribonucleic acid 
encoding for human complement factor I (CFI). 
TITLE:  
HORIZON: A Phase II, open-label, outcomes-assessor masked, multicentre, randomised, controlled 
study to evaluate the safety and efficacy of two doses of GT005 administered as a single subretinal 
injection in subjects with geographic atrophy secondary to dry age-related macular degeneration. 
PROTOCOL NO:  
GT005-03 (HORIZON). 
INDICATION:  
GT005 is under development for the treatment of geographic atrophy (GA) secondary to age-related 
macular degeneration (AMD). 
INVESTIGATOR STUDY SITES:  
Approximately 90 investigational sites will take part. Designated sites will perform screening and 
subretinal surgery for subjects allocated to GT005, and post-operative follow-up visits.  
STUDY PERIOD:  
Subject participation consists of a screening period of up to 8 weeks and a 96-week study period, 
for a total of 104 weeks. 
STUDY RATIONALE:  
AMD is the most common cause of blindness among the elderly in the industrialised world 
Jonasson 2014, affecting approximately 36 to 40 million people globally Access Economics 
Report 2010. AMD is a progressive disease that results in a blurred area or blank spot in the centre 
of vision NIH.  
AMD is classified into early, intermediate, and advanced stages Ferris 2013. Advanced stage AMD 
includes two morphological subtypes: choroidal neovascular AMD (CNV) and GA 
Chakravarthy 2010. There are no approved therapies for GA. 
Evidence has emerged which implicates chronic local inflammation and activation of the 
complement cascade in AMD pathogenesis Anderson 2010. A number of complement proteins 
have been identified as constituents of drusen, the hallmark extracellular deposits associated with 
AMD Anderson 2010.  
Rare Variant Genetic Population: Genetic studies have found AMD patients carrying rare genetic 
variants in CFI (defined by a minor allele frequency ≤1%) in combination with low CFI protein 
levels in blood serum, are more likely to have an increased risk of developing AMD which has 
progressed to the advanced stages of disease Seddon 2013; Kavanagh 2015; Geerlings 2017.  
As CFI serves as a global down-regulator of the alternative pathway Lachmann 2016, an increase 
in intraocular CFI level has the potential to dampen an over-activated complement system associated 
with AMD, reducing the progression of the disease. 
 
 
 
 


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The EXPLORE Phase II study is currently testing the hypothesis that supplementation of CFI via 
GT005 gene therapy will slow disease progression in a proportion of GA cases who harbour rare 
CFI variants associated with low serum CFI.  
Broad Genetic Population: Overactivation of the complement system is also implicated in the risk 
of disease development across the broader dry AMD population, as shown by significant enrichment 
of common genetic risk factors mapping to complement proteins involved in the alternative pathway 
e.g. complement factor H (CFH), CFI, complement factor B (CFB), and complement component 3 
(C3) [Fritsche 2013; Fritsche 2016].  
The HORIZON Phase II study is designed to test whether administering CFI will be effective in 
down-regulating 
a 
hyperactive 
complement 
system 
across 
all 
GA 
patients and 
if 
this intervention will have a therapeutic effect on disease progression. CFI rare variant genotypes 
associated with normal or low serum CFI or subjects carrying an unreported CFI rare variant 
genotype that have tested to have a normal or low serum CFI will be considered for study entry. This 
hypothesis is postulated from the observation that CFI supplementation has the potential to 
normalise variation in complement activity in blood sera taken from individuals carrying different 
combinations of common complement risk variants [Lachman 2016].  
Non-foveal GA: Recent data released on pegcetacoplan described a prespecified analysis of the 
primary endpoint where pegcetacoplan demonstrated a greater effect in subjects with non-foveal GA 
(extrafoveal lesions) at baseline [Wykoff C, AAO Abstract November 2021]. 
 
 
  
The HORIZON protocol will be composed of two stages: Stage 1 and Stage 2. Stage 1 of the protocol 
will continue to enrol the study until 180 genetically-defined subjects have randomised. Stage 2 of 
the protocol will enrol subjects with non-foveal GA (extrafoveal). In addition, subjects with foveal 
or non-foveal GA who have a CFI rare variant associated with normal or low serum CFI may also 
be enrolled in Stage 2, until approximately 250 subjects (approximately 70 additional subjects after 
Stage 1 is completed) are randomised.  
 
 
 
 
 
 
 
 
 
 
 
DOSE RATIONALE:  
 
 
 
 
  


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OBJECTIVES:  
The overall objective of the study is to evaluate the safety and efficacy (anatomical and functional 
visual outcomes) of two doses of GT005 in subjects with GA due to AMD. 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate the effect of GT005 vs 
untreated control on the progression of 
GA in subjects with GA due to AMD 
• 
The change from baseline to Week 72 in GA 
area as measured by fundus autofluorescence 
(FAF) 
Secondary 
• 
To evaluate the effect of GT005 on the 
progression of GA in subjects with GA 
due to AMD 
• 
The change from baseline through Week 96 in 
GA area as measured by FAF 
• 
To evaluate the safety and tolerability of 
GT005 
• 
Frequency of treatment emergent adverse 
events (AEs) through Week 96 
• 
To evaluate the effect of GT005 on 
retinal anatomical measures 
• 
Change in retinal morphology on multimodal 
imaging through Week 96 
• 
To evaluate the effect of GT005 on 
functional measures 
• 
Change in BCVA score via the early treatment 
for diabetic retinopathy (ETDRS) chart 
through Week 96 
• 
Change in low luminance difference (LLD) via 
the ETDRS chart through Week 96 
• 
To evaluate the effect of GT005 on visual 
function 
• 
Change in reading performance as assessed by 
Minnesota low-vision reading test (MNRead) 
chart through Week 96 
• 
Change in functional reading independence 
(FRI) index through Week 96 
• 
To evaluate the effect of GT005 on 
patient-reported outcomes 
• 
Change in quality of life measured on the 
visual functioning questionnaire-25 (VFQ-25) 
through Week 96 




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1Stage 1 subject enrolment to complete, before enrolling in Stage 2.  
 
Following consent, subjects will undergo ophthalmic and clinical assessments to determine 
eligibility for inclusion in the study. On confirmation of eligibility, subjects will be randomised to 
one of two dose groups (medium dose [
 vg] or high dose [
 vg]). Within each dose group 
subjects will be allocated to GT005 or untreated control based on a 2:1 scheme [Figure 1].  
 
  
 
Definition of Non-foveal GA:  
 
 
 
 
Stage 1 will enrol subjects with GA who have foveal or non-foveal GA until 180 subjects have been 
randomised. Stage 2 will enrol subjects with non-foveal GA. In addition, subjects with foveal or 
non-foveal GA who have a CFI rare variant associated with normal or low serum CFI may also be 
enrolled in Stage 2, until approximately 250 subjects (approximately 70 additional subjects after 
Stage 1 is completed) are randomised.  
 
  
Determination of Study Eye: 
If both eyes are eligible; the eye with the worse visual acuity will be selected as the study 
eye. If visual acuity is equivalent in both eyes, the eye with the largest GA lesion size will be 
the study eye unless the subject (in consultation with the Surgeon) expresses an alternative 
preference. The study eye will be confirmed by the Surgeon. 
 
 
 
 
 
Following randomisation, the Investigator will be informed of the subjects’ allocated treatment 
assignment (this will only include treatment assignment to GT005 or the untreated control, and not 
the GT005 dose group). To minimise bias, all imaging endpoint assessments and grading will be 
performed at a Central Reading Centre (CRC). The Sponsor, investigators, subjects, and study 
personnel performing clinical assessments will remain masked to dose received for those allocated 
to GT005.  
Subjects randomised to GT005 may undertake a visit to the surgical site between the screening and 
pre-surgery visit in order to meet the surgical team and discuss the procedure.  
Subjects allocated to GT005 will undergo subretinal surgery for the administration of GT005. 
 
 
 
 GT005 is administered as a single-time subretinal injection into the study 
eye, which will be performed under local anaesthesia or other anaesthetic options as considered 
appropriate by the Surgeon for the individual subject. Post-dosing ophthalmic and clinical 
assessments will be performed as described in Table 1; Table 2. Visits 2 to 5 will be performed for 
subjects randomised to GT005, as described in Table 1.  


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PROTOCOL: GT005-03 (HORIZON): V5.0, 15 SEP 2022 
CONFIDENTIAL 
 
 
 
 
For each subject, the study duration will be up to 8 weeks of screening (or up to 12 weeks if agreed 
by the Sponsor Medical Monitor), followed by a 96-week study period. Screening assessments may 
be conducted over several days. Subsequent follow-up visits at Weeks 12, 24, 36, 48, 72, and 96 
(V6, V7, V8, V9, V10, and V11 [end of study visit]) will be conducted for both GT005 and untreated 
control subjects. If a subject drops out, or is withdrawn from the study, every reasonable effort will 
be made to complete the assessments scheduled for the early termination visit. 
NUMBER OF SUBJECTS: 
Approximately 250 subjects are planned to be enrolled across protocol Stage 1 and Stage 2, with 
subjects randomised to one of two dose groups, medium dose (
vg) and high dose (
 vg). 
Within each dose group subjects will be allocated to the GT005 treatment group or untreated 
control based on a 2:1 scheme. 
 
 
 
Subjects who are screened, but not randomised, will be classed as Screen Failures and will be 
replaced. Subjects who have been randomised will not be replaced. The reason for subject 
withdrawal from the study will be recorded in the electronic case report form.  
INCLUSION/EXCLUSION CRITERIA: 
Inclusion Criteria: 
1. Able and willing to give written informed consent 
2. Age ≥55 years 
3. a. In Stage 1: Have a clinical diagnosis of GA secondary to AMD in the study eye, as 
determined by the Investigator, and a diagnosis of AMD in the contralateral eye (except if 
the subject is monocular) 
b. In Stage 2: Have a clinical diagnosis of GA, secondary to AMD in the study eye, as 
determined by the Investigator, that is non-foveal, as determined by the central reading 
centre, or has a CFI rare variant genotype associated with normal or low serum CFI, and 
meets inclusion criteria 3a (e.g., foveal or non-foveal GA), and a diagnosis of AMD in the 
contralateral eye (except if the subject is monocular) 
4. 
5. The GA lesion in the study eye must reside completely within the FAF image 
6. Up to 25% of the enrolled study population are permitted to have CNV in the fellow eye, 
defined as either: 
 
 
 
 
 
7. Have a BCVA of ≥24 letters (6/95 or 20/320 Snellen acuity equivalent), using ETDRS 
charts, in the study eye  
8. Meet one of the following AMD genetic subgroup criteria, as reviewed and confirmed by 
the Sponsor, and be allocated to one of the following groups below: 
a. In Stage 1 
 
 
 
 
 
 
 
 


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b. In Stage 2: Genotyping is not required for study eligibility 
9. Able to attend all study visits and complete the study procedures 
10. Women of child-bearing potential must have a negative pregnancy test within 2 weeks prior 
to randomisation or provide documentation of being surgically sterilised. A pregnancy test 
is not required for postmenopausal women (defined as being at least 12 consecutive months 
without menses) or those surgically sterilised (those having a bilateral tubal ligation/bilateral 
salpingectomy, bilateral tubal occlusive procedure, hysterectomy, or bilateral 
oophorectomy). 
Exclusion Criteria: 
1. Any carriers of the following genetic variants: 
 
 
 
 
 
 
 
2. Have a history, or evidence, of CNV in the study eye 
3. Presence of moderate/severe or worse non-proliferative, diabetic retinopathy in the study 
eye 
4. Have history of vitrectomy, sub-macular surgery, or macular photocoagulation in the study 
eye 
5. History of intraocular surgery in the study eye within 12 weeks prior to Visit 1. 
 
 
6. Have clinically significant cataract that may require surgery during the study period in the 
study eye 
7. Presence of moderate to severe glaucomatous optic neuropathy, uncontrolled intraocular 
pressure (IOP), despite the use of two or more topical agents; a history of glaucoma-filtering 
or valve surgery is also excluded 
8. Axial myopia of greater than -8 diopters in the study eye  
9. Have received any investigational product for the treatment of GA within the past 6 months, 
or 5 half-lives (whichever is longer) other than nutritional supplements such as the age-
related eye disease study formula 
10. Have received a gene or cell therapy at any time 
11. Have a contraindication to the protocol specified corticosteroid regimen 
12. Are unwilling to use two forms of contraception (one of which being a barrier method) for 
90 days post-dosing, if relevant 
13. Active malignancy within the past 12 months, except for: appropriately treated carcinoma 
in situ of the cervix, non-melanoma skin carcinoma, or prostate cancer with a stable 
prostate-specific antigen (PSA) ≥12 months 
14. Have any other significant ocular or non-ocular medical or psychiatric condition which, in 
the opinion of the Investigator, may either put the subject at risk or may influence the results 
of the study  




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CONFIDENTIAL 
 
 
 
 
endpoint, change from baseline to Week 72 in GA area, will be estimated among treatment groups 
via least squares means from a mixed model repeated measures analysis (MMRM) analysis. Details 
of the MMRM specifications will be detailed in the statistical analysis plan (SAP). Closed 
MCP-Mod procedure will be applied to test each of the GT005 doses vs pooled untreated control on 
GA change on FAF at Week 72 while ensuring control of the family-wise type I error in the strong 
sense. 
Categorical and binary endpoints will be summarised by counts and percentages by dose. No 
statistical inferential testing is planned for categorical and binary endpoints. 
Safety Assessments 
Safety evaluations include AEs, ophthalmic imaging and examinations, vital signs, laboratory safety 
(biochemistry and haematology), 
 
 
AEs will be summarised in two parts: systemic events and ocular events. For systemic events, data 
will be displayed according to treatment allocation (treated and untreated). Ocular events will be 
displayed according to treatment allocation (including GT005 dose and untreated control) and study 
eye (study eye and contralateral eye).  
All AEs (overall, by seriousness, by severity, by relationship), including adverse events of special 
interest, recorded throughout the investigation will be reported following classification according to 
the Medical Dictionary for Regulatory Activities dictionary. 
Systemic safety evaluations including vital signs, laboratory safety 
 will be 
summarised over time by dose and overall. 
Ocular safety evaluations including ophthalmic examination variables (cataract grading, IOP, etc.) 
and BCVA scores, will be summarised in the same manner as ocular efficacy variables, dependant 
on data type. 
 
 
 
 
72-Week Readouts 
The analysis based on the Week 72 data will be the primary efficacy analysis for this study. The 
database including all Week 72 data will be locked once all enrolled patients from both Stage 1 and 
Stage 2 have completed the Week 72 visit or terminated the study prior to Week 72. Subjects will 
remain in the study and will continue their scheduled visits and assessments through the planned 
study duration of 96 weeks, to allow for further evaluation of efficacy and safety. 
MONITORING COMMITTEES 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will perform safety reviews of unmasked data as well as 
evaluation of clinical outcomes and may recommend stopping a dose, dose adjustment, adjusting 
the design of the study or stopping the clinical study altogether. The DMC will be provided 
unmasked data by an Independent Statistics Centre (ISC) as per DMC Charter to ensure safety of 
the subjects. Only the DMC and ISC will be unmasked to study data during the conduct of the study. 
The DMC is an independent committee that will consist of three or more individuals who 
cumulatively have the clinical, surgical, medical, and statistical expertise to monitor the safety of 
subjects in the clinical study.  
No DMC member will be an Investigator in the study. Full details regarding the DMC mission and 
content, and DMC reviews are detailed in the DMC Charter and in the SAP. 


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Table 1: Schedule of Assessments: Subjects Allocated to GT005 
 
Local or Surgical 
Surgical Site 
Local or Surgical Site 
Early 
Termination 
Visit 
Visit Number 
1 
Tel Call 
2 
Tel Call 
3 
Tel Call 
4 
5 
6 
7 
8 
9 
10 
11 
Visit Type/Timeframe 
 
Screening1 Randomisation 
Day 1 (Dosing) 
Day 2 
Day 3 Week 1 Week 2 Week 5 Week 83 Week 
12 
Week 
24 
Week 
36 
Week 
48 
Week 
72 
Week 
96/EoS 
Pre-
surgery2 Surgery 
Post-
surgery 
Window 
-8 weeks 
 
 
 
+1 days 
± 3 
days 
±3 days ±7 days 
+3/-7 
days 
±7 days ±7 days ±7 days ±7 days ±7 days ±7 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test5 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Biochemistry/ 
haematology 
X1 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Serum CFI level6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery and dosing of 
GT005 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge (if applicable) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Local or Surgical 
Surgical Site 
Local or Surgical Site 
Early 
Termination 
Visit 
Visit Number 
1 
Tel Call 
2 
Tel Call 
3 
Tel Call 
4 
5 
6 
7 
8 
9 
10 
11 
Visit Type/Timeframe 
 
Screening1 Randomisation 
Day 1 (Dosing) 
Day 2 
Day 3 Week 1 Week 2 Week 5 Week 83 Week 
12 
Week 
24 
Week 
36 
Week 
48 
Week 
72 
Week 
96/EoS 
Pre-
surgery2 Surgery 
Post-
surgery 
Window 
-8 weeks 
 
 
 
+1 days 
± 3 
days 
±3 days ±7 days 
+3/-7 
days 
±7 days ±7 days ±7 days ±7 days ±7 days ±7 days 
Ophthalmic examination 
X1 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-surgical ocular safety 
check 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFP 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
FAF 
 X1 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
OCT macula 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
OCT A 
 X13 
 
 
 
 
 
X14 
X14 
Fluorescein angiography 
 X13 
 
 
 
 
 
X14 
X14 
BCVA with ETDRS 
X1 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LLVA with ETDRS for 
LLD 
X1 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Visual acuity check  
 
 
X17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MNRead 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
VFQ-25 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
FRI index 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Abbreviations: AAV2=adeno-associated virus serotype 2; AE=adverse event; AMD=age-related macular degeneration; BCVA=best corrected visual acuity; CFI=complement Factor I; CFP=colour fundus 
photography; EoS=end of study; ETDRS=early treatment for diabetic retinopathy; FAF=fundus autofluorescence; FRI Index=functional reading independence index; LLD=low luminance difference; LLVA= 
low luminance visual acuity; 
 MNRead=Minnesota low-vision reading test; OCT=optical coherence tomography; Tel=telephone; VFQ=visual functioning questionnaire. 
1. 
Screening assessments may be conducted over several days. The screening period may be extended up to a maximum of 12 weeks, if agreed by the Sponsor Medical Monitor. If the screening period is greater 
than 8 weeks, a standard ophthalmic exam, haematology/biochemistry and BCVA/LLVA should be repeated. If a subject is rescreened within the 8-week time interval between the screening visit and dosing, 
only the standard ophthalmic exam and BCVA/LLVA needs to be repeated, provided the original results from the other screening assessments were acceptable for study inclusion. If a subject is rescreened 
outside of the 8-week screening period, all screening assessments should be repeated with the exception of genotyping and serum CFI. In the event that GT005 administration is deferred during the surgical 


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CONFIDENTIAL 
 
 
 
 
procedure (e.g., due to an adverse event occurring during surgery) the time from screening may be extended up to 16-weeks if agreed by the Sponsor Medical Monitor. Additionally, if the time from screening 
is extended past 12 weeks, in case of GT005 deferral, FAFs should be repeated in addition to the standard ophthalmic exam, haematology/biochemistry and BCVA/LLVA.  
2. 
Pre-surgical assessments will include any local requirements of the surgical site. Pre-surgery is defined as the time between randomisation and surgery. 
3. 
Study assessments at Week 8 may be conducted at +3/-7 days of the study visit.  
4. 
Randomisation will occur following confirmation of eligibility; subjects will be informed via telephone call of the randomisation outcome.  
5. 
Only for women of child-bearing potential. 
6. 
To be completed only if not previously performed at a Sponsor-approved laboratory. 
7. 
. 
8. 
 
9. 
 
 
10. 
 
11. AEs should be captured from signing the informed consent form. Additional assessments may be conducted, as needed, to allow for safety assessment.  
12. A pre-surgical ocular safety check will be performed to verify no new adverse events that could halt surgery. Presurgical ocular safety checks should be performed as per local procedures and/or at the 
discretion of the Investigator assessing the subject. 
13. Choroidal neovascular AMD (CNV) assessment at screening/prior to surgery may be based on history or be performed using multimodal imaging techniques, which may include OCT, optical coherence 
tomography-angiography (OCT-A) and/or fluorescein angiography. Further details are provided in the Central Imaging Manual.  
14. OCT-A and fluorescein angiography may be performed during the study period if clinically indicated, for example, if a subject converts to wet AMD. 
15. 
16. 
 
 
17. A visual acuity check using a Snellen chart (near card is permissible) must be performed on the study eye if >4 weeks have lapsed since the last BCVA with ETDRS assessment. Refer to Section 7.3.9 for 
further details. 
 
 


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Table 2: Schedule of Assessments: Subjects Allocated to Untreated Control 
 
Local or Surgical Site 
Early 
Termination 
Visit 
Visit Number 
1 
Tel Call 
Tel Call 
6 
7 
8 
9 
10 
11 
Visit Type/Timeframe 
Screening1 
Randomisation 
Week 5 
Week 12 Week 24 
Week 36 
Week 48 
Week 72 
Week 96/EoS 
Window 
-8 weeks 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Review of eligibility 
X 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X2 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
X 
 
X 
X 
X 
X 
Biochemistry and haematology 
X1 
 
 
X 
X 
 
X 
X 
X 
X 
Serum CFI level4 
X 
 
 
 
 
 
 
 
 
 
Genotyping4 
X 
 
 
 
 
 
 
 
 
 
Adverse events5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic examination 
X1 
 
 
X 
X 
X 
X 
X 
X 
X 
CFP  
X 
 
 
 
 
 
X 
X 
X 
X 
FAF  
X 
 
 
X 
X 
X 
X 
X 
X 
X 
OCT macula 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
OCT-A 
X6 
 
 
X7 
X7 
Fluorescein angiography 
X6 
 
 
X7 
X7 
BCVA with ETDRS 
X1 
 
 
X 
X 
X 
X 
X 
X 
X 
LLVA with ETDRS for LLD 
X1 
 
 
X 
X 
X 
X 
X 
X 
X 
MNRead 
X 
 
 
 
X 
X 
X 
X 
X 
X 
VFQ-25 
X 
 
 
 
X 
X 
X 
X 
X 
X 
FRI index 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; AMD=age-related macular degeneration; BCVA=best corrected visual acuity; CFI=complement factor I; CFP=colour fundus photography; EoS=end of study; ETDRS=early 
treatment for diabetic retinopathy; FAF=fundus autofluorescence; FRI Index=functional reading independence index; LLD=low luminance difference; LLVA= Low luminance visual acuity; 
 
 MNRead=Minnesota low-vision reading test; OCT=optical coherence tomography; A; Tel=telephone; VFQ=visual functioning questionnaire. 
1. 
Screening assessments may be conducted over several days. The screening period may be extended up to a maximum of 12 weeks, if agreed by the Sponsor Medical Monitor. If the screening period is greater 
than 8 weeks, a standard ophthalmic exam, haematology/biochemistry and BCVA/LLVA should be repeated. If a subject is rescreened within the 8-week time interval between the screening visit and dosing, 


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only the standard ophthalmic exam and BCVA/LLVA needs to be repeated provided the original results from the other screening assessments were acceptable for study inclusion. If a subject is rescreened 
outside of the 8-week time interval all screening assessments should be repeated with the exception of genotyping and serum CFI.  
2. 
Randomisation will occur upon confirmation of eligibility; subjects will be informed via telephone call of the randomisation outcome.  
3. 
Only for women of child-bearing potential. 
4. 
To be completed only if not previously performed at a Sponsor-approved laboratory. 
5. 
AEs should be captured from signing the informed consent form. 
6. 
CNV assessment at screening may be based on history or be performed using multimodal imaging techniques, which may include OCT, OCT-A, and/or fluorescein angiography. Further details are provided 
in the Central Imaging Manual. 
7. 
OCT-A and/ or fluorescein angiography may be performed during the study period if clinically indicated, for example, if a subject converts to wet AMD. 
8. 
 
 


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1 BACKGROUND INFORMATION 
A full description of the indication, investigational medicinal product (IMP), pre-clinical and 
clinical data available for GT005 is provided in the Investigators Brochure (IB). 
1.1 
Indication 
Age-related macular degeneration (AMD) is the most common cause of blindness among the 
elderly in the industrialised world Jonasson 2014, affecting approximately 36 to 40 million 
people globally Access Economics Report 2010. AMD is a progressive disease that results in 
a blurred area or blank spot in the centre of vision NIH.  
AMD is classified into early, intermediate, and late stages Ferris 2013. Late-stage AMD 
includes two morphological sub-types: choroidal neovascular AMD (CNV) and geographic 
atrophy (GA) Chakravarthy 2010. There are no approved therapies for GA.  
1.2 
Investigational Product 
GT005 is a recombinant adeno-associated viral (AAV) vector derived from wild-type AAV 
serotype 2 (AAV2) 
 
 
 
 
The vector genome (vg) is 
designed to enable cellular transduction and induce secretion of CFI via a unique subretinal 
delivery. GT005 is stored at ≤-60°C. 
1.3 
Findings from Pre-clinical Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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A detailed description of the pre-clinical data is provided in the IB. 
1.4 
Clinical Studies 
A single first-in-human, Phase I/II study, FOCUS, evaluates the safety, dose response, and 
efficacy of three doses (low dose, 
 vg; medium dose, 
 vg; and high-dose, 
 vg) 
of GT005 administered by subretinal injection to subjects presenting with GA due to AMD is 
on-going. 
 
Safety data from the completed 
dose-escalation part of FOCUS supports continued development of GT005. Additional 
information, including preliminary data on expression kinetics of the CFI transgene product,  
may be found in the IB. The FOCUS study includes an expansion phase to enrol subjects with 
better preserved vision, who are more likely to demonstrate benefit from GT005 in an expansion 
cohort to evaluate the effects of GT005 in this open-label Phase I/II study. 
1.5 
Study Rationale 
 
The Complement Cascade 
Studies have strongly linked chronic local inflammation and the activation of the complement 
cascade to AMD pathogenesis Anderson 2010; Lachmann 2016; Fritsche 2016. A number of 
complement proteins have been identified as constituents of drusen, the hallmark extracellular 
deposits associated with AMD Anderson 2010. In addition to systemic production, CFI 
protein is expressed at low levels locally by the Müller supporting glial cells situated close to 
the RPE [Orozco 2020], the site of drusen formation. Amyloid-β, a major constituent of drusen, 
directly binds CFI, inhibiting its ability to cleave its substrate C3b to inactivated iC3b, reducing 
the regulation of an over-active complement system. Moreover, exposure of RPE cells to 
amyloid-β decreases local secretion of CFI, placing it central to the overall deregulation of 
complement activation in AMD [Wang 2008]. Genetic studies in advanced AMD have 
identified a significant enrichment of rare coding variants in the CFI gene (rare being defined 
as <1% minor allele frequency). Common variants in genes encoding complement factors 
involved in the alternative pathway (complement factor H [CFH], CFI, complement factor B 


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[CFB], and complement component 3 [C3]) are also significantly enriched in AMD cases, but 
confer a much weaker risk of disease development compared to that attributed to rare variants 
[Fritsche 2016].  
 
Rare Variant Genetic Population 
Since CFI serves as a global down-regulator of the alternative pathway (a part of the 
complement system) Lachmann 2016, an increase in intraocular CFI level has the potential to 
dampen an over-activated complement system associated with AMD, reducing disease 
progression. 
 
 
 
 
 
 Individuals who carry rare CFI variants that are enriched in AMD cases 
compared to controls and predicted to be damaging in silico, are also more likely to have low 
CFI levels in their serum. This is hypothesised to be the phenotypic consequence of a failure of 
protein secretion conferred by the single copy of the pathogenic genetic variant (termed 
‘haploinsufficiency’) Seddon 2013; Kavanagh 2015; Geerlings 2017. Collectively these CFI 
haploinsufficient variants account for approximately 3% of GA cases.  
EXPLORE Phase II study (starting 2020) is currently testing the hypothesis that 
supplementation of CFI via GT005 gene therapy will slow disease progression in a proportion 
of GA cases who harbour rare CFI variants associated with low serum CFI. 
 
 
 
 
 
 
 
 The 
HORIZON study has been updated to include 100% of the GA population (based on genetics), 
which includes CFI rare variant subjects associated with low serum CFI (previously only 
enrolled in EXPLORE) and a small proportion of subjects that carry other complement common 
variants, that previously had not been accounted for. 
 
Broad Genetic Population 
The HORIZON Phase II clinical study aims to assess the safety and efficacy of two doses of 
GT005 in a broad population of GA subjects, regardless of genotype.  
The mechanism of action of GT005 is to supplement normal CFI protein in the eye to dampen 
macular degeneration caused by local dysregulation of complement activity. For the broader 
GA population, our approach is to consider more widely any effect of genetic risk variants that 
map to proteins in the alternative complement pathway that may influence response to GT005.  
Genetic studies across familial and broad AMD have identified rare and common risk variants 
that map to other complement proteins in the alternative pathway, also implicating them in 
disease development [Fritsche 2013; Fritsche 2016]. Rare, functionally damaging variants in 
CFH, CFB and C3 strongly predispose to AMD [Raychaudhuri 2011; Seddon 2013; Zhan 2013; 
Saksens 2016]. In vitro functional studies indicate these variants alter the protein-protein 
interactions necessary for normal complement regulation, leading to excessive over-activation 


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of the alternative pathway, which is hypothesised to manifest over decades in the degenerative 
processes of AMD [Raychaudhuri 2011; Seddon 2013; Zhan 2013; Yu 2014].  
Other more common AMD risk variants mapping to CFH and CFI are also implicated in AMD, 
however their contribution to disease development is much weaker, given their overall high 
prevalence across healthy individuals who never develop AMD [Fritsche 2016]. However in 
combination, these weak risk variants may exert a larger (additive) effect on the delicate balance 
between complement activation and regulation [Harris 2012]. 
A common CFH AMD risk variant expected in this study is rs10922109 with an odds ratio 
(OR) of 0.38, and this is detected in 42.6% Caucasian AMD cases, compared to 22% in matched 
Caucasian controls [Fritsche 2016]. The second CFH AMD risk variant is rs1061170, which is 
a coding missense variant that changes the amino acid sequence at position 402 from a tyrosine 
to a histidine (p.(Tyr402His), and this is found in 58% AMD cases and 36.4% controls, with an 
OR of 2.38 [Fritsche 2016].  
The CFI common AMD risk variant is rs10033900, which has a weaker OR of 1.15, and is 
found in 51.1% AMD cases compared to 47.7% controls. The C3 common AMD risk variant 
rs2230199 has a weak OR of 1.43, and found in 26.6% AMD cases compared to 20.8% controls. 
The protective variant at the C2/CFB/SKIV2L gene locus rs429608 is a synonym for 
rs116503776, which an OR of 0.57, and is found in 9% AMD cases vs 14.8% controls 
[Fritsche 2016]. 
The functional consequence of common risk variants of CFH have been recently shown to 
subtly change the delicate balance between inhibitory and activating proteins of the alternative 
pathway, modifying AMD risk [Laine 2007; Clark 2013; Cipriani 2020]. No data exists yet to 
explain a functional mechanism linking the CFI common risk variant and AMD development. 
However a similar role in tipping the alternative complement pathway regulation towards 
overactivation is hypothesised, where the risk variant reduces normal CFI protein expression 
levels by a very small magnitude, and this may be enough to predispose a carrier over their 
lifetime to develop AMD. Indeed, a recent study of the human plasma proteome identified a 
significant but very modest reduction in CFI protein levels in normal carriers of the CFI 
common risk allele [Sun 2018], and work is ongoing to explore this in more detail in AMD 
patients. The main functional consequence of C3 and C2/CFB/SKIV2L risk variants are thought 
to be amino acid changes affecting C3 and CFB respectively, which adversely affect binding to 
other complement factor proteins, leading to hyperactivation of the alternative pathway, which 
contributes to disease development [(Fritsche 2016; Zhan 2013)] 
 
 
 
 
 
 
 
 
 
 
 


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During the course of the study, based on emerging data, AMD genotype subgroup enrolment 
capping may be introduced to achieve a minimum subgroup sample size. 
 
Non-foveal GA 
Recent data released on pegcetacoplan described a prespecified analysis of the primary endpoint 
where pegcetacoplan demonstrated a greater effect in subjects with non-foveal lesions at 
baseline. Patients with GA typically present first with non-foveal lesions, which then progress 
toward the fovea where central vision is impacted. With the data from two Phase III studies 
combined, monthly and every-other-month treatment with pegcetacoplan decreased GA lesion 
growth by 26% (P<0.0001) and 23% (P=0.0002), respectively, in patients with non-foveal 
lesions compared to pooled sham at 12 months [Wykoff C, AAO Abstract November 2021].  
Based on the encouraging data for pegcetacoplan, the HORIZON protocol will be composed of 
two stages: Stage 1 and Stage 2. Stage 1 of the protocol will continue to enrol the study until 
180 foveal and non foveal genetically-defined subjects with GA have randomised. Stage 2 of 
the protocol will enrol subjects with non-foveal GA (extrafoveal), and subjects with a CFI rare 
variant associated with normal or low serum CFI who have foveal or non-foveal GA, until 
approximately 250 subjects (approximately 70 additional subjects after Stage 1 is completed) 
are randomised. 
 
 
 
 
Dose Rationale 
 
 
 
 


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It has been shown that a 22 μg/mL increase in systemic CFI concentration can reduce the 
activity of the C3b feedback cycle of the highest risk sera to that of the lowest risk 
Lachmann 2016. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.6 
Risk/Benefit Assessment 
A summary of data and guidance to the Investigator is provided in the IB. 
Potential Risks 
The risks associated with this study can be divided into those related to the GT005 product and 
those related to the surgical delivery of GT005.
1.6.1.1 Risks Associated with GT005 
There were no GT005-related systemic adverse effects with all doses tested in both the monkey 
and mouse toxicity studies. In mice, 
 


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The potential risks associated with gene therapy are related to intraocular inflammation, 
immunogenicity, developmental risks, germ line transmission, and environmental risks as 
discussed below. 
 
 
 
 
  
An immune response to human CFI is the most likely cause for the observed inflammatory 
changes in both studies. This is based upon detection of anti-CFI antibodies which correlated 
with incidence and severity of the findings in the retina and geniculate nucleus in monkeys. 
Since the generation of antibodies to human CFI is not expected following subretinal 
administration of GT005 in subjects, these adverse findings are likely species-specific.  
 
 
Immunogenicity of the recombinant AAV platform has been extensively assessed in over 200 
clinical studies to date [Ginn 2018], several of which were ocular gene therapy studies using 
subretinal injection of AAV2 vector. There have been no reported ocular toxicities observed 
which have been attributed to an immune response to the capsid in the treated subjects. When 
administered subretinally, the humoral and cellular immune response to the capsid has been 
limited compared to systemically administered recombinant AAVs. After repeat administration 
of voretigene neparvovec (Luxturna®), there was little to no change reported in antibody titres 
to AAV capsid when measured in systemic circulation and seemingly no correlation between 
presence of anti-capsid antibodies and clinical safety or efficacy voretigene neparvovec FDA 
ACM 2017; Mingozzi 2013. 
 
 
 
 
 
 


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Raised CFI levels are expected locally in the retina without impacting the systemic 
complement system. While inhibition of the complement system has been associated with an 
increased risk of microbial infection, supplementing CFI locally does not block complement 
activation but merely normalises complement regulation. As such, increased susceptibility to 
infection would not be predicted. CFI is a normal plasma protein and acute phase protein plasma 
levels may rise by 150% at times of inflammation Gleeson 2016. Following the local injection 
of GT005, it is unlikely that serum levels will exceed the ranges seen in healthy individuals in 
various physiological states.  
Reproductive and developmental abnormalities have not been reported following subretinal 
or systemic AAV-based gene therapy Provost 2005. 
 
 
 
 
 
 
 
 
 
 
 
Environmental risks are considered to be low, because the GT005 AAV vector is replication-
deficient and has been stripped of all genetic machinery that would enable infective virions to 
develop. 
 
 
 
 
 
 
 
 
 
  
1.6.1.2 Risks Associated with the Surgical and Study Procedures  
The surgical technique employed for this clinical study has been developed for and successfully 
standardised based on the Choroideremia subretinal gene therapy clinical studies 
[MacLaren 2014; Xue 2017]. Risk mitigations strategies have also been developed to minimise 
foveal or retinal stretch during vector delivery, or prevent post-surgical ocular inflammation. A 
careful pre-operative assessment of the retina is done as part of surgical planning, with a range 
of visual function tests as well as retinal imaging to determine the functional and structural 
integrity of the targeted retina. The risks include: 


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Intraocular inflammation 
 A 
transient visual loss may be observed in the first days post-surgery due to the bleb-related foveal 
detachment. This can be minimised by avoiding injecting into areas of retinal thinning and by 
not detaching the fovea, if it is deemed not necessary. Retinal detachment usually regresses 
over 24 hours when the subretinal fluid resolves and retinotomy self-seals. Structural recovery 
of the retina following iatrogenic detachment of the macula generally occurs within 1 month 
[Xue 2017]. Persistent retinal detachment, due to persistence of the vector bleb, can occur in 
less than 1 in 100 cases and may be effectively managed by retinopexy with or without 
appropriate intraocular tamponade. An ocular examination of the eye treated with GT005 will 
be performed by the Vitreoretinal Surgeon or designee on post-surgical Day 2, at Week 1 
(Day 8) and Weeks 5, 12, 24, 36, 48, 72, and 96 to ensure adequate monitoring. Subjects will 
also be contacted by telephone per the schedule of assessments for the review of AEs. 
Cataract formation is associated with any vitrectomy procedure and is also a risk of periocular 
or topical steroid use. In a published study from Feng 2014, cataract appeared in 
approximately 40% of subjects following pars plana vitrectomy and resulted in a cataract 
extraction over the following 2 years. In publicly available safety data, voretigene neparvovec 
(Luxturna®), a subretinally delivered AAV2-RPE65 for the treatment of RPE65 retinal 
dystrophy, was administered in 81 eyes and of those, 11 eyes (14%) from seven subjects had 
documented progression of existing cataract or formation of new cataract. Three subjects had 
their cataract successfully extracted and other cataract cases did not receive elective extraction 
procedures voretigene neparvovec FDA ACM 2017. The study population of advanced AMD 
subjects is expected to have a mean age above or equal to 60 years and therefore may have 
already undergone a cataract extraction. At screening, subjects participating in this HORIZON 
GT005 study and assessed as likely to require cataract surgery during the study period will be 
not be included, or will be offered the option of removing their cataract before being 
(re)screened in the study. Participants who develop cataracts during the study may undergo 
cataract surgery if deemed clinically necessary; if surgery is performed, it should be carried out 
at least 4 weeks before Week 72 visit. 
IOP elevation 
 
 publicly available safety data, voretigene neparvovec 
(Luxturna®), elevation in IOP was reported in eight of 81 eyes treated (10%). Subjects enrolled 
in the HORIZON study will have IOP checked at every hospital visit to ensure adequate 
monitoring and therapies will be prescribed as needed based on local standard. At screening, 
subjects with moderate or advanced glaucoma will not be included in the study to minimise this 
risk.  
Worsening of vision is an uncommon risk associated with the surgical procedure or vitreous 
tap and could be the result of endophthalmitis or retinal damage. Risk is mitigated by design of 
the surgical procedure, surgeon qualification standards and close monitoring post-operatively. 
 
Potential Benefits 
AMD is a progressive degenerative disease and is the most common cause of blindness among 
the elderly in the western world. Supplementing AMD subjects with human CFI (a down 
regulator of the complement system) has the potential to dampen an over-activated complement 
system associated with AMD and slow down disease progression. Using AAV2 vector-based 
CFI gene transfer (GT005) could have the potential to provide sustained expression of human 
CFI in subjects’ eyes with one single-time injection. The true impact of GT005 can only be 


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hypothesised as participants may not receive any clinical benefit. Given the degenerative nature 
of AMD, it is not expected to see any gain in visual acuity as once RPE and photoreceptors 
have degenerated, the function is definitively lost in the atrophic area. The potential benefit 
would be to slow down macular atrophy extension and ultimately prevent future vision loss. 
 
Risk Benefit Analysis 
GT005 is currently being evaluated in an ongoing Phase I/II clinical study and therefore the 
potential risks are based on clinical data from an ongoing dose-escalation safety study, 
pre-clinical data, and available scientific knowledge on other ophthalmic AAV2 gene therapy 
products (e.g. voretigene neparvovec [Luxturna®]). The main product-related risks are the 
generation of cellular and/or humoral immune responses to the AAV capsid. ATA immune 
responses seen in toxicology studies are considered to be species-specific and are therefore not 
expected in subjects with lifelong CFI exposure.  
The surgical technique for the subretinal delivery of gene therapy builds upon established 
subretinal procedures such as subretinal tissue plasminogen activator injection and has been 
standardised for the Choroideremia gene therapy clinical studies MacLaren 2014; Xue 2017. 
Careful pre-dosing assessments and perioperative measures are planned to minimise and 
monitor any complication(s).  
The risk to subjects exposed to GT005 is therefore considered to be low and upon careful 
evaluation of the potential benefits afforded by the development of such a treatment, the 
risk/benefit ratio of GT005 in the study population is favourable. 


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2 STUDY OBJECTIVES AND ENDPOINTS 
The overall objectives of the study are to evaluate the effect of GT005 on the progression of 
GA in subjects with GA due to AMD. 
OBJECTIVES 
ENDPOINTS 
Primary 
• To demonstrate the effect of GT005 vs 
untreated control on the progression of 
GA in subjects with GA due to AMD 
• 
The change from baseline to Week 72 in 
GA area over time as measured by FAF 
Secondary 
• To evaluate the effect of GT005 on the 
progression of GA in subjects with GA 
due to AMD 
• The change from baseline through 
Week 96 in GA area as measured by FAF 
• 
To evaluate the safety and tolerability 
of GT005 
• 
Frequency of treatment emergent AE 
through Week 96 
• 
To evaluate the effect of GT005 on 
retinal anatomical measures 
• 
Change in retinal morphology on 
multimodal imaging through Week 96 
• 
To evaluate the effect of GT005 on 
functional measures 
• 
Change in best corrected visual acuity 
(BCVA) Score via the early treatment for 
diabetic retinopathy (ETDRS) chart 
through Week 96 
• 
Change in low luminance difference 
(LLD) via the ETDRS chart through 
Week 96 
• 
To evaluate the effect of GT005 on 
visual function 
• 
Change in reading performance as 
assessed by Minnesota low-vision reading 
test (MNRead) chart through Week 96 
• 
Change in functional reading 
independence (FRI) index through 
Week 96 
• 
To evaluate the effect of GT005 on 
patient-reported outcomes 
• 
Change in quality of life measured on the 
visual function questionnaire-25 (VFQ-25) 
through Week 96 


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3 STUDY DESIGN 
3.1 
Study Overview 
This is a Phase II, open-label, outcomes-assessor masked, untreated-control, multicentre, 
randomised controlled study to evaluate the safety and efficacy of two doses of GT005 
administered as a single-time subretinal injection in subjects with GA secondary to dry AMD.  
Approximately 250 subjects are planned to be randomised to one of two doses of GT005 or the 
untreated control group (2:1). Subjects who are screened, but not randomised, will be classed 
as Screen Failures and will be replaced.  
Subjects entered into the study must have genotyping and serum CFI evaluation performed by 
a Sponsor-approved laboratory, either through participation in another Gyroscope sponsored 
study or during the HORIZON screening period. Data from subjects screened in another 
Gyroscope sponsored study at the same investigative site as HORIZON may be used to fulfil 
the screening and eligibility requirements for this study. This is only permissible if the screening 
data is collected within the screening period specified in the clinical protocol. Following 
consent, subjects will undergo ophthalmic and clinical assessments to determine eligibility for 
inclusion in the study. Should subjects fail to meet the eligibility for HORIZON, they will be 
classed as Screen Failures for this study and may be considered for entry into another 
Gyroscope sponsored study.  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
Subjects will be randomised and stratified in accordance with the randomisation stratification 
guidance in Protocol Section 3.4.2 and the Determination of Study Eye guidance in Protocol 
Section 3.4.3.  
Following randomisation, the Investigator will be informed of the subjects’ allocated treatment 
assignment (this will only include treatment assignment to GT005 or the untreated control). To 
minimise bias, all imaging endpoint assessments and grading will be performed at a Central 
Reading Centre (CRC). All imaging efficacy assessments are to be performed in a fully masked 
fashion (individuals are unaware of a specific participant’s treatment assignment). Imaging 
paramters related to bleb will be designated to a separate dose-masked (individuals are unaware 
of a specific participant’s dose assignment) reader at the CRC. The Sponsor, investigators, 


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subjects, and study personnel performing clinical assessments will remain masked to dose 
received for those allocated to GT005.  
Subjects randomised to GT005 may undertake a visit to the surgical site between the screening 
and pre-surgery visit in order to meet the surgical team and discuss the procedure.  
 
 
 
 
 
 
 
 
 
 
  
For each subject, the study duration will be up to 8 weeks of screening (or up to 12 weeks if 
agreed by the Sponsor Medical Monitor) followed by a 96-week study period. Screening 
assessments may be conducted over several days. AEs should be captured from date of 
informed consent. Furthermore, all subjects will be assessed for the occurrence of AEs at each 
visit and will undergo functional visual and retinal imaging and anatomical assessments and 
biological sampling as per the schedule of assessments Table 1; Table 2.  
Subsequent follow-up visits at Weeks 12, 24, 36, 48, 72, and 96 (V6, V7, V8, V9, V10, and 
V11) will be conducted for both GT005 and untreated control subjects. Visit 11 will be Week 96 
and end of study visit. If a subject drops out, or is withdrawn from the study, every reasonable 
effort will be made to complete the assessments scheduled for the Early Termination Visit. 
3.2 
Dose Selection 
GT005 is a recombinant, non-replicating AAV2 expressing human CFI.  
 
 
 
 
 
 
 
 
 
3.3 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will perform safety reviews of unmasked data as well 
as evaluation of clinical outcomes and may recommend stopping a dose, dose adjustment, 
adjusting the design of the study or stopping the clinical study altogether. The DMC will be 
provided unmasked data by an Independent Statistics Centre (ISC) as per DMC Charter to 
ensure safety of the subjects. Only the DMC and ISC will be unmasked to study data during the 
conduct of the study. 




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A treatment assignment will be allocated by interactive response technology (IRT) (additional 
details will be found in the IRT reference manual provided to each site). Authorised personnel 
at investigative sites will use the IRT system to randomise subjects. IRT will assign subjects to 
a treatment code number based on a pre-defined randomisation list that will be created by a 
statistician who is independent from the study. In case of technical randomisation queries, a 
24-hour helpline is available as detailed in the IRT reference manual.  
Upon randomisation, subjects will be immediately informed of allocation. For subjects 
allocated to the untreated control arm, Day 1 will be defined as the day following randomisation 
for the calculation of Week 5 to 96 visits. 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain 
a list of subject numbers and names to enable records to be found at a later date if required. 
 
Determination of Study Eye 
If both eyes are eligible; the eye with the worse visual acuity will be selected as the study eye. 
If visual acuity is equivalent in both eyes, the eye with the largest GA lesion size will be 
the study eye unless the subject (in consultation with the Surgeon) expresses an alternative 
preference. The study eye will be confirmed by the Vitreoretinal Surgeon. 
 
 
 


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Breaking the Randomisation Code 
IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unmasking of a subject’s treatment 
assignment is warranted. Subject safety must always be the first consideration in making such 
a determination. If the Investigator decides that unmasking is warranted, the Investigator should 
make every effort to contact the Sponsor Medical Monitor prior to unmasking the subject’s 
treatment assignment, unless this could delay emergency treatment of the subject. To break the 
blind, the Investigator may open the provided emergency envelope to reveal the code to be 
entered in IRT to unmask the subject’s treatment. 
The integrity of the emergency envelope(s) should be routinely checked by the study monitors. 
The emergency envelope(s) must be collected from the investigative site prior to study close-
out, ensuring they are intact.  
3.5 
Duration of Subject Participation  
All subjects randomised to GT005 will receive a single-time subretinal injection. 
All subjects, those allocated to GT005 or untreated control, will be followed for 96 weeks. After 
the final follow-up visit, all GT005-treated subjects will be invited to participate in an extension 
study (ORACLE) for long-term follow-up to assess safety and efficacy. Subjects allocated to 
untreated control may be eligible for other interventional GT005 studies. 
3.6 
Early Study Termination  
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events (SAEs) and adverse events of special interest (AESI) will be reviewed 
as they are reported from the study centre to identify safety concerns. The DMC will review 
unmasked data and may recommend stopping a dose, dose adjustment, adjusting the design of 
the study, or stopping the clinical study altogether. The study may be terminated by the Sponsor 
at any time. Reasons for termination may include but are not limited to, the following:  
• 
The incidence or severity of an AE or safety profile of GT005 in this or other studies 
indicates a potential health hazard for study subjects 
• 
Insufficient subject enrolment or any information becoming available during the study 
that substantially changes the expected benefit risk profile of GT005 
3.7 
End of Study Definition 
The end of the study will be defined as the last visit by the last subject. 
 
 


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4 SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects entered into the study must meet the following criteria: 
1. 
Able and willing to give written informed consent 
2. 
Age ≥55 years 
3. 
 
 
  
 
 
 
 
 
4. 
5. 
The GA lesion in the study eye must reside completely within the FAF image 
6. 
Up to 25% of the enrolled study population are permitted to have CNV in the fellow eye, 
defined as either: 
 
 
 
 
 
7. 
Have a BCVA of ≥24 letters (6/95 or 20/320 Snellen acuity equivalent), using ETDRS 
charts, in the study eye 
8. 
Meet one of the following AMD genetic subgroup criteria, as reviewed and confirmed by 
the Sponsor, and be allocated to one of the following groups below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. Able to attend all study visits and complete the study procedures 
10. 
Women of child-bearing potential must have a negative pregnancy test within 2 weeks 
prior to randomisation or provide documentation of being surgically sterilised. A 


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pregnancy test is not required for postmenopausal women (defined as being at least 
12 consecutive months without menses) or those surgically sterilised (those having a 
bilateral tubal ligation/bilateral salpingectomy, bilateral tubal occlusive procedure, 
hysterectomy, or bilateral oophorectomy). 
4.2 
Exclusion Criteria 
Subjects will NOT be included in the study if they meet any of the following criteria: 
1. 
Any carriers of the following genetic variants: 
 
 
 
 
 
 
 
2. 
Have a history, or evidence, of CNV in the study eye 
3. 
Presence of moderate/severe or worse non-proliferative, diabetic retinopathy in the study 
eye 
4. 
Have history of vitrectomy, sub-macular surgery, or macular photocoagulation in the 
study eye 
5. 
History of intraocular surgery in the study eye within 12 weeks prior to Visit 1. 
 
 
6. 
Have clinically significant cataract that may require surgery during the study period in 
the study eye 
7. 
Presence of moderate to severe glaucomatous optic neuropathy, uncontrolled IOP, despite 
the use of two or more topical agents; a history of glaucoma-filtering or valve surgery is 
also excluded 
8. 
Axial myopia of greater than -8 diopters in the study eye  
9. 
Have received any investigational product for the treatment of GA within the past 
6 months or 5 half-lives (whichever is longer), other than nutritional supplements such as 
the age-related eye disease study (AREDS) formula 
10. 
Have received a gene or cell therapy at any time  
11. 
Have a contraindication to the protocol specified corticosteroid regimen 
12. 
Are unwilling to use two forms of contraception (one of which being a barrier method) 
for 90 days post-dosing, if relevant 
13. 
Active malignancy within the past 12 months, except for: appropriately treated carcinoma 
in situ of the cervix, non-melanoma skin carcinoma, or prostate cancer with a stable 
prostate-specific antigen (PSA) ≥12 months 
14. 
Have any other significant ocular or non-ocular medical or psychiatric condition which, 
in the opinion of the Investigator, may either put the subject at risk or may influence the 
results of the study 


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4.3 
Screen Failures and Replacements  
Subjects who are screened but not randomised will be classed as Screen Failures and will be 
replaced. A subject can be screened twice if the reason for ineligibility is transient (e.g., a 
cataract requiring cataract extraction), to allow the 8-week time interval between baseline 
assessment of the screening visit and dosing to be maintained (or up to 12 weeks if agreed by 
the Sponsor Medical Monitor). If the screening period is extended past the original 8-week 
screening period, a standard ophthalmic exam, haematology and biochemistry, and visual 
acuity (BCVA and low luminance visual acuity [LLVA]) assessments should be repeated. 
If a subject is rescreened within the 8-week time interval between the screening visit and dosing, 
only the standard ophthalmic exam and visual acuity (BCVA and LLVA) needs to be repeated 
provided the original results from the other screening assessments were acceptable for study 
inclusion. If a subject is rescreened outside of the 8-week screening period, all screening 
assessments should be repeated with the exception of genotyping and serum CFI.  
4.4 
Randomisation Criteria 
Subjects who have been randomised, will not be replaced.  
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain 
a list of subject numbers and names to enable records to be found at a later date if required. 
Following confirmation of eligibility for the study, subjects will be allocated to one of the 
dosing groups specified in Section 3.2. 
4.5 
Contraception 
Females of child-bearing potential (not surgically sterile, 1 year post-menopausal or 2 years 
after amenorrhea) are required to use two methods of contraception (one of which being a 
barrier method) and must agree to continue to use these methods of contraception for 90 days 
post-dosing. Acceptable methods of contraception include barrier method with spermicide, 
intrauterine device, or steroidal contraceptive (oral, transdermal, implanted, and injected) in 
conjunction with a barrier method or abstinence. True abstinence is defined when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. 
Male subjects who have female partners of child-bearing potential, should, with their partner, 
use a barrier method in conjunction with a second method of contraception for 90 days 
post-dosing. 
 
 
  
4.6 
Discontinuation/Withdrawal Procedures 
In all circumstances, subjects will be made aware of their right to refuse participation in a 
clinical study and are entitled to freely withdraw their informed consent, without giving reasons. 
Subjects should be assured that withdrawal from the study will not cause prejudice, will not 
result in any determinant, and will not affect treatment. In addition, refusal to give consent or 
withdrawal of consent to participate in research must not lead to any liability or discrimination 
(e.g. with regard to insurance or employment) against the person concerned. 


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As GT005 is a gene therapy, once surgery has taken place, subjects can withdraw from the 
study but cannot withdraw from treatment. 
The reason for discontinuation/withdrawal of subjects must be determined by the Investigator 
and recorded in the subject’s medical record and in the electronic case report form (eCRF). If a 
subject is withdrawn for more than one reason, each reason should be documented in the source 
document and the most clinically relevant reason should be entered on the eCRF. The date of 
withdrawal from the study must be recorded in the eCRF.  
Reasons for discontinuation include but are not limited to: 
• Withdrawal by subject 
• Withdrawal by Investigator 
• Death 
• Lost to follow-up 
Should a subject decide to withdraw from the study after GT005 administration, or should the 
Investigator decide to withdraw the subject, all efforts will be made to complete and report the 
observations up to the time of withdrawal as specified in the early termination visit schedule 
Table 1; Table 2.  
All subjects participating in the clinical study will receive an alert card from the Investigator, 
which has been previously agreed by the Sponsor and approved by the Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB). At a minimum it will contain the name 
of the subject, the Investigator contact number and information regarding the medical treatment 
received by the subject. 
Whether a subject is withdrawn from the study at their own request or based on a decision of 
the Investigator, follow-up should be maintained, subject to the consent of the subject. 
4.7 
Lost to Follow-up  
Long-term safety assessment of subjects treated with a gene therapy product is a regulatory 
requirement and every effort will be made to continue monitoring long-term subject safety. If 
a subject is lost to follow-up, every effort should be made to contact the subject’s Primary Care 
Practitioner or General Practitioner, with the subject’s consent, to obtain information on the 
subject’s status. 
4.8 
Long-term Follow-up  
All subjects who receive treatment with GT005, including those that have withdrawn from the 
study for any reason, will be invited to participate in a long-term follow-up study (ORACLE) 
after the final follow-up visit at Week 96. Any unresolved AEs from this study will be 
monitored until the event has resolved, subsided or stabilised in the long-term study. If a subject 
does not agree to participate in the long-term follow-up study, any ongoing AEs will be 
followed until the event has resolved, subsided or stabilised.  


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5 STUDY TREATMENT 
GT005 is a recombinant, non-replicating AAV2 expressing human CFI.  
5.1 
Acquisition and Accountability 
GT005 will be supplied to the surgical site.  
The Investigator, or designee (e.g. Pharmacist), will ensure that all GT005 is stored in a secured 
area, under recommended temperature monitored storage conditions, in accordance with 
applicable regulatory requirements and will be dispensed by qualified staff members who have 
been designated as unmasked. 
The designated unmasked study member(s) is (are) responsible for GT005 accountability, 
reconciliation, and record maintenance throughout the study. Accountability records must be 
maintained throughout the course of the study and these must be available for inspection by the 
study monitor during the study. All expired GT005 should be recorded in the accountability 
records and will be destroyed locally, as per local guidelines once final accountability is 
completed.  
Instructions for the handling and preparation of GT005 are detailed in the Pharmacy Manual. 
5.2 
Formulation, Appearance, Packaging and Labelling  
GT005 is a genetically modified organism that will be supplied to the surgical site as a vial of 
frozen sterile liquid. GT005 is an aqueous suspension of recombinant AAV2 vector particles in 
 
 GT005 will be labelled in accordance with Annex 13: Manufacture of 
Investigational Products. 
 
 
 
  
 
 
 
5.3 
Product Preparation, Storage, and Dispensing 
GT005 post-administration measures regarding disposables are detailed in the Pharmacy 
Manual. 
 
 
 
 
  
 
  
 
 




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5.6 
Concomitant Medication/Therapy Rescue Medication  
 
Required/Permitted Medication 
During the course of the study, subjects will be allowed to continue taking all prescribed and 
non-prescribed medications, unless specified in the exclusion criteria (see Section 4.2).  
Prior to administering the corticosteroid therapy, investigators must refer to relevant Summary 
of Product Characteristics and/or label guidance for use. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Note that AREDS based supplements are permitted as no effect on progression of GA has been 
reported. 
Concomitant medications will be checked throughout the study and any change in medication 
after the date on which the subject signs the informed consent should be recorded in the eCRF. 
 
Prohibited Medication 
There are no contraindicated medications for GT005 treatment. Potential subjects who 
previously received a gene/cell-based therapy at any time are excluded. 
5.7 
Treatment of Overdose of GT005 
In the event of overdosing of GT005, the site personnel must document and report the error to 
the overseeing Investigator. In the event of inflammation, subjects should be treated with 
corticosteroids.  
5.8 
Administration Compliance 
The product is delivered as a single-time administration by subretinal injection. The subretinal 
injection is undertaken by a qualified and trained Vitreoretinal Surgeon at a centralised surgical 
site. The Investigator at the surgical site is responsible for ensuring GT005 is handled in 
accordance with the protocol and is only administered to subjects enrolled into the study that 
are allocated to receive GT005 through IRT. 
 


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6 STUDY PROCEDURES 
The schedule of observations and assessments during the study are summarised in Table 1; 
Table 2 for subjects allocated to GT005 and subjects allocated to the untreated control, 
respectively. As treatment assignment will not be known until randomisation, the screening 
assessments listed in the schedule of assessments are the same in both tables.  
Subjects enrolled at local investigational sites and randomised to GT005 may be invited to 
travel to a conveniently located surgical site for treatment and immediate post-operative follow-
up visits only as summarised in Table 1.  
Definition of Local Site versus Surgical Site 
Local investigational sites are defined as sites that are approved to participate in this clinical 
study, but require identified subjects to be transferred for surgery. Subject consent, screening, 
and post-operative follow-up visits will be conducted according to the visit schedule outlined 
in schedule of assessments [Table 1] and [Table 2].  
Surgical sites are defined as sites that are approved to participate in this clinical study and to 
perform the surgical procedure as part of this clinical protocol. If a subject is screened at the 
surgical site, all assessments will be performed at this site. 
Following successful screening and randomisation, pre- and post-surgical assessments should 
be performed at the surgical site for subjects randomised to GT005. Subjects will complete the 
remainder of assessments at the local site as per the schedule of assessments [Table 1] and 
[Table 2]. 
6.1 
Study Visits 
 
Screening (Visit 1: Local or Surgical) 
Genotyping Visit 
Subjects entered into the study must have genotyping and serum CFI evaluation performed by 
a Sponsor-approved laboratory, either through participation in another Gyroscope sponsored 
study, or during the HORIZON screening period. Subjects being considered for inclusion (who 
have not been previously genotyped in a Gyroscope sponsored study) will be required to 
provide a consent, agreeing to provide a sample for genetic testing or permit the analysis of an 
existing sample for this HORIZON protocol. Following subject consent, samples will be 
collected and shipped to a central laboratory for genotyping. Samples will be used for genetic 
testing for variants relating to AMD.  
Where necessary, and to facilitate the completion of all screening assessments, Visit 1 can occur 
over a number of days.  
Screening Assessments 
A HORIZON study written informed consent must be obtained for each subject prior to any 
conduct of study-related procedures. The screening assessments will determine the eligibility 
of each subject and should be performed within 8 weeks of the planned dosing date (or up to 
12 weeks if agreed by the Sponsor Medical Monitor). Refer to Protocol Section 4.3 for 
rescreening guidelines.  
Data from subjects screened in another Gyroscope sponsored study, conducted at the same 
investigative site as the HORIZON study, may be used to fulfil the screening and eligibility 


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requirements for this study. This is only permissible if the screening data is collected within the 
screening period specified in the clinical protocol. Should subjects fail to meet the eligibility 
for HORIZON, they will be classed as Screen Failures for this study and may be considered for 
entry into another Gyroscope sponsored study.  
The following screening assessments are required for ALL subjects: 
• AEs 
• Demographics 
• Medical/surgical history 
• Concomitant medication 
• Pregnancy test (for women of child-bearing potential only) 
• Vital signs 
• Biochemistry and haematology1 
• Serum CFI Level (only required if not already available from a Sponsor-approved 
laboratory)  
• Genotyping (only required if not already available from a Sponsor-approved genetics 
laboratory)2  
 
 
• Ophthalmic examination 
• CFP 
• FAF 
• OCT Macula 
• CNV assessment; may be based on history or be performed using multimodal imaging 
techniques, which may include OCT, OCT-A and/or FA. Further details are provided in 
the Central Imaging Manual.  
• 
 
 
 
 
 
 
 
• BCVA using ETDRS1 
• LLVA using ETDRS for LLD1 
• Reading performance (MNRead) 
• Visual function questionnaire (VFQ-25) 
• FRI Index 


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1The screening period may be extended up to a maximum of 12 weeks, if agreed by the Sponsor 
Medical Monitor. If the screening period is greater than 8 weeks, standard ophthalmic exam, 
haematology/biochemistry and BCVA/LLVA should be repeated.  
2In Stage 2, genotyping will be required for stratification of subjects into AMD subgroups 
(Groups 1–5). 
 
Randomisation (Telephone Call) 
Randomisation will occur upon confirmation of eligibility. The Investigator will follow the 
randomisation procedure (IRT), as described in Section 3.4, and inform the subject of treatment 
allocation (GT005 or untreated control). 
For subjects randomised to the untreated control, Day 1 will be defined as the day following 
randomisation for the calculation of Week 5 to 96 visits. 
For subjects randomised to GT005, the day of surgery is described as Day 1 in the study timeline 
(Section 6.1.3). The interval between randomisation and Day 1 must be sufficient to allow 
arrangements to be made for surgery, and to prepare the subject, as appropriate, for treatment. 
Randomisation therefore resides within the interval between screening and surgery, which 
should not exceed 8 weeks, unless agreed by the Sponsor Medical Monitor, who may approve 
an extension for up to a maximum of 12 weeks. 
The Investigator will ask the subject if any changes have occurred since the screening visit and 
record in the eCRF: 
• AEs 
• Concomitant medication 
 
Visit 2, Day 1 (Surgical Site) 
Visit 2 will only apply to subjects randomised to GT005.  
This visit will be performed at a centralised surgical site and will be split in three parts to be 
conducted over 2 days: pre-surgery (Day 1), surgery (Day 1) and post-surgery (Day 2).  
6.1.3.1 Pre-surgery Day 1 (Surgical Site) 
Pre-surgical assessments will include any local requirements of the surgical site. Pre-surgery is 
defined as the time between randomisation and surgery. The following assessments are required 
pre-surgery: 
• Medical/surgical history 
• Concomitant medication 
• Pregnancy test (for women of child-bearing potential only) 
• Vital signs 
• AEs 
• 
 
 
• 
 


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• Pre-surgical ocular safety check to verify there are no new ocular AE that would halt 
surgery 
• Snellen visual acuity (refer to Section 7.3.9)  
6.1.3.2 Surgery Day 1 (Surgical Site) 
Deferred GT005 Delivery  
In the event the GT005 administration is deferred during the surgical procedure (e.g. due to an 
AE occurring during surgery) the time from screening may be extended up to 16 weeks if agreed 
by the Sponsor Medical Monitor. Additionally, if the time from screening is extended past 
12 weeks, in case of GT005 deferral, FAFs will be repeated, in addition to standard ophthalmic 
examination, haematology and biochemistry, and visual acuity (BCVA and LLVA).  
The following assessment are required during surgery: 
 
 
• AEs 
• Concomitant medications 
 
 
 
 
The procedure for the administration of GT005 is described in Section 5.4.  
 
Post-Surgery Day 2 (Surgical Site) 
The following assessment are required post-surgery and prior to the discharge (if applicable) of 
the subject: 
• Concomitant medication 
 
 
• Vital signs 
• AEs 
• Ophthalmic examination 
 
 
• OCT macula 
 
Day 3 (Telephone Call) 
Day 3 telephone call will only apply to subjects randomised to GT005.  
The following information will be recorded: 
• Concomitant medication 
 
 
• AEs 


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Visit 3, Week 1 (Surgical Site) 
Visit 3 (Week 1) will only apply to subjects randomised to GT005.  
The following assessments will be performed: 
• Concomitant medication 
 
 
• AEs 
• Vital signs 
• Ophthalmic examination 
• BCVA using ETDRS 
• OCT macula 
 
 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
Week 2 (Telephone Call) 
Week 2 telephone call will only apply to subjects randomised to GT005.  
The following information will be recorded: 
• Concomitant medication 
 
 
• AEs 
 
Visit 4, Week 5 (Local or Surgical Site for GT005 Subjects/Telephone Call for 
Untreated Control Subjects) 
At Week 5, subjects may choose to attend a local investigative site or surgical site for clinical 
assessments and ophthalmic imaging, with review of images by both the Investigator and the 
surgeon.  
Subjects allocated to untreated control will receive a telephone call to review concomitant 
medications and AEs. 
Visit 4 (Week 5) assessments listed below will only apply to subjects randomised to GT005.  
The following assessments will be performed: 
• Concomitant medication 
 
 
• Vital signs 
• AEs 
• Biochemistry and haematology 


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• Ophthalmic examination 
• FAF 
• OCT macula 
 
 
• BCVA using ETDRS 
• CFP 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
Visit 5, Week 8 (Local or Surgical Site) 
Visit 5 (Week 8) will only apply to subjects randomised to GT005 
• Corticosteroid compliance  
• AEs 
• Concomitant medication  
• Ophthalmic examination  
• BCVA with ETDRS  
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
Visit 6, Week 12 (Local or Surgical Site) 
The following assessments will be performed in ALL subjects unless otherwise specified: 
• Concomitant medication 
 
 
 
• AEs 
• 
 
• Biochemistry and haematology 
• 
  
• Ophthalmic examination 
• FAF 


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• OCT macula 
 
 
• 
 
 
• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
Visit 7, Week 24 (Local or Surgical Site) 
The following assessments will be performed for ALL subjects unless otherwise specified: 
• Concomitant medication 
• Vital signs 
• AEs 
• Biochemistry and haematology 
 
 
 
 
  
• Ophthalmic examination 
• FAF 
• OCT macula 
 
 
 
 
 
• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• Reading performance (MNRead) 
• Visual function questionnaire (VFQ-25) 
• FRI index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 


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Visit 8, Week 36 (Local or Surgical Site) 
The following assessments will be performed for ALL subjects unless otherwise specified: 
• Concomitant medication 
• AEs 
• Ophthalmic examination 
• FAF 
• OCT macula 
 
 
• 
 
 
• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• Reading performance (MNRead) 
• Visual function questionnaire (VFQ-25) 
• FRI index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
Visit 9, Week 48 (Local or Surgical Site) 
The following assessments will be performed for ALL subjects unless otherwise specified: 
• Concomitant medication 
• Vital signs 
• Biochemistry and haematology 
 
 
 
 
 
 
 
 
  
• AEs 
• Ophthalmic examination 
• CFP 
• FAF 


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• OCT macula 
 
 
• 
 
 
• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• Reading performance (MNRead) 
• Visual function questionnaire (VFQ-25) 
• FRI index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
Visit 10, Week 72 (Local or Surgical Site) 
The following assessments will be performed for ALL subjects unless otherwise specified: 
• Concomitant medication 
• Vital signs 
• Biochemistry and haematology 
• AEs 
• Ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
 
 
 
 
 
• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• Reading performance (MNRead) 
• Visual function questionnaire (VFQ-25) 
• FRI index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 


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Visit 11, Week 96/End of Study and Early Termination Visit (Local or Surgical 
Site) 
The following assessments will be performed in ALL subjects unless otherwise specified: 
• Concomitant medication 
• Vital signs 
• Biochemistry and haematology 
 
 
  
 
 
 
 
 
  
• AEs 
• Ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
 
 
 
 
 
• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• Reading performance (MNRead) 
• Visual function questionnaire (VFQ-25) 
• FRI index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
Unscheduled Visit 
If clinically indicated, subjects may need to return to the site for an unscheduled visit. The 
Investigator will perform assessments considered to be appropriate for the subject, considering 


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the reason behind the need to arrange an unscheduled visit. These results should be recorded in 
the subject’s medical notes and eCRF. 


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7 STUDY ASSESSMENT 
7.1 
Demographic and Screening Assessments 
Informed Consent Procedure  
The informed consent process will be conducted prior to performing any study related 
procedures. Subjects entered into the study must have genotyping and serum CFI evaluation 
performed by a Sponsor-approved laboratory, either through participation in a previous Sponsor 
study, or during the HORIZON screening period. Informed consent will include permission for 
genotyping (genotyping and serum CFI evaluation are not required for subjects who have these 
data from another Gyroscope study) and a consent from each subject or legal representative to 
enrol into HORIZON and undergo ophthalmic and clinical assessments to determine eligibility 
for inclusion in the study. Data from subjects screened in another Gyroscope sponsored study 
at the same investigative site as HORIZON may be used to fulfil the screening and eligibility 
requirements for this study. This is only permissible if the screening data is collected within the 
screening period specified in the clinical protocol. Should subjects fail to meet the eligibility 
for HORIZON, they will be classed as Screen Failures for this study and may be considered for 
entry into another Gyroscope sponsored study. 
 
 
 
 
  
It is the responsibility of the Investigator, or a suitably qualified person delegated by the 
Investigator to obtain written informed consent from each subject. The Investigator or designee 
will explain that the subject is under no obligation to enter the study and that they may withdraw 
at any time during the study, without having to give a reason.  
A copy of the signed Informed Consent Forms (ICFs) will be given to the subject. The original 
signed form(s) will be retained at the study site.  
Subject Eligibility 
It is the responsibility of the Investigator, or a suitably qualified person delegated by the 
Investigator to confirm the eligibility of each subject for the study. Review and confirmation of 
eligibility is to be documented in the subjects’ medical records. 
Demographics  
Subject demographics, including year of birth, race, ethnicity and sex at screening will be 
captured. 
Medical/Surgical History 
Prior medical history (including all ocular history) will be reviewed and recorded in the eCRF. 
This will comprise of (and be updated throughout the study): 
• all current and prior ocular medical and surgical history 
• all current and prior significant general medical and surgical history 
• pertinent family (e.g. related parents and children) and social history 


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7.2 
Concomitant Medication and Corticosteroid Compliance 
 
Concomitant Medication 
All concomitant medication will be reviewed and recorded, including: 
• current medication use 
• any drug allergy or contraindication to steroids 
 
 
7.3 
Ophthalmic Assessments 
Details of the required assessments will be provided in the Central Imaging Manual.  
Camera equipment used at investigative sites will be required to meet the specifications of the 
CRC as specified in the Central Imaging Manual.  
 
Ophthalmic Examination 
Ophthalmological examinations in both eyes will be performed as follows: anterior segment 
examination via slit lamp biomicroscopy, IOP via Goldmann applanation tonometry (GAT) or 
a Tono-Pen®, posterior segment and fundus examination via dilated indirect ophthalmoscopy. 
Ocular inflammation will be assessed. 
Slit lamp will be conducted on both eyes. The eyelids, cornea, conjunctiva, anterior chamber, 
iris/pupil and lens should be evaluated. Findings will be graded as normal, abnormal non-
clinically significant, or abnormal clinically significant. Cataract will be graded using the 
AREDS clinical lens grading system Appendix 17.1. IOP should be assessed using the same 
method (GAT or Tono-Pen®) throughout the study regardless of method chosen. 
Dilated indirect ophthalmoscopy will assess the vitreous, macula, choroid, optic nerve, retina, 
and cup- to-disc ratio of both eyes. Findings will be graded as normal, abnormal non-clinically 
significant, or abnormal clinically significant. 
 
Pre-surgical Ocular Safety Check 
A pre-surgical ocular safety check should be performed to verify there are no new ocular 
adverse events that would halt surgery. Pre-surgical ocular safety checks should be performed 
as per local procedures and/or at the discretion of the Investigator assessing the subject. 
 
Colour Fundus Photography 
CFP of the fundus of both eyes will be performed by certified technicians following pupil 
dilation. All fundus photographs will be sent by the sites to the CRC for review (unless 
otherwise specified); the CRC will transfer the data to the data management group and/or ISC. 
For complete technical specifications for fundus photography, refer to the Central Imaging 
Manual (which will include procedures from the CRC regarding how measurements are to be 
taken).  
 
Fundus Autofluorescence 
To assess changes in the area of GA, FAF will be performed for both eyes. 
All FAF images will be performed by certified technicians at the site after dilation of the 
subject’s pupil and sent to a CRC for review; the CRC will transfer the data to the data 


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management group and/or ISC. For complete technical specifications for FAF, refer to the 
Central Imaging Manual (which will include procedures from the CRC regarding how 
measurements are to be taken). 
 
Optical Coherence Tomography (Macula 
) 
OCT is a method of using low-coherence interferometry to determine the echo time delay and 
magnitude of backscattered light reflected off an object of interest. This method can be used to 
scan through the layers of a structured tissue sample, such as the retina, with very high axial 
resolution (3 to 15 μm), providing images demonstrating three dimensional structure. Because 
of the unique optically clear pathway through the eye, OCT has been used most extensively for 
imaging disorders affecting the retina. 
OCT will be performed for both eyes. OCT measurements will be taken by certified technicians 
at the site after dilation of the subject’s pupil. All OCT scans will be submitted by the sites 
(unless otherwise specified) to a CRC where the scans will be evaluated. The CRC will transfer 
the data to the data management group and/or ISC. For complete technical specifications for 
OCT, refer to the Central Imaging Manual (which will include procedures from the CRC 
regarding how measurements are to be taken).  
 
Optical Coherence Tomography A 
OCT A allows for non-invasive evaluation of retinal and choroidal vascular abnormalities that 
is useful as a diagnostic tool for Investigators to identify CNV. Other imaging modalities as 
described in the Central Imaging Manual may be utilised to assess for CNV. OCT-A may be 
performed as clinically indicated during the course of the study, for example, if a subject 
converts to wet AMD.  
 
Fluorescein Angiography 
Fluorescein angiography is used to examine the circulation of the retina and choroid using a 
fluorescent dye and a specialised camera. Sodium fluorescein is added into the systemic 
circulation, the retina is illuminated with blue light at a wavelength of 490 nanometers, and an 
angiogram is obtained by photographing the fluorescent green light emitted by the dye.  
Fluorescein angiography may be performed to assess CNV to confirm eligibility and as 
clinically indicated during the course of the study, for example, if a subject converts to wet 
AMD. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Visual Acuity Check 
A visual acuity check using a Snellen chart (near card is permissible) must be performed 
pre-surgery on the study eye if >4 weeks have elapsed between BCVA with ETDRS and 
surgery. If the Snellen vision is >2 lines (BCVA equivalent to 10 letters) worsened compared 
to the previous BCVA with ETDRS, a BCVA with EDTRS must be repeated prior to surgery. If 
the BCVA with EDTRS results is ≤2 lines worsened compared to the previous BCVA with 
ETDRS, record the subjects vision in the eCRF and surgery can proceed. If the repeat BCVA 
with EDTRS check remains >2 lines (BCVA equivalent to 10 letters) worsened, surgery must 
be postponed pending discussion and approval by the Sponsor Medical Monitor. 
 
Best Corrected Visual Acuity 
To evaluate changes in visual acuity over the study period, BCVA will be assessed for both 
eyes using the ETDRS visual acuity chart. 
The BCVA test should be performed prior to pupil dilation, and distance refraction should be 
carried out before BCVA is measured. Initially, letters are read at a distance of 4 metres from 
the chart. If <20 letters are read at 4 metres, testing at 1 metre should be performed. BCVA is 
to be reported as number of letters read correctly by the subject. At the Screening Visit, eyes 
with a BCVA of ≥24 ETDRS letters (6/95 or 20/320 Snellen acuity equivalent or better), using 
ETDRS charts will be eligible for the study.  
If a subject cannot read any letters on the BCVA chart, the subject will be tested for finger 
counting, hand movements or light perception.  
 
Low Luminance Difference 
To evaluate the subject’s low luminance deficit, LLD will be measured for both eyes. The test 
should be performed after BCVA testing, prior to pupil dilation, and distance refraction should 
be carried out before LLVA is measured. LLVA is measured by placing a 2.0-log-unit neutral 
density filter over the front of each eye and having the subject read the normally illuminated 
ETDRS chart. The LLD is calculated as the difference between BCVA and LLVA. Initially, 
letters are read at a distance of 4 metres from the chart in each eye. If <20 letters are read at 
4 metres, testing at 1 metre should be performed.  
 
Reading Performance (MNRead) 
Monocular (study eye separate from contralateral eye) Reading Speed will be assessed by the 
MNRead acuity test Appendix 17.2. The reading test will be provided in the native language 
of the participating subject. 
 
Visual Function Questionnaire (VFQ-25) 
The VFQ-25 is a validated 25-item version of the 51-item visual function questionnaire 
developed at RAND under the sponsorship of the National Eye Institute Appendix 17.3.  
 
Functional Reading Independence Index 
The FRI index is a patient-reported outcome measure developed specifically for use in GA 
patients Appendix 17.5. The FRI index evaluates the level of independence subjects have in 
performing everyday activities that require reading, such as writing a cheque or reading a 
prescription. Scores derived from the index range from 1 (unable to do) to 4 (total 
independence). The FRI index will be provided in the native language of the participating 
subject. 


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7.4 
Safety 
 
Vital Signs 
Vital signs including heart rate, temperature, and blood pressure will be measured. Blood 
pressure (systolic and diastolic) to be measured in triplicate after five minutes rest in a sitting 
position. The same method should be used throughout the study. Heart rate will be assessed as 
a single measurement.  
 
Adverse Events 
Subjects will be questioned in a general way at each study visit to establish whether AEs have 
occurred since the previous visit (e.g. “How have you been feeling since your last visit?”). 
Additionally, the Investigator will evaluate other collected data (e.g. questionnaires) to 
ascertain whether an AE has occurred. All AEs will be captured from the time the subject 
provides written informed consent and monitored throughout the study. Additional imaging 
safety assessments may be collected at any visit, as needed, in order to follow-up on any AEs.  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
Pregnancy Test 
Females of child-bearing potential are defined as those who have experienced menses in the 
past 12 months and do not meet the criteria for women not of child-bearing potential. Women 
not of child-bearing potential are females who are permanently sterile (e.g. bilateral tubal 
ligation, hysterectomy, or bilateral oophorectomy) or post-menopausal. Post-menopausal is 
defined as 12 consecutive months with no menses without an alternative medical cause. 
Females of child-bearing potential will undergo urine pregnancy testing at Visit 1 (screening) 
and for those subjects allocated to GT005, an additional test prior to surgery on Day 1 (Visit 2).  
 
Laboratory Safety Tests 
Blood samples for serum chemistry and haematology will be taken for evaluation of laboratory 
safety parameters Table 3. The Investigator must review the safety laboratory test results, 
document the review, and record any clinically relevant changes occurring or observed during 
the study in the AE section of the eCRF.  
All clinically relevant laboratory test abnormalities occurring during the study will be repeated 
at appropriate intervals until they return to baseline or to a level deemed acceptable by the 
Investigator and the Sponsor Medical Monitor (or designated representative), or until the 




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7.4.5.4 Genotyping 
Subjects entered into the study must have genotyping performed by a Sponsor-approved 
laboratory, either through participation in a previous Gyroscope-sponsored study, or during the 
HORIZON screening period. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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8 ADVERSE EVENT REPORTING 
All AEs will be captured from the date of written informed consent and monitored throughout 
the study. AEs will be elicited by direct non-leading questioning or by spontaneous reports. 
8.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the IMP. An undesirable medical condition can be 
symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g. laboratory findings, electrocardiogram). In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run in or 
washout periods, even if no IMP has been administered.  
Natural progression or deterioration of the (disease/symptoms) under study will be recorded as 
part of the efficacy evaluation and should not be recorded as an AE/SAE. 
8.2 
Definition of Serious Adverse Event 
A SAE is any AE that: 
1) Results in death 
2) Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a more 
severe form, might have caused death 
3) Results in in-patient hospitalisation or prolongation of existing hospitalisation, 
excluding admission for social or administrative reasons 
4) Results in a persistent or significant disability/incapacity, where disability is a 
substantial disruption of a person's ability to conduct normal life functions 
5) Results in congenital anomaly/birth defect in the offspring of a subject who received the 
IMP 
6) Is an important medical event that may not result in death, be life threatening, or require 
hospitalisation when, based upon appropriate medical judgement, may jeopardise the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include a sight-threatening AE 
that requires surgical intervention to prevent permanent sight loss 
In addition to the above criteria, any additional AE that an Investigator considers serious should 
be immediately reported to the Sponsor and included in the SAE database. 
Hospitalisation is defined as any unplanned overnight admission into hospital. For chronic or 
long-term in-patients, in-patient admission also includes transfer within the hospital to an 
acute/intensive care in-patient unit. 
Prolongation of hospitalisation is defined as any extension of an in-patient hospitalisation 
beyond the stay anticipated/required in relation to the original reason for the initial admission, 
as determined by the Investigator or treating physician. For protocol-specified hospitalisation 
in clinical studies, prolongation is defined as any extension beyond the length of stay described 
in the protocol. Prolongation in the absence of a precipitating, treatment-emergent, clinical AEs 
(i.e. not associated with the development of a new AE or worsening of a pre-existing condition) 


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may meet criteria for "seriousness" but is not an adverse experience and thus is not subject to 
immediate reporting to the Sponsor.  
Pre-planned or elective treatments/surgical procedures should be noted in the subject’s 
screening documentation. Hospitalisation for a pre-planned or elective treatment/surgical 
procedure should not be reported as an SAE unless there are complications or sequelae which 
meet the criteria for seriousness described above. 
8.3 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor can be appropriate. AESIs should also be assessed as to whether it 
fits the criteria of an SAE and reported appropriately. AESI should be reported as per reporting 
requirements (Section 8.5.1). 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
It is anticipated that there may be transient decreases to visual acuity related to the subretinal 
injection surgical procedure. A transient visual loss may be observed in the first days post-
surgery due to bleb-related foveal detachment, if performed. Transient surgery-related events 
of decreases in visual acuity are defined as decreases occurring in close temporal association 
(within 24 hours) with the surgical administration of the study medication, and which are 
resolving at Week 1 (Visit 3) post-surgery.  
Additionally, there is a known risk of cataract associated with any vitrectomy procedure. A 
published review from Feng 2014 shows cataract to be common following pars plana 
vitrectomy with about 40% of patients requiring a cataract extraction over the following 2 years.  
Transient, surgically-related decreases in visual acuity, as well as cataract will not be classified 
as AESI. 
8.4 
Classification of an Adverse Event 
 
Severity Assessment 
AEs will be classified as mild, moderate, or severe according to the following criteria: 
Mild: Does not interfere with subject's usual function. 
Moderate: Interferes to some extent with subject's usual function.  
Severe: Interferes significantly with subject's usual function. 
AE severity will be assessed at the site by the Investigator or a medically qualified designee. 


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Causality Assessment 
The relationship of an AE to IMP or surgical procedures will be classified by the Investigator 
or medically qualified designee. 
When assigning relatedness of the AE, consideration will be given to whether there is a 
plausible relationship to either the IMP or the surgical procedure.  
The following are definitions of relatedness that will be used in this study: 
• Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose-response relationship, pharmacology, positive de-challenge and/or re-
challenge) to assume a causal relationship to the IMP or the surgical procedure. In the 
sense that it is plausible, conceivable or likely 
• Not related: reports including good reasons and sufficient information (e.g. implausible 
time sequence and/or attributable to concurrent disease or other drugs) to rule out a 
causal relationship to the IMP or the surgical procedure with IMP administration 
• Unknown: there is insufficient information to assess plausibility of causal relationship 
to the IMP or the surgical procedure 
 
Expectedness Assessment 
An expected adverse reaction is where the nature or severity of the AE is consistent with the 
applicable product information (as specified in the IB), otherwise it is considered unexpected. 
 
Action Taken Regarding the Investigational Medicinal Product 
The action taken regarding IMP must be described by selecting one of the following: 
• No action taken (once GT005 is administered, this gene therapy cannot be removed) 
• Drug withdrawn 
• Dose reduced or partially administered 
• Unknown or not applicable 
 
Outcome  
All AEs should have the outcome recorded as one of the following: 
• Recovered or resolved 
• Recovering or resolving 
• Not recovered or not resolved 
• Recovered with sequelae or resolved with sequelae 
• Fatal 
• Unknown 
8.5 
Reporting Requirements 
 
Serious Adverse Events and Adverse Event of Special Interest 
All SAEs/AESIs regardless of treatment group or suspected relationship to IMP or surgical 
procedure must be recorded and reported immediately (within 24 hours of the Investigator’s 
knowledge of the event) to the pharmacovigilance contact specified below. If the immediate 


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report is submitted by telephone, this must be followed by detailed written reports using the 
relevant report form.  
The SAE/AESI must be reported immediately (within 24 hours of awareness), independent of 
the circumstances or suspected cause, if it occurs or comes to the attention of the Investigator 
at any time during the study period. 
The following information is the minimum that must be provided to the Sponsor 
pharmacovigilance contact within 24 hours for each SAE/AESI: 
• Study number 
• Centre number 
• Subject number 
• AE 
• Investigator name and contact details 
The additional information included in the form must be provided to the Sponsor or 
representative as soon as it is available. The Investigator should always provide an assessment 
of causality for each event reported to the Sponsor. Upon receipt of the initial report, the 
Sponsor will ask for the Investigator's causality assessment if it was not provided with the initial 
report. 
The Investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The Investigator should also try to separate a primary AE considered as the foremost 
untoward medical occurrence from secondary AEs which occurred as complications. 
All SAEs/AESI must be reported in the eCRF. Alternatively, if the eCRF cannot be accessed, 
please contact 
 by telephone, fax or email: 
 SAE hotline – Europe/Australia: 
Telephone: 
 
Fax: 
 
e-mail: 
 
 SAE hotline – United States: 
Telephone: 
 
Fax: 
 
e-mail: 
 
Where the Investigator requires advice regarding the handling of SAEs/AESIs, the contact in 
case of emergency is: 
 (Europe/Australia only) 
 (United States only) 
8.6 
Follow-up of Adverse Events 
All observed or volunteered AEs, regardless of treatment group or suspected causal relationship 
to IMP, will be recorded on the AE page(s) of the eCRF.  


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Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the Investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
requiring immediate notification to the Sponsor or its designated representative. For all AEs, 
and where possible, sufficient information reviewed to assess causality of the AE (i.e. IMP, 
surgical procedure, or other illness). The Investigator is required to assess causality and record 
that assessment on the eCRF.  
AEs will be followed until the event has resolved, subsided or stabilised. This includes those 
subjects allocated to GT005 who are enrolled in the long-term follow-up study (ORACLE). 
Subjects who are withdrawn from the study as a result of an IMP-related AE will be followed 
up until the event has resolved without sequalae, subsided, stabilised, or the subject withdraws 
consent or is lost to follow-up. 
All SAEs, regardless of attribution to IMP or the surgical procedure, should be followed-up 
until the event has resolved without sequalae, subsided, stabilised, or the subject withdraws 
consent or is lost to follow-up. The Sponsor (or designee) will follow-up SAE reports to 
completion. Investigators are expected to timely provide the requested additional information 
for a complete assessment and documentation of the SAE reports. 
8.7 
Pregnancy 
A pregnancy is not considered to be an AE or SAE; however, it must be reported to 
 
Clinical Safety within 24 hours of knowledge of the event. 
 Clinical Safety will then 
provide the Investigator/site the exposure in utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax/email it back to
 Clinical Safety. 
Pregnancies will be reported from the time of treatment administration until the end of the study. 
The Investigator must instruct all female subjects of child-bearing potential to inform them 
immediately should they become pregnant during the study. The Investigator should counsel 
the subject, discuss the risks of continuing with the pregnancy, and the possible effects on the 
foetus. The pregnancy should be followed until the outcome of the pregnancy, whenever 
possible. Once the outcome of the pregnancy is known, the follow-up EIU form should be 
completed and faxed/emailed to 
 Clinical Safety. If the outcome of the pregnancy 
meets the criteria for immediate classification as an SAE (i.e. postpartum complication, 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator should 
follow the procedures for reporting an SAE.  
If the female partner of a male subject becomes pregnant after the subject has received IMP or 
within the safety follow-up period, the Investigator should notify 
 Clinical Safety as 
described above. After the partner has provided written consent, she should be counselled and 
follow the same procedures as a female participant in the study who becomes pregnant. 
Monitoring of the partner should continue until conclusion of the pregnancy as outlined above. 
8.8 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
If the subjects withdraws from the study due to an AE,SAE, or AESI, every effort should be 
made to follow-up on any ongoing AEs. Any subject treated with GT005 should receive 
appropriate medical follow-up. 


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8.9 
Reporting to Competent Authorities/Ethics Committees/Other Investigators 
The Sponsor will ensure that processes are in place for submission of reports of suspected 
unexpected serious adverse reactions (SUSARs) occurring during the study to the Competent 
Authorities, IEC or IRB and other investigators. Reporting will be done in accordance with the 
applicable regulatory requirements. 
For study centres in the United States, Investigational New Drug application safety reports will 
be submitted directly to the investigators. It is the Investigators’ responsibility to notify their 
IEC or IRB in a timely manner.  




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The primary estimand will focus on the effect attributable to different doses of GT005 on GA 
change on FAF at Week 72 by taking into account any potential unfavourable effects of GT005. 
The primary estimand is defined by the following elements: 
• Population: Subjects with GA secondary to AMD  
• 
Variable: Change from baseline in GA lesion size on FAF at Week 72 
• Treatment: The randomised treatment (different doses) of the investigational therapy 
GT005, assuming no further benefit for subjects who withdraw from the study due to 
AEs or who receive alternative therapies for GA. 
• Intercurrent events: defined in Table 4 . 
Table 4: Intercurrent Events and Corresponding Primary Data Handling Strategies. 
Intercurrent event 
Data handling strategy 
Subject receives alternative GA medications or 
therapies in the study eye 
GA lesion size data collected in the study eye after the 
subject initiates alternative GA medications or therapies 
will be censored and imputed assuming no further benefit. 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 Further details on 
data imputation approaches will be presented in the SAP prior to DBL. 
The primary endpoint, change from baseline to Week 72 in GA area, will be estimated among 
treatment groups via least squares means from a mixed model repeated measures analysis 
(MMRM) analysis. Details of the MMRM specifications will be described in the SAP. 
 
 
 
  
 
 
 
 
 
 
 
 




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All AEs (overall, by seriousness, by severity, by relationship), including AESI of special 
interest, recorded throughout the investigation will be reported following classification 
according to the Medical Dictionary for Regulatory Activities (MedDRA). 
Systemic safety evaluations including vital signs, laboratory safety 
 will be 
summarised over time by dose (where applicable) and overall. 
Ocular safety evaluations including ophthalmic examination variables (cataract grading, IOP, 
etc.) and BCVA scores, will be summarised in the same manner as ocular efficacy variables, 
dependant on data type. 
  
 
 
 
  
9.5 
72-Week Readouts 
The analysis based on the Week 72 data will be the primary efficacy analysis for this study. 
The database including all Week 72 data will be locked once all enrolled patients from both 
Stage 1 and Stage 2 have completed the Week 72 visit or terminated the study prior to 
Week 72. Subjects will remain in the study and will continue their scheduled visits and 
assessments through the planned study duration of 96 weeks, to allow for further evaluation of 
efficacy and safety. 
9.6 
Data Monitoring Committee 
A DMC will perform safety reviews of unmasked data as well as an evaluation of clinical 
outcomes, and may recommend stopping a dose, dose adjustment, adjusting the design of the 
study or stopping the clinical study altogether. The DMC will be provided unmasked data by 
an ISC as per DMC Charter to ensure safety of the subjects. Only the DMC and ISC will be 
unmasked to study data during the conduct of the study. 
The DMC is an independent committee that will consist of three or more individuals who 
cumulatively have the clinical, surgical, medical, and statistical expertise to monitor the safety 
of subjects in the clinical study.  
No DMC member will be an Investigator in the study. Full details regarding the DMC mission 
and content, and DMC reviews are detailed in the DMC Charter and in the SAP. 
9.7 
Handling Missing Data 
Missing or censored data will be handled in accordance with the data handling strategy for 
intercurrent events as described in Table 4. The details of the statistical approaches for missing 
and/or censored data imputation will be described in the SAP, and may include additional 
missing data handling rules. 
 
 
 


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10 STUDY MANAGEMENT 
10.1 
Monitoring Procedures 
The Investigator is responsible for the validity of all data collected at the site. The Sponsor is 
responsible for monitoring this data to verify that the rights and wellbeing of subjects are 
protected, that study data are accurate (complete and verifiable to source data), and that the 
study is conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
regulatory requirements. 
Sponsor assigned monitors will conduct regular site visits. The Investigator will allow direct 
access to all relevant files (for all subjects) and clinical study supplies (dispensing and storage 
areas) for the purpose of verifying entries made in the eCRF, and assist with the monitor’s 
activities, if requested. Adequate time and space for monitoring visits should be made available 
by the Investigator. 
The site must complete the eCRFs according to the eCRF Completion Guidelines, on an 
ongoing basis to allow regular review by the study monitor, both remotely via the internet and 
during site visits. The study monitor will use functions of the eCRF to address any queries 
raised while reviewing the data entered by the study site personnel in a timely manner. 
Whenever a subject name is revealed on a document required by the Sponsor (e.g. laboratory 
print-outs) the name must be blacked out permanently by the site personnel, leaving the initials 
visible, and annotated with the subject number as identification. 
10.2 
Recording of Study Data 
In compliance with GCP, the medical records/medical notes, etc., should be clearly marked and 
permit easy identification of a subject’s participation in the specified clinical study. 
The Investigator must record all data relating to protocol procedures, IMP administration, 
laboratory data, safety data, and efficacy ratings on the eCRFs provided for the study. The 
Investigator, by completing the signature log, may formally designate authority to complete 
eCRFs to appropriately qualified staff having certified user access to the eCRF. Subject 
questionnaires will be printed or electronic. 
The Investigator must, as a minimum, provide an electronic signature (e-signature) to each case 
report book to attest to the accuracy and completeness of all the data. If any changes are made 
to the eCRF, after a form has been locked and electronically signed, the Investigator will be 
required to perform an additional e-signature authorising agreement with any new information 
or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change will be 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on each 
item entered. 
10.3 
Source Data Verification  
The study monitor will perform source document verification (SDV) according to the study 
monitoring plan. The study monitor will indicate verification by electronically applying SDV 
flags to the eCRF and will ensure that all required electronic signatures are being implemented 
accordingly. 
 


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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Inspections and Auditing Procedures 
Authorised personnel from external Competent Authorities and Sponsor-authorised Quality 
Assurance personnel may carry out inspections and audits. The purpose of an audit is to 
ensure that ethical, regulatory, and quality requirements are fulfilled in all studies performed 
by the Sponsor. 
Auditors and Inspectors must have direct access to study documents and site facilities, and to 
any other locations used for the purpose of the study in question (e.g. laboratories). 
In the event of the site being notified directly of a regulatory inspection, the Investigator must 
notify the Sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 


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12 DATA HANDLING AND RECORD KEEPING 
12.1 
Data Quality 
The handling of data, including data quality assurance, will comply with regulatory guidelines 
(e.g. ICH and GCP) and the Sponsor’s (or designee) standard operating procedures and working 
instructions. Data management and control processes specific to this study will be described in 
a Data Management Plan. All steps and actions taken regarding data management and quality 
assurance will be documented in a Data Handling Report. Data management will implement 
edit checks on the eCRF to enforce data entry guidelines, data consistency, and compliance to 
the protocol and regulatory requirements. The site Investigator or designee will be responsible 
for entering study data on the eCRFs. Data management will track eCRFs and review them for 
completeness, the presence of mandatory values, consistency, and dated electronic signatures. 
In addition to checking for SDV flags, data management will electronically attach data 
clarification queries directly onto the eCRFs during the review process to ensure data quality. 
Once study centre personnel have provided acceptable responses to the queries and 
implemented the changes on the eCRFs, data management will close the queries with the 
appropriate resolution status. 
At the end of the study, the database will be locked and the data will be released for reporting 
and statistical analysis. 
12.2 
Data Management 
An eCRF will be utilised for collecting subject data. Each site is required to have a computer 
and internet connection available for site entry of clinical data. All entries in the eCRF will be 
done under the electronic signature of the person performing the action. This electronic signature 
consists of an individual and confidential username and password combination. It is declared to be 
the legally binding equivalent of the handwritten signature. Only Sponsor authorised users will 
have access to the eCRF as appropriate to their study responsibilities. Users must have successfully 
undergone software application training prior to entering data into the eCRF. 
Data management will be conducted by a Contract Research Organisation (CRO), directed by the 
Sponsor. All data management procedures will be completed in accordance with the Sponsor and 
the contracted CRO standard operating procedures.  
The Sponsor will ensure that an appropriate eCRF is developed to capture the data accurately, and 
suitable queries are raised to resolve any missing or inconsistent data. The Investigator will receive 
their data, from the clinical study, in an electronic format (PDF files) which will be an exact copy 
of the eCRF, and will include the full audit trail, for archiving purposes and future reference. 
Any queries generated during the data management process will also be tracked by the contracted 
data management CRO/will be raised within the eCRF. It is the central study monitor’s 
responsibility to ensure that all queries are resolved by the relevant parties. 
The Sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the Sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history, and concomitant medication terms will be performed by 
the contracted CRO, and reviewed and approved by the Sponsor. Concomitant medications will 
be coded using World Health Organisation DRUG and AEs/medical history terms will be coded 
using MedDRA. 


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12.3 
Sponsor Discontinuation Criteria 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. 
Should this be necessary, the procedures for an early termination or temporary halt will be 
arranged after consultation with all parties. 
12.4 
Subject and Data Confidentiality 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential. Personally Identifiable Information/Personal Health Information from 
or about a subject will not be collected by the Sponsor. The collection and processing of 
personal data will be limited to those data that are necessary to investigate the efficacy, safety, 
tolerability, quality, and utility of the IMP used in this study, and these data will be subject to 
applicable data privacy protection laws and regulations. 
12.5 
Sample Preparation, Handling and Storage 
All biological samples will be collected by an appropriately trained healthcare professional and 
handled as per the relevant laboratory procedures manual. Sample collection tubes will be 
supplied by the central laboratory and will be labelled with waterproof labels containing 
appropriate study identifiers (e.g. protocol number, subject number, date of sample collection 
and visit number). Once collected, samples will be shipped to the central laboratory for analysis. 
Biological samples will be retained until all required analysis have been completed or a period 
of up to 5 years after completion of the study, whichever is sooner. 
12.6 
Record Archiving and Retention 
During the pre-study and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the Investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product or for as long as necessary to comply 
with applicable legislation. However, these documents should be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the Sponsor. The 
Investigator should take measures to prevent accidental or premature destruction of these 
documents. The final archiving arrangements will be confirmed by the monitor when closing-out 
the site. The Sponsor will inform the Investigator, in writing, as to when these documents no 
longer need to be retained. 
If the Investigator relocates or retires, or otherwise withdraws his/her responsibility for 
maintenance and retention of study documents, the Sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 
The Sponsor is responsible to ensure that the collection and evaluation of data by vendors 
adheres to protocol specifications. Electronic data from the Sponsors contracted vendors will 
be archived by the Sponsor. 
 


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13 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE  
13.1 
Institutional Review Board/Independent Ethics Committee Ethical Conduct of 
the Study 
This study must be conducted in compliance with IECs/IRBs, informed consent regulations, 
the Declaration of Helsinki, ICH GCP Guidelines, and the FDA, 21 CFR Part 11, Electronic 
Records, Electronic Signatures, and FDA, Guidance for Industry: Computerised Systems Used 
in Clinical Trials. 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the Investigator or Institution should have written and dated 
approval/favourable opinion from the IEC or IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided to 
subjects, and a statement from the IEC or IRB that they comply with GCP requirements. The 
IEC or IRB approval must identify the protocol version as well as the documents reviewed. 
After IEC or IRB approval, changes will require a formal amendment. Once the study has 
started, amendments should be made only in exceptional circumstances. Changes that do not 
affect subject safety or data integrity are classified as administrative changes and generally do 
not require ethical approval. If ethically relevant aspects are concerned, the IEC or IRB must 
be informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by the local or site IEC or the IRB. 
13.2 
Subject Information and Consent 
Following consent subjects will undergo screening assessments for HORIZON to determine 
eligibility for inclusion in the study.  
Prior to study entry, the Investigator, or a person designated by the Investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject or impartial 
witness. Sufficient time will be allowed to discuss any questions raised by the subject.  
 
 
 
The Sponsor will provide a sample informed consent form. The final version controlled form 
must be agreed to by the Sponsor and the IEC or IRB, and must contain all elements included 
in the sample form, in language readily understood by the subject. Each subject’s original 
consent form, personally signed and dated by the subject and by the person who conducted the 
informed consent discussion, will be retained by the Investigator. The Investigator will supply 
all enrolled subjects with a copy of their signed informed consent form. 
The informed consent form may need to be revised during the study should important new 
information become available that may be relevant to the safety of the subject or as a result of 
protocol amendments. In this instance approval should always be given by the IEC or IRB. It 
is the Investigator’s responsibility to ensure that all subjects subsequently entered into the study 
and those currently in the study sign the amended form. This is documented in the same way as 
previously described. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 


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The Investigator should, with the consent of the subject, inform the subject’s primary physician 
about their participation in the clinical study. 
Written and/or oral information about the study in a language understandable by the subject 
will be given to all subjects. 
13.3 
Reporting of Significant Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
A significant safety issue or a serious breach is defined as a breach likely to affect, to a 
significant degree, the safety and rights of a subject or the reliability, and robustness of the data 
generated in this clinical study. In the event of a significant safety issue or a serious breach, the 
Sponsor shall inform the Competent Authority and IEC or IRB within 7 days of becoming 
aware of the breach. 


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14 ADMINISTRATION PROCEDURES 
14.1 
Regulatory Approval 
The study will be authorised by the Competent Authority. 
Enrolment of subjects will not start until approval has been received from both the IEC or IRB 
and Competent Authorities. 
The study will be conducted in accordance with the Declaration of Helsinki, GCP and all other 
national requirements. 
14.2 
Publication Policy 
The Sponsor encourages acknowledgement of all individuals/organisations involved in the 
funding or conduct of the study, including Medical Writers or Statisticians subject to the 
consent of each individual and entity concerned, including acknowledgement of the Sponsor. 
The results of this study may be published in line with International Committee of Medical 
Journal Editor guidelines and internal procedures or communicated at scientific meetings. A 
plan for scientific publication and presentation of the results will be developed and implemented 
by the Sponsor. 
The procedures for publications and data presentations are set out in the clinical study 
agreement entered into with the Sponsor (or designee) in connection with this study. 
14.3 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH guideline on structure 
and contents of CSRs. A final CSR will be prepared where any subject has provided written 
informed consent, regardless of whether the study is completed or prematurely terminated. 
Where appropriate an abbreviated report may be prepared. The CSR will be in compliance with 
any applicable regulatory requirements, national laws in force and will be in English. 
14.4 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and the 
Sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
Sponsor and Investigator responsibilities in relation to the study. 
 
 
 
 
 
Financial Disclosure Statements will need to be completed as per local regulatory requirements.  
14.5 
Insurance, Indemnity and Compensation 
 
 
 
 
 
. 


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For covered clinical studies (see 21CFR54), the Investigator will provide the Sponsor with 
financial information as per local regulatory requirements. Each Investigator will notify the 
Sponsor of any relevant changes during the conduct of the study and for 1 year after the study 
has been completed.  


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15 PROTOCOL AMENDMENTS 
15.1 
Protocol Amendments and Protocol Deviations 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favourable opinion of a written amendment by the IEC or IRB and Competent 
Authority, except when necessary to eliminate immediate safety concerns to the subjects or 
when the change involves only logistics or administration. The Investigator and the Sponsor 
will sign the protocol amendment. 
In the event that an amendment to this protocol is required, it will be classified into one of the 
following three categories: 
• Administrational changes are those that are not considered ‘substantial’ (e.g. 
administrative changes) and as such are not required to be notified to the IECs/IRBs or 
Competent Authorities but are contained in the protocol under a subsequent notification 
of a substantial amendment 
• Substantial amendments are those considered ‘substantial’ to the conduct of the 
clinical study where they are likely to have a significant impact on: 
- 
the safety or physical or mental integrity of the subjects 
- 
the scientific value of the study 
- 
the conduct or management of the study, or the quality or safety of the IMP used in 
the study 
Substantial amendments must be notified to the IEC or IRBs and Competent Authorities. Prior 
to implementation, documented approval must be received from the IEC or IRB. 
• Urgent amendments are those that require urgent safety measures to protect the study 
subjects from immediate hazard and as such may be implemented immediately by the 
Sponsor with subsequent IEC/IRB and Competent Authority notification, forthwith 
15.2 
Protocol Deviations and Exceptions 
A protocol deviation is non-adherence to protocol specific study procedures or schedules or the 
requirements of ICH-GCP that have been identified retrospectively. Protocol deviations are not 
acceptable from a regulatory perspective and any deviation not supported by an amendment 
will be considered a potential breach of GCP. Deviations from the protocol should only occur 
when necessary to eliminate immediate hazards to the subjects. 
Protocol deviations will be identified and recorded by investigative site personnel on the eCRF 
and by the study monitor in the Monitoring Visit Reports and/or electronic data capture. 
Protocol deviations must be reported to Competent Authorities and IRB or IEC as per local or 
national guidelines. 
As a matter of policy, the Sponsor will not grant exceptions to protocol specific entry criteria 
to allow subjects to enter a study. If such an action is considered ethically, medically, and 
scientifically justified for a particular subject, prior approval from the Sponsor and the 
responsible IEC or IRB, in accordance with the standard operating procedure, is required before 
the subject will be allowed to enter the study. If investigative site personnel learn that a subject 
who did not meet protocol eligibility criteria was entered in a study, they must immediately 
inform the Sponsor. 


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16 REFERENCES 
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Anderson DH, et al. The pivotal role of the complement system in aging and age-related 
macular degeneration: Hypothesis re-visited. Prog Ret Eye Res 2010;29:95–112. 
Botquin V, et al. Adeno-associated virus type 2 interferes with early development of mouse 
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Chakravarthy U, et al. Clinical risk factors for age-related macular degeneration: a systematic 
review and meta-analysis. BMC Ophthalmol 2010;10:31. 
Chang S, LXII Edward Jackson Lecture: Open angle glaucoma after vitrectomy: Am J 
Ophthalmol 2006;141:1033–1043. 
Cipriani V, et al. Increased circulating levels of factor h-related protein 4 are strongly associated 
with age-related macular degeneration. Nat Commun 2020;11:778.  
Chew E, et al. Evaluation of the Age-Related Eye Disease Study Clinical Lens Grading System 
AREDS Report No. 31. Ophthalmol 2010; 117: 2112–2119. 
Clark SJ, et al. Tissue-specific host recognition by complement factor H is mediated by 
differential activities of its glycosaminoglycan-binding regions. J Immunol 2013;190:2049–
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Couto L, et al. Direct exposure of mouse spermatozoa to very high concentrations of a serotype-
2 adeno-associated virus gene therapy vector fails to lead to germ cell transduction. Hum Gene 
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Feng H, et al. Cataract formation following vitreoretinal procedures. Clin Ophthalmol 
2014;8:1957–1965. 
Ferris FL, et al. Clinical classification of age-related macular degeneration. Ophthalmol 2013; 
120:844–851. 
Fritsche LG, et al. Seven new loci associated with age-related macular degeneration. Nat Genet 
2013;45:433–439.  
Fritsche LG, et al. A large genome-wide association study of age-related macular degeneration 
highlights contributions of rare and common variants. Nat Genet 2016;48:134–43. 
Geerlings MJ, et al. The complement system in age-related macular degeneration: A review of 
rare genetic variants and implications for personalized treatment. Mol Immunol 2017;84:65–76. 
Ginn SL, et al. Gene therapy clinical trials worldwide to 2017: An update. J Gene Med 2018;20. 
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Gleeson PJ, et al. Chromosomal rearrangement—A rare cause of complement factor I 
associated atypical haemolytic uraemic syndrome. Immunobiology 2016;221:1124–1130. 
Gyroscope Therapeutics. Data on file.  
Harris CL, et al. The complotype: dictating risk for inflammation and infection. Trends 
Immunol. 2012;33:513–21. 
Holz FG, et al. Efficacy and safety of lampalizumab for geographic atrophy due to age-related 
macular degeneration: Chroma and spectri Phase 3 randomized clinical trials. JAMA 
Ophthalmol 2018;136:666–677.  
Jonasson F, et al. Five-year incidence, progression and risk factors for age-related macular 
degeneration: The age, gene/environment susceptibility study. Ophthalmol 2014;121:1766–
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Kavanagh D, et al. Rare genetic variants in the CFI gene are associated with advanced age-
related macular degeneration and commonly result in reduced serum factor I levels. Hum Mol 
Genet 2015;24:3861–3870. 
Kersey J, et al. Corticosteroid-induced glaucoma: a review of the literature. Eye 2006;20:407–
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Lachmann PJ, et al. Further studies of the down-regulation by Factor I of the C3b feedback 
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Laine M, et al. Y402H polymorphism of complement factor H affects binding affinity to c-
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Mandava NK, et al. Plasma and vitreous complement levels in humans with proliferative 
diabetic retinopathy. The Association for Research in Vision and Ophthalmology; Apr–May, 
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MacLaren RE, et al. Retinal gene therapy in patients with choroideremia: Initial findings from 
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Orozco LD, et al. Integration of eQTL and a single-cell atlas in the human eye identifies causal 
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Provost N, et al. Biodistribution of rAAV vectors following intraocular administration: 
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Saksens NTM, et al. Rare genetic variants associated with development of age-related macular 
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Seddon JM, et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced 
age-related macular degeneration. Nat Genet 2013;45:1366–1370. 
Sun BB, et al. Genomic atlas of the human plasma proteome. Nature 2018;558:73–79. 
Wang J, et al. Altered function of factor I caused by amyloid ß: Implication for pathogenesis of 
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Wykoff C, Treatment of Geographic Atrophy Secondary to Age-Related Macular Degeneration 
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American Association of Ophathalmology; 12-15 November 2021, Ernest N. Morial 
Convention Center, New Orleans, LA, USA. 
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17 APPENDICES 
17.1 
Age-Related Eye Disease Study Clinical Lens Grading System 
Overview 
The age-related eye disease study (AREDS) developed the Clinical Lens Grading System for 
grading the presence and severity of nuclear, cortical and posterior subcapsular (PSC) lens 
opacities (the three main types of age-related cataract) in a clinical setting. The system was 
designed to require minimal examiner training for persons already proficient in the use of the 
slit lamp. 
General Instructions 
Dilation – Pupils should be dilated to at least 5mm. 
Grading of opacities – the lenses are examined at the slit lamp with 10× magnification for the 
presence and severity of the types of lens opacity: Nuclear, cortical and posterior subcapsular. 
For each type of opacity the examined lens will be compared to a series of three reference 
standard photographs combined onto one print. The severity of opacity witnessed of the lens 
being assessed will be determined to equal the opacity on one of the three reference photographs 
or have an opacity which falls in between two of the reference standard photographs.  
Grading of Nuclear sclerosis  
Nuclear Landmarks - In the normal or non-sclerotic lens, the “nucleus” consists of a central 
dark interval (sulcus), adjacent bean-shaped brighter areas (lentils—one anterior and one 
posterior to the sulcus), and brighter curved bands (lamellae, or nuclear surface bands) anterior 
and posterior to the lentils and separated from them by narrow dark bands.-Although nuclear 
sclerosis standard 1 shows signs of moderate opalescence, many of these features are visible. 
For grading the severity of nuclear sclerosis two factors are considered:  
I. 
The optical density of the nuclear landmarks, especially the sulcus 
II. 
The definition of these structures (contrast between light and dark bands) 
Optical density is given greater weight. In the early stages of nuclear sclerosis, increased optical 
density is noticeable only in the normally dark bands, particularly the sulcus, but in advanced 
stages the density of all bands becomes greater. With increasing nuclear sclerosis, the definition 
of nuclear landmarks decreases, and finally disappears. For grading nuclear status the primary 
consideration is the degree of reflectance (sometimes termed “opalescence”) of the sulcus, with 
secondary consideration given to the definition of the nuclear features, i.e. contrast of the dark 
and bright bands. 
Nuclear standard photographs - Three standard photographs with increasing amounts of nuclear 
opalescence are used for grading. 
In nuclear standard 1 the density of the sulcus has increased so that only a suggestion of the 
sulcus can be detected. Towards the upper and lower ends of the sulcus, segments of what 
appears to be the equator of the fetal nucleus (or a zone just beneath its surface) are visible as 
steeply curved white lines. Only a small part of the anterior lentil is visible. The posterior 
nuclear surface band cannot be seen at all and the anterior one is very faint. 


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In nuclear standard 2, the sulcus has become so dense that only a faint shadow marks its location 
at the center of the lens, and the entire nucleus has become dense enough that lentils and 
lamellae are not distinguishable. 
Nuclear standard 3 shows a further increase in nuclear density, to the point that neither the 
sulcus nor other features are distinguishable. 
Slit lamp settings - Grading of nuclear opalescence is done with the illuminating beam of the 
slit lamp angled at 45° to the viewing axis, the slit beam width set at 0.3mm and the slit beam 
height set at 9mm. 
Codes for nuclear grading –  
I. 
None (grade 0) 
II. 
Mild (grade 1) 
III. 
Moderate (grade 2) 
IV. 
Severe (grade 3) 
Grading of Cortical Opacities 
Grading of cortical opacities is done at the slit lamp using a red reflex image. The slit beam 
height and width are set by the assessor according to their usual practice as long as 
retroillumination is obtained. The position may be changed as needed so that all areas of the 
lens can be viewed against the red reflex. With retroillumination cortical opacities appear darker 
than the adjacent red reflex. 
An area is considered involved by opacity if it is definitely more opaque than adjacent 
uninvolved areas. Opacities not seen against the red reflex are not counted. For comparison 
with the standard photographs, all areas of opacity are mentally rearranged into a contiguous 
mass and the total area of involvement is compared with the standard photographs. Vacuoles 
(small round cyst-like features) are not considered to be part of cortical opacity unless they are 
organised, e.g., part of a linear formation. When determining the extent of involvement, sizable 
clear areas bounded by opacity are subtracted from the total. Areas occupied by posterior 
cortical opacities that are not overlapped by anterior cortical opacities are added to obtain the 
total area of involvement. The density of opacity is not taken into account. Cortical and PSC 
opacities are differentiated from each other mainly by location, and secondarily by 
configuration. 
Cortical standard photographs - Cortical opacities typically are wedge-shaped and radially 
oriented, extending from the periphery toward the center. Their appearance varies from dense 
opacity to diffuse collections of dots separated by clear areas. 
Three standards with increasing amounts of cortical opacity are used for grading cortical 
opacities. In each standard the dashed white line defines the margins of the opacities. 
In cortical opacity standard 1, three small spokes project in from the periphery between 5 and 
7 o'clock, with a clear space between the spokes at 5:00 and 5:45. 
In standard 2, a pie-shaped wedge extends from 3 to 6 o'clock, with a separate small spoke at 
2:30. 


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standard 3 shows a semi-circle of cortical opacity extending from 3:30 to 9:30, with a dense 
spoke projecting from it centrally, and a group of vacuoles near the 3:30 margin (included as 
opacity because they are organised). 
Codes for cortical grading - Grading of cortical opacities is done by comparing the proportion 
of pupillary involvement with cortical opacities in the lens to be graded and the proportion of 
involvement in the standard photographs. Only opacities seen against the red reflex image are 
counted. 
Cortical percent involvement of the entire visible lens:  
I. 
0-10% (grade 0) 
II. 
10-25% (grade 1) 
III. 
25-50% (grade 2) 
IV. 
>50% (grade 3) 
Grading of Posterior Subcapsular Opacities: 
Grading rules are similar to those for cortical opacities except that the red reflex image is 
focused at the plane of the posterior capsule. In this position the pupillary margin should be 
blurred. PSC opacities are considered to be present only when an area is definitely more opaque 
than adjacent areas as seen against the red reflex. For comparison with the standard 
photographs, all areas of PSC opacity are mentally rearranged into a contiguous mass and the 
total area of involvement is compared with the standard photographs. Mittendorf dots are 
disregarded. The density of PSC opacities is not taken into account. 
PSC opacities are seen just beneath the posterior lens capsule. Frequently they are centred near 
the posterior pole of the lens. Although they usually appear as a lacy configuration which may 
contain vacuoles (any such are considered part of PSC), they may range from a darkly opaque 
network to a barely discernible diffuse haze. Because PSC opacities are fairly compact with 
few clear areas, small spaces within PSC are not subtracted from the estimate of extent. 
Three standard photographs with increasing amounts of PSC opacity are used for grading PSC 
opacities. In each standard the dashed white line defines the margins of the opacities. 
In PSC standard photograph 1, a roundish opacity is located just left of centre in the photograph. 
In PSC standard 2 a larger opacity, also left of centre, includes vacuoles around nearly half of 
its perimeter. Within its margins of the density of the involved area is uneven, but the entire 
region is considered opacified. 
PSC standard 3 shows a roundish opacity that is even larger and involves the centre of the lens. 
(An array of cortical spokes, located peripherally between 6:30 and 10:00 and rather unfocused, 
is not considered part of PSC.) 
PSC grading is done by comparing the size of the PSC opacity in the lens to be graded with the 
size of the PSC opacity in the standard photographs. Only opacities seen against the red reflex 
image are counted. 
PSC percent pupillary involvement of the 5mm diameter central circle of the lens: 
I. 
0-2% (grade 0) 
II. 
2-20% (grade 1) 


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III. 
20-50% (grade 2) 
IV. 
>50% grade 3) 
Reference Photographs taken from: [Chew 2010] 
 
 


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17.2 
Reading performance (MNRead) 


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17.3 
Visual Function Questionnaire (VFQ-25) 
Visual Function Questionnaire (VFQ-25) developed at RAND under the sponsorship of the 
National Eye Institute. 
 


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17.4 Vitreous Haze Grading Scale 
 
 
 


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SAP_001.pdf: 
Clinical Development 
CPPY988A1 
CPPY988A12201 (GT005-03) / NCT04566445
HORIZON: A Phase II, Open-Label, Outcomes-Assessor Masked, 
Multicenter, Randomized, Controlled Study to Evaluate the Safety 
and Efficacy of Two Doses of GT005 Administered as A Single 
Subretinal Injection in Subjects With Geographic Atrophy 
Secondary to Dry Age-Related Macular Degeneration 
Statistical Analysis Plan (SAP)  
Document type: 
SAP Documentation 
Document status: 
Amendment 3 
Release date: 
13-Jun-2024
Number of pages: 
34 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
13-
July-
2023 
Prior 
to 
DB 
lock 
Creation of 
final 
version 
N/A - First version 
NA 
08-
Jan-
2024 
Prior 
to 
DB 
Lock 
Creation of 
Amendment 
1 
Added Week 48 analysis and moved the 
Week 72 analysis (primary objective) to 
the final analysis 
Section 1 
Section 2.13 
 
 
 
Revised the definition of estimand 
Section 1.2.1 
Section 2.5 
 
 
 
Updated the calculation of Study Day  
Section 2.1.1 
 
 
 
Removed the SAF 
Section 2.2 
 
 
 
Updated the analysis set used for patient 
disposition, demographics and other 
baseline characteristics  
Section 2.3 
 
 
 
Revised the analysis scope for prior, 
concomitant and post therapies  
Section 2.4.2 
 
 
 
Removed sensitivity and supplementary 
analyses for the primary objective  
Section 2.5 
 
 
 
Removed AEs by primary SOC, PT and 
maximum severity  
Section 2.7.1 
 
 
 
Added detailed information for PROs 
Section 2.10 
 
 
 
 
 
 
 
 
 
Added the analyses scope for Week 48  
Section 2.13 
 
 
 
Revised the imputation rule  
Section 5.1 
 
 
 
Removed the analysis part for multiple 
imputation 
Section 5.4 


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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
 


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Table of contents 
Table of contents ..................................................................................................................................... 4 
List of abbreviations ............................................................................................................................... 6 
1 
Introduction ............................................................................................................................................. 7 
1.1 
Study design .............................................................................................................................. 7 
1.2 
Study objectives, endpoints and estimands ............................................................................... 9 
1.2.1 
Primary estimand(s) .............................................................................................. 11 
2 
Statistical methods ................................................................................................................................ 11 
2.1 
Data analysis general information ........................................................................................... 11 
2.1.1 
General definitions ............................................................................................... 12 
2.2 
Analysis sets ............................................................................................................................ 13 
 
 13 
2.3 
Subject disposition, demographics and other baseline characteristics .................................... 14 
2.3.1 
Subject disposition ................................................................................................ 14 
2.3.2 
Demographics and other baseline characteristics ................................................. 14 
2.3.3 
Medical history ..................................................................................................... 15 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, compliance) ........... 15 
2.4.1 
Study treatment ..................................................................................................... 15 
2.4.2 
Prior, concomitant and post therapies ................................................................... 16 
2.5 
Analysis supporting primary objective(s) ................................................................................ 16 
2.5.1 
Primary endpoint(s) .............................................................................................. 16 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................................... 16 
2.5.3 
Handling of intercurrent events ............................................................................ 17 
2.5.4 
Handling of missing values not related to intercurrent event ............................... 17 
2.5.5 
Sensitivity analyses ............................................................................................... 17 
2.5.6 
Supplementary analyses ....................................................................................... 17 
2.6 
Analysis supporting secondary objectives ............................................................................... 17 
2.6.1 
Secondary endpoint(s) .......................................................................................... 18 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................................... 18 
2.6.3 
Handling of missing values/censoring/discontinuations ....................................... 19 
2.7 
Safety analyses ........................................................................................................................ 19 
2.7.1 
Adverse events (AEs) ........................................................................................... 20 
2.7.2 
Deaths ................................................................................................................... 21 
2.7.3 
Loss in best corrected visual acuity ...................................................................... 21 
2.7.4 
Laboratory data ..................................................................................................... 22 
2.7.5 
Other safety data ................................................................................................... 22 
2.8 
Pharmacokinetic endpoints ...................................................................................................... 23 
2.9 
PD and PK/PD analyses .......................................................................................................... 23 
2.10 
Patient-reported outcomes ....................................................................................................... 23 


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 25 
 
 25 
2.13 
Data analysis at Week 48 ........................................................................................................ 27 
3 
Sample size calculation ......................................................................................................................... 28 
4 
Change to protocol specified analyses .................................................................................................. 28 
5 
Appendix ............................................................................................................................................... 29 
5.1 
Imputation rules ....................................................................................................................... 29 
5.1.1 
AE date imputation ............................................................................................... 29 
5.1.2 
Concomitant medication date imputation ............................................................. 31 
5.2 
AEs coding/grading ................................................................................................................. 33 
5.3 
Laboratory parameters derivations .......................................................................................... 33 
5.4 
Statistical models ..................................................................................................................... 33 
5.4.1 
Analysis supporting primary objective(s) ............................................................. 33 
5.5 
Rule of exclusion criteria of analysis sets ............................................................................... 33 
6 
References ............................................................................................................................................. 34 
 


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List of abbreviations 
 
 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AMD 
Age-related Macular Degeneration 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
 
 
 
 
CFI 
Complement factor I 
CFP 
Color Fundus Photography 
CI 
Confidence Interval 
CIR 
Copy Increment from Reference 
CRO 
Contract Research Organization 
CSFT 
Central Sub Field Thickness 
CSR 
Clinical Study Report  
DBL 
Database Lock 
ETDRS 
Early Treatment for Diabetic Retinopathy 
FAF 
Fundus autofluorescence 
FAS 
Full Analysis Set  
FIR 
Fist Interpretable Results 
FRI 
Functional Reading Independence 
GA 
Geographic atrophy 
IOP 
Intraocular Pressure 
LLD 
Low Luminance Difference 
LLVA 
Low-luminance Visual Acuity 
LSM 
Least-Squares Mean 
MAR 
Missing at Random 
 
  
MMRM 
mixed model repeated measures 
MNRead 
Minnesota low-vision Reading test 
OCT 
Optical Coherence Tomography 
PD 
Protocol Deviation 
PT 
Preferred Term  
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error  
SOC 
System Organ Class 
 
 
TEAE 
treatment-emergent Adverse Event 
VFQ-25 
Visual Function Questionnaire-25 
WHO 
World Health Organization 


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1 
Introduction 
The HORIZON study (CPPY988A12201) is being terminated early as Novartis has made the 
decision to stop the current clinical development program for GT005 in subjects with 
geographic atrophy (GA) based on the results from the futility interim analysis. All GT005-
treated subjects will be transferred into the long-term safety follow-up study, ORACLE 
(CPPY988A12203B).  
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analyses planned in/changed from the study protocol, and to provide detailed 
statistical methods that will be used for the HORIZON Clinical Study Report (CSR).  
The analyses will be conducted at three time points as described below: 
• The interim analysis for futility will be performed when approximately 60% of subjects 
have GA data available at Week 48 
• The Week 48 analysis will be conducted when all enrolled subjects from both Stage 1 
and Stage 2 complete (or discontinue prior to) the Week 48 Visit  
• The final analysis will be conducted once all enrolled subjects complete (or discontinue 
prior to) the Week 96 visit and final Database Lock (DBL) is achieved 
Details for the futility analysis will be described in a separate Data Monitoring Committee SAP. 
For the Week 48 analysis and the final analysis, data will be analyzed according to the data 
analysis plan described in this document that will be incorporated into the CSR. 
A First Interpretable Results (FIR) document will be provided for the Week 48 analysis to 
document the corresponding analysis results based on the available data at the time of the 
analysis. 
This SAP is based on the HORIZON Clinical Study Protocol V5.0, dated 15 September 2022. 
1.1 
Study design 
This is a Phase II, open-label, outcomes-assessor masked, untreated-control, multicenter, 
randomized controlled study to evaluate the safety and efficacy of two doses of GT005 
administered as a single-time subretinal injection in subjects with geographic atrophy (GA) 
secondary to dry age-related macular degeneration (AMD).  
Approximately 250 subjects are planned to be randomized to one of two doses of GT005 or the 
untreated control group (2:1). Subjects who are screened, but not randomized, will be classed 
as Screen Failures and will be replaced. 
Subjects entered the study must have genotyping and serum Complement factor I (CFI) 
evaluation performed by a Sponsor-approved laboratory, either through participation in another 
Gyroscope sponsored study or during the HORIZON screening period. Data from subjects 
screened in another Gyroscope sponsored study at the same investigative site as HORIZON 
may be used to fulfill the screening and eligibility requirements for this study. This is only 
permissible if the screening data is collected within the screening period specified in the clinical 
protocol. Following consent, subjects will undergo ophthalmic and clinical assessments to 






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Secondary objective(s)  
Endpoint(s) for secondary objective(s) 
• To evaluate the effect of GT005 on 
the progression of GA in subjects 
with GA due to AMD 
 
• The change from baseline through Week 96 in 
GA area as measured by FAF   
• To evaluate the safety and tolerability 
of GT005  
 
• Frequency of treatment emergent adverse event 
(TEAE) through Week 96   
• To evaluate the effect of GT005 on 
retinal anatomical measures 
 
• Change in retinal morphology on multimodal 
imaging through Week 96   
• To evaluate the effect of GT005 on 
functional measures  
• Change in best corrected visual acuity (BCVA) 
Score via the early treatment for diabetic 
retinopathy (ETDRS) chart through Week 96  
• Change in low luminance difference (LLD) via 
the ETDRS chart through Week 96 
 
• To evaluate the effect of GT005 on 
visual function  
• Change in reading performance as assessed by 
Minnesota low-vision reading test (MNRead) 
chart through Week 96  
• Change in functional reading independence 
(FRI) index through Week 96 
 
• To evaluate the effect of GT005 on 
patient-reported outcomes  
• Change in quality of life measured on the visual 
function questionnaire-25 (VFQ-25) through 
Week 96  




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Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. These summary 
statistics will be presented by treatment group unless otherwise specified. Where appropriate, 
point estimates and confidence intervals (CI) of treatment differences will be provided. 
2.1.1 
General definitions  
2.1.1.1 
Study treatment  
The following treatment groups will be presented: 
• Untreated control  
• Medium dose GT005 (
 vg) 
• High dose GT005 (
 vg) 
2.1.1.2 
Baseline and post-Baseline 
Baseline (Day 1) is defined as 
• the day following randomization for subjects randomized to untreated control 
• the day of successfully receiving GT005 administration for subjects randomized to 
GT005 
• or the latest surgery date for subjects who were randomized to GT005 but failed to 
receive GT005 administration on the first attempt to surgery  
The baseline value for efficacy and safety variables is the last available value (scheduled or 
unscheduled) collected prior to the date of Baseline, or on the date of Baseline but prior to the 
time of GT005 administration for GT005 treatment groups.  
All data collected after the date of Baseline are defined as post-baseline. The study day for a 
baseline or post-baseline scheduled or unscheduled visit is defined as: 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑑𝑑𝑑𝑑𝑑𝑑= ൜
(Date of visit) – (Date of randomization) 
Untreated
(Date of visit) – (Date of treatment administration) +  1
GT005  
The study day for a scheduled or unscheduled visit before baseline is defined as 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑑𝑑𝑑𝑑𝑑𝑑= ൜
(Date of visit)– (Date of randomization) − 1
Untreated
(Date of visit) – (Date of treatment administration)
GT005  
2.1.1.3 
End of study mapping 
The end of study date is the date when a subject completes or discontinues the study. For 
reporting data by visit in outputs, the end of study visit will be allocated to the actual (reported) 
visit number. If the end of study date is not on a scheduled visit, then the end of study visit will 
be allocated, based on study day, to the closest future scheduled study visit. 






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statistics or number and percentage of subjects as appropriate by treatment group and in total 
for the FAS. 
Baseline ocular characteristics for the study eye will be summarized by treatment group and in 
total for the FAS. Ocular baseline characteristics include: 
• Study eye selection (left eye OS or right eye OD) 
• Best corrected visual acuity BCVA (in ETDRS letters)  
• Low-luminance visual acuity (LLVA) (in ETDRS letters) 
• Low luminance deficit (LLD) (BCVA - LLVA in ETDRS letters) 
• GA lesion area (mm2) as assessed by FAF  
• GA contour (Unifocal, Multifocal, Cannot Grade) as assessed by FAF 
• GA foveal involvement (Foveal, Non-foveal, Cannot Grade) as assessed by FAF and 
optical coherence tomography (OCT) 
• Junctional zone pattern (Atypical, Banded, Diffuse, Focal, Cannot Grade) as assessed 
by FAF 
• Presence of hard drusen (Yes, No, Cannot Grade) as assessed by color fundus 
photography (CFP) 
• Presence of soft drusen (Yes, No, Cannot Grade) as assessed by CFP 
• Presence of calcified drusen (Yes, No, Cannot Grade) as assessed by CFP 
• Presence of cuticular drusen (Yes, No, Cannot Grade) as assessed by CFP 
• Presence of subretinal hemorrhage (Yes, No, Cannot Grade) as assessed by CFP 
• Presence of intraretinal hemorrhage (Yes, No, Cannot Grade) as assessed by CFP 
• Presence of reticular pseudodrusen (Yes, No, Cannot Grade) as assessed by OCT 
• Central subfield thickness (CSFT) (µm) as assessed by OCT 
• Years since GA diagnosis 
2.3.3 
Medical history 
Medical histories/current medical conditions will be listed by treatment arm, including the 
reported term/PT/SOC, laterality if applicable, start/end date, ongoing status (Yes, No) 
indicating whether the event is ongoing by the time of analysis, etc. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment  
The FAS will be used for the analyses below.  
GT005 is administered as a single-time subretinal injection into the study eye of subjects 
randomized to one of the two GT005 doses. The surgical procedure for subretinal administration 


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of GT005 is based on a standardized methodology. It is conducted by an appropriately qualified 
Vitreoretinal Surgeon in an operating room under appropriate anesthesia. Subjects allocated to 
the untreated control will not receive any treatment. 
Study treatment will be summarized by the number and percentage of subjects randomized, 
subjects underwent study surgery, subjects treated with GT005, subjects who did not complete 
the study surgery successfully (including the primary reason for preventing successful 
completion of surgery, related/unrelated to the surgery procedure). The number and percentage 
of subjects discontinued study prior to surgery (including the primary reason for discontinuation) 
will also be provided. 
2.4.2 
Prior, concomitant and post therapies 
Prior medications are defined as drugs taken and stopped prior to the date of randomization. 
Any medication given at least once between the date of randomization and the last study visit 
will be a concomitant medication, including those that were started pre-randomization and 
continued after randomization. Prior or concomitant medication will be identified based on 
recorded or imputed start and end dates of taking the medication. 
Prior and concomitant medications will be coded according to the WHO Drug Reference List 
dictionary with Anatomical Therapeutic Classification (ACT) class and preferred term (PT). 
Concurrent procedures will be summarized by treatment group and in total for ocular (study 
eye and fellow eye) and non-ocular events, presented with the number and percentage of 
patients by System Organ Class (SOC) and PT.  
Prior medications and concomitant medications will be listed by treatment arm, including the 
reported name of medication/standardized medication name, indication, route of administration, 
laterality if applicable, start/end date, etc. 
2.5 
Analysis supporting primary objective(s) 
The primary objective of this study is to demonstrate the effect of GT005 vs untreated control 
on the progression of GA in subjects with GA due to AMD. This will be evaluated by measuring 
the GA area over time using FAF. 
2.5.1 
Primary endpoint(s) 
The primary endpoint is the change from baseline to Week 72 in GA area as measured by FAF.  
2.5.2 
Statistical hypothesis, model, and method of analysis  
The primary endpoint will be estimated among treatment groups via least-squares means from 
a mixed model repeated measures (MMRM) analysis with missing at random assumption. The 
model will include the change from baseline in GA area measured by FAF as the dependent 
variable, baseline GA area as the covariate, assessment visit, treatment group, two interaction 
terms (assessment visit and treatment group, assessment visit and baseline GA area) as the fixed 
effect and subject as a random effect.  


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An unstructured within subject correlation structure will be used for the covariance matrix. If 
the unstructured covariance matrix results in a lack of convergence then other covariance 
structures will be investigated. Toeplitz, First Order Autoregressive AR(1), and Compound 
Symmetry will be applied, in the specified order, until the model converges. 
The estimated least-squares mean (LSM) for the change in GA area, and treatment difference 
of each GT005 dose against untreated control, as well as the corresponding 90% confidence 
interval, will be summarized by visit and treatment group. A line plot for the estimated LSM 
with 90% CI by visit and treatment group will also be provided.  
2.5.3 
Handling of intercurrent events  
The underlying question for the primary estimand is: what is the effect attributable to different 
doses of GT005 on GA change on FAF at Week 72 in subjects who have not received alternative 
GA medications or therapies in the study eye. 
For this estimand, data following the below intercurrent event will be dealt with in the following 
specific way: 
• Subject receives alternative GA medications or therapies in the study eye: GA lesion 
size data collected in the study eye after the subject initiates alternative GA medications 
or therapies will be censored and imputed assuming missing at random. 
2.5.4 
Handling of missing values not related to intercurrent event 
For missing data not related to the defined intercurrent event, the estimand based on an MAR 
approach will be considered specifically for each treatment arm the subjects are assigned.  
2.5.5 
Sensitivity analyses  
Not applicable. 
2.5.6 
Supplementary analyses 
Not applicable. 
2.6 
Analysis supporting secondary objectives  
There are six secondary objectives: 
1. Evaluate the effect of GT005 on the progression of GA in subjects with GA due to AMD 
2. Evaluate the safety and tolerability of GT005  
3. Evaluate the effect of GT005 on retinal anatomical measures  
4. Evaluate the effect of GT005 on functional measures: BCVA and LLD 
5. Evaluate the effect of GT005 on visual function: MNRead and FRI  
6. Evaluate the effect of GT005 on patient-reported outcomes  


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2.6.1 
Secondary endpoint(s) 
The corresponding secondary endpoints are: 
1. Change from baseline through Week 96 in GA area as measured by FAF   
2. Frequency of TEAE through Week 96   
3. Change in retinal morphology on multimodal imaging through Week 96   
4.a Change in BCVA ETDRS letters through Week 96  
4.b Change in LLD in ETDRS letters through Week 96 
5.a Change in reading performance as assessed by MNRead chart through Week 96  
5.b Change in FRI index through Week 96   
6. Change in quality of life measured byVFQ-25 through Week 96  
2.6.2 
Statistical hypothesis, model, and method of analysis 
1. Change from baseline through Week 96 in GA area as measured by FAF   
• MMRM as described in Section 2.5.2 will be applied to the change from baseline 
through Week 96 in GA area, with intercurrent event and missing data handled in the 
same way as for the primary estimand (Sections 2.5.3, 2.5.4).  
The estimated least-squares mean (LSM) for the change in GA area, and treatment 
difference against untreated control, as well as the corresponding 90% confidence 
interval, will be summarized by visit and treatment group. A line plot for the 
estimated LSM with 90% CI by visit and treatment group will also be provided.  
2. Frequency of TEAE through Week 96   
• Summary tables for adverse events of special interest (AESI) will be provided as 
described in Section 2.7.1.1. 
• Summary tables for treatment-emergent serious AE (TESAE) will be presented as 
described in Section 2.7.1. 
• Subjects who did not receive treatment due to surgical procedure related AEs will be 
listed separately by treatment group. 
3. Change in retinal morphology on multimodal imaging through Week 96   
• The presence of the following retinal morphology will be summarized based on 
observed data by visit for the number and percentage of subjects in reported 
categories: 
i. 
Junctional zone of GA (Increased FAF, Normal FAF, Not Applicable, 
Cannot Grade) assessed by FAF. 
ii. Junctional zone patterns (Atypical, Banded, Diffuse, Focal, Cannot Grade) 
assessed by FAF. 


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4.a Change in BCVA in ETDRS letters through Week 96  
• Change in BCVA through Week 96 will be estimated among treatment groups via 
least-squares means from MMRM Model. The model will include the change from 
baseline in BCVA measured by ETDRS as the dependent variable, BCVA at the 
baseline as the covariate, assessment visit, treatment group, two interaction terms 
(assessment visit and treatment group, assessment visit and BCVA at the baseline) 
as the fixed effect and participant as a random effect. The estimated LSM for the 
change in BCVA, and treatment difference against untreated control, as well as the 
corresponding 90% confidence interval, will be summarized by visit and treatment 
group. A line plot for the estimated LSM with 90% CI by visit and treatment group 
will also be provided. All BCVA assessments will be listed by treatment group, site, 
and subject.  
4.b Change in LLD in ETDRS letters through Week 96 
• The LLD and the changes from baseline will be summarized based on observed data 
by assessment visit and treatment group.  
5.a Change in reading performance as assessed by MNRead chart through Week 96  
• The Maximum reading speed (MRS) for each eye as assessed by MNRead Chart and 
change from baseline will be summarized based on observed data by visit and 
treatment group. Reading speed (words per minute) will be computed for each of the 
19 sentences read using the following formula: 
60 × 𝑚𝑚𝑚𝑚𝑚𝑚(0,10 −𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒) 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑖𝑖𝑖𝑖 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
⁄
 
The mean of three higher reading speeds will be reported as the maximum reading 
speed.  
5.b Change in FRI index through Week 96   
• The FRI index and the changes from baseline will be calculated and summarized 
based on observed data by assessment visits and treatment group. 
6. Change in quality of life measured byVFQ-25 through Week 96  
• The VFQ-25 sub-scales and composite scores and the changes from baseline will be 
calculated and summarized based on observed data by assessment visits and 
treatment group. 
2.6.3 
Handling of missing values/censoring/discontinuations 
Missing data handling of secondary endpoints are specified in Section 2.6.2. 
2.7 
Safety analyses 
For all safety analyses, the FAS will be used. All listings and tables will be presented by the 
treatment group. 


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2.7.1 
Adverse events (AEs) 
Only AEs that occurred during the study period (from the date of randomization to the end of 
study) will be summarized. AEs recorded after screening but before the date of randomization 
will be listed only.   
Treatment-emergent Adverse Event (TEAE): An adverse event is considered treatment 
emergent if the start date/time of the event is on or after the date of randomization, irrespective of 
the treatment arm. The primary summaries of AEs will be based on TEAEs.  
The number and percentage of subjects with AEs will be summarized separately for ocular 
(study eye and fellow eye) and non-ocular events by treatment group in the following ways 
unless otherwise specified: 
• Overall summary of death, subjects with any AE, any severe AE, any study treatment-
related AE, any surgical procedure related AE, any AE leading to study discontinuation, 
any serious AE (SAE), any study treatment-related SAE, any surgical procedure related 
SAE, any SAE leading to study discontinuation 
• AEs by primary SOC and PT 
• AEs related to study treatment by SOC and PT (separately for study eye and non-ocular) 
• AEs related to surgical procedure by SOC and PT (separately for study eye and non-
ocular) 
• SAEs by primary SOC and PT 
• SAEs related to study treatment by SOC and PT (separately for study eye and non-ocular) 
• SAEs related to surgical procedure by SOC and PT (separately for study eye and non-
ocular) 
A subject with multiple adverse events within a primary SOC is only counted once towards the 
total of the primary SOC. 
All AEs, deaths, and SAEs (including those from the pre- and post-treatment periods) will be 
listed and those collected after the use of alternative GA therapies/medications, or during the 
pre-treatment, post-study period will be flagged. In addition, subjects who are not receiving 
treatment due to surgical procedure-related AEs will be listed separately by treatment group.  
The MedDRA version used for reporting the AEs will be described in footnote. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on “on-
treatment/treatment emergent” adverse events which are not serious adverse events with an 
incidence greater than 2% (or other cutting point as appropriate) and on “on-treatment/treatment 
emergent” serious adverse events and SAE suspected to be related to study treatment will be 
provided by system organ class and preferred term on the safety set population (i.e., the FAS of 
this study). 
If for the same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 




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2.7.4 
Laboratory data 
Laboratory parameters listed in Table 2-1 will be presented graphically using boxplots of 
absolute change from baseline values by treatment group and visit. No summary by visit tables 
will be provided. 
A summary table with number and percentage of subjects satisfying the criteria representing 
clinically relevant abnormalities defined in Table 2-1 at any visit will be presented. A listing of 
subjects satisfying at least one criterion in Table 2-1 at any visit will also be presented. 
Table 2-1 
Clinically notable laboratory values 
Test 
Critically Low 
Critically High 
Units 
Hemoglobin 
< 7.0 
> 20.0 
g/dL 
White Cell Count 
< 2.0 
> 35.0 
x10E3/uL 
Platelets 
< 50 
> 1000 
x10E3/uL 
Glucose 
< 40 
> 500 
mg/dL 
Calcium 
< 6.0 
> 12.0 
mg/dL 
Phosphate 
< 0.9 
 
mg/dL 
Sodium 
< 120 
> 160 
mmol/L 
Potassium 
< 3.0 
> 6.0 
mmol/L 
Magnesium 
<0.74 
> 1.0 
mmol/L 
AST 
 
 41 
U/L 
ALT 
 
 45 
U/L 
Total bilirubin 
 
 21 
umol/L 
2.7.5 
Other safety data 
2.7.5.1 
ECG and cardiac imaging data 
No applicable.  
2.7.5.2 
Vital signs 
A listing of subjects satisfying at least one criterion in Table 2-2 at any visit will be presented. 
Table 2-2 
Clinically notable vital signs 
Variable 
Category 
Critical values 
Systolic blood  
High 
Either >180 with an increase from baseline >30 or >200 absolute 
pressure (mmHg) 
Low 
Either <90 with a decrease from baseline >30 or <75 absolute 
 
 
 
Diastolic blood  
High 
Either >105 with an increase from baseline >20 or >115 absolute 
pressure (mmHg) 
Low 
Either <50 with a decrease from baseline > 20 or <40 absolute 
 
 
 
Pulse rate (bpm) 
High 
Either >120 with an increase from baseline of >25 or > 130 
absolute 
Low 
Either <50 with a decrease from baseline >30 or <40 absolute 


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2.8 
Pharmacokinetic endpoints   
Not applicable. 
2.9 
PD and PK/PD analyses 
Not applicable. 
2.10 
Patient-reported outcomes 
Functional Reading Independence (FRI) Index 
The FRI index is a new patient-reported outcome measure developed specifically for use in GA 
patients. The FRI index evaluates the level of independence patients have in performing 
everyday activities that require reading, such as writing a cheque or reading a prescription. 
Scores derived from the index range from 1 (unable to do) to 4 (total independence).  
The composite score is the sum of the seven sub-questions.  
If responses are missing for main questions or sub-questions, scores may be imputed based on 
the scoring for missing items algorithm provided in  Table 2-3 below. 
Table 2-3 
Scoring missing FRI items 
Question or sub-question with 
missing data  
Missing 
response 
within 
context of other  
sub-questions  
Coding and imputation  
 
Main Questions 1–7   
If missing main question and 
responses of “Yes” or “No” to 
sub-questions a-e…  
Impute “Yes” to main question 
and score according to 
algorithm  
If missing main question and 
“Your vision” or “For other 
reasons” to sub-question g….  
Impute “No” to main question 
and score according to 
algorithm  
If missing main question and 
no responses to any sub-
questions…  
Code as “missing”  
Sub-questions a–c  
If missing sub-questions a-c…  
Code as “missing” and score 
according to algorithm  
Sub-question d  
If missing sub-question d and 
“No” response to all sub-
questions a-c…  
Impute “No" for sub-question d 
and score according to 
algorithm  
Sub-question e 
If “Yes” to performing activity 
and “missing” for sub-question 
e and no responses to sub-
question f…  
Impute “No" for sub-question e 
and score according to 
algorithm  
If “Yes” to performing activity 
and “missing” for sub-question 
e and response of “Some of the 
time”, “Most of the time” or 
Impute “yes" for sub-question e 
and score according to 
algorithm  


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“All of the time” to sub-
question f…  
Sub-question f  
If “Yes” to performing activity, 
“Yes” to sub-question e and 
“missing” for sub-question f…  
Impute “Some of the time" for 
sub-question f and score 
according to algorithm  
Sub-question g  
If “No” to main question and 
“missing” for sub-question g…  
Impute “For other reasons” for 
sub-question g and score 
according to algorithm  
Visual Function Questionnaires (VFQ-25) 
The VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related 
constructs, plus an additional single-item general health rating question. The VFQ-25 subscales 
and composite scores and changes from baseline will be calculated and summarized by 
assessment visit. Each subscale score has a range of 0 to 100 inclusive and will be calculated 
from the re-scaled raw data as described in Table 2-4. A missing response will not be re-scaled 
(except for the response to question 15c, see below, which will be re-set to 0 if the response to 
question 15b is 1).  
Table 2-4 
Rescaling of VFQ-25 questions 
Answer to question 
Rescaling for 
questions 1, 3, 4 
and 15c 
Rescaling for 
question 2 
Rescaling for 
questions 5-14, 
16 and 16a 
Rescaling for 
questions 17-25 
1 
100 
100 
100 
0 
2 
75 
80 
75 
25 
3 
50 
60 
50 
50 
4 
25 
40 
25 
75 
5 
0 
20 
0 
100 
6 
N/A 
0 
N/A* 
N/A 
    Item 15c has four-response levels, but is expanded to a five-levels using item 15b. 
    Note: If 15b=1, then 15c should be recoded to “0” 
              If 15b=2, then 15c should be recoded to missing 
              If 15b=3, then 15c should be recoded to missing 
*Response choice “6” indicates that the person does not perform the activity because of non-vision related problems. If this 
choice is selected, the item is coded as “missing”. 
The subscale scores are then calculated according to Table 2-5. 
Table 2-5 
Questions contributing to VFQ-25 subscales 
Subscale 
Questions 
General vision 
2 
Ocular pain 
4 and 19 
Near activities 
5, 6 and 7 
Distance activities 
8, 9 and 14 
Social functioning 
11 and 13 
Mental health 
3, 21, 22 and 25 
Role difficulties 
17 and 18 




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MON 
MISSING 
MON < RANDM 
MON = RANDM 
MON > RANDM 
YYYY 
MISSING 
                 ( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
YYYY < TRTY 
  
( 2.a ) 
Before Randomization 
( 2.b ) 
Before Randomization 
( 2.b ) 
Before Randomization 
( 2.b ) 
Before Randomization 
YYYY = TRTY 
  
( 4.a ) 
Uncertain 
( 4.b ) 
Before Randomization 
( 4.c ) 
Uncertain 
( 4.c ) 
After Randomization 
YYYY > TRTY 
  
( 3.a ) 
After Randomization 
( 3.b ) 
After Randomization 
( 3.b ) 
After Randomization 
( 3.b ) 
After Randomization 
Before imputing AE start date, find the AE start reference date.  
1. If the (imputed) AE end date is complete and the (imputed) AE end date < randomization 
date then AE start reference date = min (informed consent date, earliest visit date). 
2. Else AE start reference date = randomization date 
Impute AE start date -  
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set 
to NULL. 
2. If the AE start date year value is less than the randomization date year value, the AE 
started before randomization. Therefore: 
a. If AE day and month are missing, the imputed AE start date is set to the mid-
year point (01JulYYYY). 
b. If AE month is missing but day is not missing, the observed start date will be 
used with month imputed as JulYYYY. 
c. Else if AE month is not missing, the imputed AE start date is set to the mid-
month point (15MONYYYY). 
3. If the AE start date year value is greater than the randomization date year value, the AE 
started after randomization. Therefore: 
a. If the AE day and month are missing, the imputed AE start date is set to the year 
start point (01JanYYYY). 
b. If AE month is missing but day is not missing, the observed start date will be 
used with month imputed as JulYYYY. 
c. Else if the AE month is not missing, the imputed AE start date is set to the later 
of (month start point (01MONYYYY), AE start reference date + 1 day). 
4. If the AE start date year value is equal to the randomization date year value: 
a. And the AE day and month are missing the imputed AE start date is set to the 
AE reference start date + 1 day. 
b. If AE month is missing and day is not missing, the observed start date will be 
used with month imputed as the reference start month. 
c. Else if the AE month is less than the randomization month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
d. Else if the AE month is equal to the randomization date month or greater than 
the randomization date month, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 


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If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date. 
5.1.2 
Concomitant medication date imputation 
5.1.2.1 
Concomitant treatment end date imputation 
1. If CM end day is missing and CM month/year are non-missing then impute CM day as the 
minimum of the last study visit date and the last day of the month. 
2. If CM end day/month are missing and CM year is non-missing then impute CM day as the 
minimum of the last study visit date and the end of the year (31DECYYYY). 
3. Only include if ongoing records will have an imputed CM end date. If CM day/month/year 
is missing then use the last study visit date + 1 day as the imputed CM end date.  
4. If imputed CM end date is less than the CM start date, use the CM start date as the imputed 
CM end date. 
5. If imputed CM end date is greater than date of death, date of cutoff, or the last visit date, 
then use the minimum of date of death, date of cutoff, and the last visit date as the imputed 
CM end date. 
5.1.2.2 
Concomitant treatment start date imputation  
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
  
  
                     Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Randomization Date 
Not used 
RANDM 
RANDY 
 
The following matrix explains the logic behind the imputation. 
 
 
  
MON 
MISSING 
MON < RANDM 
MON = RANDM 
MON > RANDM 
YYYY 
MISSING 
 ( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
YYYY < TRTY 
  
( 2.a )  
Before Randomization 
( 2.b ) 
Before Randomization 
( 2.b ) 
Before Randomization 
( 2.b ) 
Before Randomization 
YYYY = TRTY 
  
( 4.a ) 
Uncertain 
( 4.b ) 
Before Randomization 
( 4.a ) 
Uncertain 
( 4.c ) 
After Randomization 
YYYY > TRTY 
  
( 3.a ) 
After Randomization 
( 3.b ) 
After Randomization 
( 3.b ) 
After Randomization 
( 3.b ) 
After Randomization 
  
If the CM start date year value is missing, the imputed CM start date is set to one day prior to 
randomization date.  
If the CM start date year value is less than the randomization date year value, the CM started 
before randomization. Therefore: 
a. If the CM day and month are missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY). 


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b. If CM month is missing but day is not missing, the observed start date will be used with 
month imputed as JulYYYY. 
c. Else if the CM month is not missing, the imputed CM start date is set to the mid-month 
point (15MONYYYY). 
If the CM start date year value is greater than the randomization date year value, the CM started 
after randomization. Therefore: 
a. If the CM day and month are missing, the imputed CM start date is set to the year start 
point (01JanYYYY). 
b. If CM month is missing but day is not missing, the observed start date will be used with 
month imputed as JanYYYY. 
c. Else if the CM month is not missing, the imputed CM start date is set to the month start 
point (01MONYYYY). 
If the CM start date year value is equal to the randomization date year value: 
a. And the CM day and CM month are missing or the CM day is missing and CM month 
is equal to the randomization date month, then the imputed CM start date is set to one 
day prior randomization date. 
b. Else if the CM month is less than the randomization date month, the imputed CM start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the randomization date month, the imputed CM 
start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date. 
5.1.2.3 
Medical history date of diagnosis imputation 
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the randomization date. 
• If DIAG year < randomization date year and DIAG month is missing, the imputed DIAG 
date is set to the mid-year point (01JULYYYY) 
• else if DIAG month is not missing, the imputed DIAG date is set to the mid-month 
point (15MONYYYY) 
• If DIAG year = randomization date year  
• and (DIAG month is missing OR DIAG month is equal to randomization month), the 
imputed DIAG date is set to one day before randomization date 
• else if DIAG month < randomization month, the imputed DIAG date is set to the mid-
month point (15MON YYYY) 
• else if DIAG month > randomization month => data error 
• If DIAG year > randomization date year => data error 
5.1.2.4 
Other imputations 
Not applicable. 


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5.2 
AEs coding/grading 
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
The below severity grade will be used in this study: 
• Mild: usually transient in nature and generally not interfering with normal activities 
• Moderate: sufficiently discomforting to interfere with normal activities 
• Severe: prevents normal activities 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Statistical models 
5.4.1 
Analysis supporting primary objective(s)  
The following MMRM will be used for the primary efficacy endpoint. The model will include 
the change from baseline in GA area measured by FAF as the dependent variable, GA area at 
the baseline as the covariate, assessment visit, treatment group, two interaction terms 
(assessment visit and treatment group, assessment visit and GA area at the baseline) as the fixed 
effect and participant as a random effect. 
For this analysis, the data structure is one record per subject per scheduled visit. The data will 
include all subjects and have records for all scheduled visits, regardless of whether the 
assessment was missed or not at a given visit. Missing values will not be imputed and will be 
passed to the model as missing. The SAS PROC MIXED will be used to perform the analysis. 
5.5 
Rule of exclusion criteria of analysis sets  
The below classification of non-PDs will be used for the analysis sets.  
Table 5-1 
Subject Classification 
Analysis Set 
Non-PD criteria that cause participants to be excluded 
All Enrolled Set 
Not signed the informed consent 
Full Analysis Set 
Not randomized 


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6 
References 
Bretz, F. a. (2017). Multiple test strategies for comparing several doses with a control in 
confirmatory trials from Handbook of Methods for Designing, Monitoring, and 
Analyzing Dose-Finding Trials. Chapman and Hall/CRC.