Clinical trial NCT04437368
Conditions: Dry Age-related Macular Degeneration
Keywords: Geographic atrophy Retinal disease Eye disease Retinal degeneration Macular atrophy Dry age-related macular degeneration
Sponsor: Gyroscope Therapeutics Limited
Start date: 2019-04-26; Completion date: 2024-04-05
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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, outcomes assessor-masked, multicentre, randomized study to assess 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 202 subjects were planned to be randomized to GT005 or the untreated control group.

Subjects entered the study had genotyping and serum complement factor I(CFI) levels assessed. Assessments were either performed at a sponsor-approved laboratory during the EXPLORE screening period or provided through participation in a previous Gyroscope sponsored study. If subjects failed to meet the eligibility criteria for EXPLORE, they were classified as screen failures for this study and could be considered for entry into another Novartis/Gyroscope sponsored study.

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

Upon confirmation of eligibility, subjects in part 1 were randomized to one of two groups: low dose \[2E10 vg\], or high dose \[2E11 vg\]. Within each group, subjects were allocated to GT005 or untreated control based on a 2:1 ratio. Once part 1 enrolment was completed, and the last active subject completed screening and either was screen-failed or randomized, then Part 2 could commence. In part 2, subjects were randomized to the low dose \[2E10\] group or untreated control based on a 2:1 ratio. The study eye was identified for all subjects.

Subjects were stratified by GA lesion size on fundus autofluorescence (FAF) (≤10 mm2 or \>10 mm2) and presence of choroidal neovascularisation (CNV) in the fellow eye (Yes or No). 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. Once enrolment capping at 20% based on the 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. Of all subjects enrolled and randomized in the study, the presence of CNV in the fellow eye was capped at 25% per stratum. A permuted-block randomization 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, all imaging endpoint assessments and grading were performed at a Central Reading Centre (CRC), in a masked fashion. For part 1, the Sponsor, subject, investigators, and study personnel performing clinical assessments remained masked to dose received for those allocated to GT005. For part 2, the Sponsor, investigators, subjects, and study personnel performing clinical assessments were unmasked to dose received, since only the low dose was administered.

Subjects randomized to GT005 underwent a single time subretinal administration of the study drug. Vitreous samples were collected during surgery. Following surgery, a prophylactic steroid regimen was prescribed.

The study consisted 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 adverse events (AEs) at each visit and underwent functional visual and retinal imaging,anatomical assessments, and biological sampling as per the schedule of assessments.

This study was conducted in compliance with Independent ethics committees (IECs) / Institutional review board (IRBs), informed consent regulations, the Declaration of Helsinki, International Council on Harmonisation (ICH) Good Clinical Practices (GCP) Guidelines, and the Food and Drug Administration (FDA) guidance.

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 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 / NCT05481827) study.

In both Part 1 and Part 2, patients with geographic atrophy secondary to age-related macular degeneration were enrolled. In Part 1, patients with CFI rare variant genotype and low serum CFI level and in Part 2, patients were enrolled regardless of genotypes. Efficacy results were analyzed by arm and also by part. AE and disposition data were reported per arm, but the parts were combined, according to the analysis plan.

Part 1 enrolled subjects with CFI rare variant; Part 2 enrolled subjects regardless of genotype.

There were no subjects in the high dose arm in Part 2.

Arms: arm 1: GT005 Low dose \[2E10 vg\] (Parts 1 and 2) arm 2: GT005 High dose \[2E11 vg\] (Part 1) arm 3: Untreated control (Parts 1 and 2)
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 documents:
Prot_000.pdf: 
GYROSCOPE THERAPEUTICS 
PAGE 1 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0, 06 DEC 2022 
CONFIDENTIAL 
EXPLORE: A PHASE 2, OUTCOMES ASSESSOR-MASKED, MULTICENTRE, 
RANDOMISED 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 AGE-RELATED 
MACULAR DEGENERATION 
STUDY PROTOCOL 
STUDY NUMBER:   
VERSION: 
DATE: 
SUPERSEDED 
VERSION/DATE: 
PRODUCT NAME/CODE: 
EudraCT NUMBER: 
SPONSOR 
GT005-02 / NCT04437368 
6.0  
06 DEC 2022 
5.0 (03 June 2021) 
GT005 
A RECOMBINANT, NON-REPLICATING ADENO-
ASSOCIATED VIRAL VECTOR SEROTYPE 2 
(AAV2) EXPRESSING HUMAN COMPLEMENT 
FACTOR I 
2019-003421-22 
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 GT005-02 (EXPLORE): V6.0, 06 DEC 2022 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 7 
PROTOCOL SIGNATURES .................................................................................................. 9 
AMENDMENT HISTORY .................................................................................................... 10 
COMPLIANCE STATEMENT ............................................................................................ 20 
PROTOCOL SYNOPSIS ....................................................................................................... 21 
1. 
BACKGROUND INFORMATION ............................................................................. 35 
1.1 
Indication ....................................................................................................................... 35 
1.2 
Investigational Product ................................................................................................. 35 
1.3 
Findings from Preclinical Studies ................................................................................ 35 
1.4 
Clinical Studies .............................................................................................................. 37 
1.5 
Study Rationale ............................................................................................................. 37 
1.5.1 The Complement Cascade ..................................................................................... 37 
1.5.2 Rare Variant Genetic Population (Part 1)............................................................ 37 
1.5.3 Broad Genetic Population (Part 2) ....................................................................... 38 
1.5.4 Dose Rationale ....................................................................................................... 38 
1.6 
Risk/Benefit Assessment ............................................................................................... 39 
1.6.1 
Potential Risks ............................................................................................. 39 
1.6.1.1 
Risks Associated with GT005 ....................................................................... 39 
1.6.1.2 
Risks Associated with the Surgical Procedure and Study Procedures ......... 41 
1.6.2 
Potential Benefits......................................................................................... 42 
1.6.3 
Risk Benefit Analysis ................................................................................... 42 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................... 44 
3 
STUDY DESIGN ........................................................................................................... 46 
3.1 
Study Overview ............................................................................................................. 46 
3.2 
Dose Selection ................................................................................................................ 47 
3.3 
Data Monitoring Committee ........................................................................................ 48 
3.4 
Randomisation and Masking........................................................................................ 48 
3.4.1 
Masking........................................................................................................ 48 
3.4.2 
Randomisation/Stratification ...................................................................... 48 
3.4.3 
Breaking the Randomisation Code ............................................................. 49 
3.5 
Duration of Subject Participation ................................................................................ 49 
3.6 
Early Study Termination .............................................................................................. 50 
3.7 
End of Study Definition ................................................................................................ 50 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS.............................................. 51 
4.1 
Inclusion Criteria .......................................................................................................... 51 
4.2 
Exclusion Criteria ......................................................................................................... 51 
4.3 
Screen Failures and Replacements .............................................................................. 52 
4.4 
Randomisation Criteria ................................................................................................ 53 
4.5 
Contraception ................................................................................................................ 53 
4.6 
Discontinuation/Withdrawal Procedures .................................................................... 53 
4.7 
Lost to Follow-up ........................................................................................................... 54 
4.8 
Long-term Follow-up .................................................................................................... 54 
5 
STUDY TREATMENT................................................................................................. 55 
5.1 
Acquisition and Accountability .................................................................................... 55 
5.2 
Formulation, Appearance, Packaging and Labelling (include comparator 
information) ................................................................................................................... 55 
5.3 
Product Preparation, Storage, and Dispensing .......................................................... 55 
5.4 
Dosing and Administration .......................................................................................... 56 


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PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
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5.5 
Measures to Minimise Bias: Randomisation and Masking ....................................... 56 
5.6 
Concomitant Medication/Therapy Rescue Medication ............................................. 57 
5.6.1 
Required/Permitted Medication .................................................................. 57 
5.6.2 
Prohibited Medication ................................................................................. 57 
5.7 
Treatment of Overdose of GT005 ................................................................................ 58 
5.8 
Administration Compliance ......................................................................................... 58 
6 
STUDY PROCEDURES ............................................................................................... 59 
6.1 
Study Visits .................................................................................................................... 59 
6.1.1 
Screening (Visit 1: Local or Surgical Site) ................................................. 59 
6.1.2 
Randomisation (Telephone Call) ................................................................ 61 
6.1.3 
Visit 2, Day 1 (Surgical Site) ....................................................................... 61 
6.1.3.1 
Pre-surgery (Surgical Site) .......................................................................... 62 
6.1.3.2 
Surgery – Day 1 (Surgical Site) ................................................................... 62 
Post-surgery – Day 2 (Surgical Site)........................................................... 62 
6.1.4 
Day 3 (Telephone call) ................................................................................ 63 
6.1.5 
Visit 3 (Week 1) (Surgical Site) ................................................................... 63 
6.1.6 
Week 2 (Telephone call) .............................................................................. 63 
6.1.7 
Visit 4, Week 5 (Local or Surgical Site for GT005 Subjects/Telephone Call 
for Untreated Control Subjects) .................................................................. 64 
6.1.8 
Visit 5, Week 8 (Local or Surgical Site)...................................................... 64 
6.1.9 
Visit 6, Week 12 (Local or Surgical Site).................................................... 65 
6.1.10 
Visit 7, Week 24 (Local or Surgical Site).................................................... 65 
6.1.11 
Visit 8, Week 36 (Local or Surgical Site).................................................... 66 
6.1.12 
Visit 9, Week 48 (Local or Surgical Site).................................................... 67 
6.1.13 
Visit 10, Week 72 (Local or Surgical Site).................................................. 67 
6.1.14 
Visit 11, Week 96/End of Study and Early Termination Visit (Local or 
Surgical Site) ............................................................................................... 68 
6.1.15 
Unscheduled Visit ........................................................................................ 69 
7 
STUDY ASSESSMENT ................................................................................................ 70 
7.1 
Demographic and Screening Assessments .................................................................. 70 
7.2 
Concomitant Medication 
 Compliance ........................................ 71 
7.2.1 
Concomitant Medication ............................................................................. 71 
7.2.2       
) ....................................... 71 
7.3 
Ophthalmic Assessments .............................................................................................. 71 
7.3.1 
Ophthalmic Examination ............................................................................ 71 
7.3.2 
Pre-surgical Ocular Safety Check .............................................................. 71 
7.3.3 
Colour Fundus Photography ...................................................................... 71 
7.3.4 
Fundus Autofluorescence ........................................................................... 72 
7.3.5 
Optical Coherence Tomography (Bleb or Macula) .................................... 72 
7.3.6 
Optical Coherence Tomography-A ............................................................. 72 
7.3.7 
Fluorescein Angiography ............................................................................ 72 
 
 72 
7.3.9 
Visual Acuity Check .................................................................................... 73 
7.3.10 
Best Corrected Visual Acuity ...................................................................... 73 
7.3.11 
Low Luminance Difference ........................................................................ 73 
7.3.12 
Reading Performance .................................................................................. 73 
7.3.13 
Visual Function Questionnaire .................................................................. 73 
7.3.14 
Functional Reading Independence Index .................................................. 74 
7.4 
Safety .............................................................................................................................. 74 
7.4.1 
Vital Signs .................................................................................................... 74 


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PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
7.4.2 
Adverse Events ............................................................................................. 74 
 
 74 
7.4.3 
Pregnancy Test ............................................................................................ 74 
7.4.4 
Laboratory Safety Tests ............................................................................... 75 
7.4.5 
 ......................... 76 
7.4.5.1 
Serum CFI Level ........................................................................................... 76 
 
 76 
 
 76 
7.4.5.4 
Genotyping ................................................................................................... 76 
 
 76 
8 
ADVERSE EVENT REPORTING .............................................................................. 78 
8.1 
Definition of an Adverse Event .................................................................................... 78 
8.2 
Definition of Serious Adverse Event ............................................................................ 78 
8.3 
Adverse Events of Special Interest .............................................................................. 79 
8.4 
Classification of an Adverse Event .............................................................................. 79 
8.4.1 
Severity Assessment ..................................................................................... 79 
8.4.2 
Causality Assessment................................................................................... 80 
8.4.3 
Expectedness Assessment ............................................................................ 80 
8.4.4 
Action Taken Regarding the Investigational Medicinal Product .............. 80 
8.4.5 
Outcome ....................................................................................................... 80 
8.5 
Reporting Requirements............................................................................................... 81 
8.5.1 
Serious Adverse Events and Adverse Events of Special Interest ............... 81 
8.6 
Follow-up of Adverse Events ........................................................................................ 82 
8.7 
Pregnancy ....................................................................................................................... 82 
8.8 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events........ 83 
8.9 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ..................... 83 
9 
STATISTICS METHODS ............................................................................................ 84 
9.1 
Sample Size Determination .......................................................................................... 84 
9.2 
Analysis Populations Definitions.................................................................................. 84 
9.3 
Significance Testing and Estimations .......................................................................... 84 
9.4 
Statistical/Analytical Methods ..................................................................................... 84 
9.4.1 
Demographics and Baseline Characteristics .............................................. 84 
9.4.2 
Efficacy Assessments ................................................................................... 84 
9.4.3 
Safety Assessments ...................................................................................... 85 
 
 86 
9.4.5 Interim Analyses ............................................................................................................ 86 
9.4.6 Data Monitoring Committee ........................................................................................ 86 
9.4.7 Handling missing data .................................................................................................. 86 
10 
STUDY MANAGEMENT ............................................................................................ 87 
10.1 Monitoring Procedures ................................................................................................. 87 
10.2 Recording of Study Data............................................................................................... 87 
10.3 Source Data Verification .............................................................................................. 87 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 88 
11.1 Inspections and Auditing Procedures .......................................................................... 88 
12 
DATA HANDLING AND RECORD KEEPING ....................................................... 89 
12.1 Data Quality ................................................................................................................... 89 
12.2 Data Management ......................................................................................................... 89 
12.3 Sponsor Discontinuation Criteria ................................................................................ 90 
12.4 Subject and Data Confidentiality................................................................................. 90 
12.5 Sample Preparation, Handling and Storage ............................................................... 90 


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PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
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12.6 Record Archiving and Retention ................................................................................. 90 
13 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE91 
13.1 Institutional Review Board/Independent Ethics Committee Ethical Conduct of the 
Study ............................................................................................................................... 91 
13.2 Subject Information and Consent ................................................................................ 91 
13.3 Reporting of Significant Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ................................................................................................................................ 92 
14 
ADMINISTRATION PROCEDURES ........................................................................ 93 
14.1 Regulatory Approval..................................................................................................... 93 
14.2 Publication Policy .......................................................................................................... 93 
14.3 Clinical Study Report.................................................................................................... 93 
14.4 Contractual and Financial Details ............................................................................... 93 
14.5 Insurance, Indemnity and Compensation ................................................................... 93 
15 
PROTOCOL AMENDMENTS .................................................................................... 95 
15.1 Protocol Amendments and Protocol Deviations ......................................................... 95 
15.2 Protocol Deviations and Exceptions ............................................................................ 95 
16 
REFERENCES .............................................................................................................. 96 
17 
APPENDICES ............................................................................................................... 99 
17.1 AREDS Clinical Lens Grading System ....................................................................... 99 
17.2 Reading performance (MNRead) .............................................................................. 102 
17.3 Visual Function Questionnaire (VFQ-25) ................................................................. 104 
17.4 Vitreous Haze Grading Scale ..................................................................................... 120 
17.5 Functional Reading Independence Index .................................................................. 121 


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PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
LIST OF TABLES 
Table 1: Schedule of Assessments: Subjects Allocated to GT005 ...................................... 30 
Table 2: Schedule of Assessments: Subjects Allocated to Untreated Control .................. 33 
Table 3: Prohibited Medications for Study Eye Only ......................................................... 58 
Table 4: Laboratory Parameters ........................................................................................... 75 
Table 5: Intercurrent events and corresponding primary data handling strategies ........ 85 
 
 
LIST OF FIGURES 
Figure 1: Study Design ........................................................................................................... 24 
 


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PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition  
AAV 
Adeno-associated virus 
 
 
 
 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AMD 
Age-related macular degeneration 
ANCOVA 
Analysis of covariance 
AREDS 
Age-related eye disease study 
ATA 
Anti-transgene antibodies 
BCVA 
Best corrected visual acuity 
BSS 
Balanced salt solution 
C3 
Complement component 3 
CFI / CFI 
Complement factor I (gene / protein) 
CFP 
Colour fundus photography 
CFR 
Code of Federal Regulations 
CNV 
Choroidal neovascularisation  
CRC 
Central Reading Centre 
CRO 
Clinical Research Organisation 
CSR 
Clinical study report 
DBL 
Database lock 
DNA 
Deoxyribonucleic acid 
DMC 
Data Monitoring Committee 
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 consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ISC 
Independent Statistics Centre 
LLD 
Low luminance difference 
LLVA 
Low luminance visual acuity 


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Abbreviation 
Definition  
MedDRA 
Medical dictionary for regulatory activities 
MAIA 
Macular Integrity Assessment 
MHRA                       
MMRM 
Medicines and Healthcare Products Regulatory Agency 
Mixed model repeated measures 
 
 
NA 
Not applicable 
NHP 
Non-human primate 
OCT 
Optical coherence tomography 
OCT-A 
Optical coherence tomography-angiography 
QID 
Four times daily 
PRL 
Preferred retinal locus  
PSA 
Prostate-specific antigen 
RPE 
Retinal pigment epithelium 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SDV 
Source data verification 
SUSAR 
Suspected unexpected serious adverse reactions 
Tel 
Telephone 
V 
Visit 
 
 
Vg 
Vector genomes 
 




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PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
AMENDMENT HISTORY 
Protocol Version 
Change 
Justification 
V1.0, 13 Sept 2019 
(Initial) 
NA 
NA 
V2.0, 31 Oct 2019 
•
Primary Endpoint
•
Correction of administrative error to align
primary endpoint with wording in the
protocol body, and clarify GA measurement is
from baseline to Week 48
•
Number of Subjects
•
Number of subjects increased from 48 to
54 to include an assumed 10% withdrawal
rate
•
Masking
•
Clarified that the primary endpoint is masked
to the assessor, and that the assessor will
receive the same images for all subjects in
order to maintain masking
•
Screen Failures and Replacements
•
Clarified that subjects who are withdrawn
from the study after randomisation will not be
replaced
•
Contraception
•
Definition of true abstinence added, in
response to MHRA grounds for non-
acceptance
•
Long-term Follow Up
•
Clarified that the long-term follow-up will be
performed in a separate study under a separate
consent
•
Formulation, Appearance,
Packaging and Labelling
•
Changes made to reflect compliance of
labelling requirements with Competent
Authority regulations in EU, USA and RoW
•
Protocol Deviations and
Exceptions
•
Clarification of handling of protocol
deviations, in response to MHRA grounds for
non-acceptance
V3.0, 13 May 2020 
•
Dose rationale updated
•
Incorporated data from completed dose
escalation from FOCUS (Phase 1/2 study)
•
Number of subjects enrolled
•
Number of subjects increased to 75 to
adequately power for a stastitically
significant effect assuming the true
underlying change in GA area is inhibited by
a 40% treatment effect
•
Schedule of Assessments
•
Screening period extended, incorparated a
requirement for a pre-operative vision check
if previous vision >4 weeks prior for patient
safety and incorporated requirement of PRL
identification pre-operatively. Clarified
reporting of related SAEs from time of
consent and all AEs from time of
randomisation
•
Inclusion/Exclusion Criterion
•
Clarification regarding performing
and obtaining genotyping results
prior to commencement of
screening assessments.
•
Given the low prevalance of CFI mutations
and desire to minimise patient study
activities, genotyping results will be received
to confirm eligibility prior to other screening
activities commencing


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PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
Protocol Version 
Change 
Justification 
 
 
 
 
 
• 
Additional Week 8 Visit added. 
• 
To support additional safety monitoring, 
 
 
 
 
 
 
 
 
 
 
 
• 
Removed requirement to remain in 
medical facitility overnight 
following surgery. 
• 
Emerging safety profile from the completed 
dose escalation in the Phase 1/2 FOCUS does 
not support need for overnight stay in a 
medical facility 
 
 
 
 
 
 
 
• 
Potential risk section updated. 
 
 
 
 
 
 
 
 
 
  
• 
Updated guidance on 
GT005 destruction. 
• 
Provide more detailed instruction and clarity 
 
• 
Throughout the document 
• 
Inconsistences removed and language 
clarified. As these are minor revisions, they 
have not been summarised 
V4.0, 13 NOV 2020 
• 
Extension of the duration of subject 
participation from 48 to 96 weeks  
• 
Subject participation duration has been 
extended to 96 weeks to enable the 
generation of  long term treatment effects and 
durability of effect  
 
• 
Inclusion/Exclusion Criterion  
• 
Inclusion criterion 3 has been updated to 
ensure subjects have dry AMD and/or GA, 
secondary to AMD in both eyes  
• 
Exclusion criterion 4 added to provide 
clarification on required duration of prior 
intraocular surgery before screening  
• 
Inclusion criterion 6 broadened to BCVA of 
24 letters (6/95 and 20/320 Snellen acuity 
equivalent), to evaluate the treatment effect 
of subjects with worse-seeing vision 
• 
Inclusion criteria 7 revised to include an 
evidence-based approach to enrolment of 
subjects into the study 
• 
Inclusion criterion 8 no longer required as 
genotyping requirements have been included 
in criterion 7 
• 
Exclusion criterion 12 updated to broaden the 
malignancies/cancer types excluded from the 
study  
 
• 
Inclusion of additional secondary 
efficacy endpoint  
• 
Corrected the imaging modality 
for retinal anatomical measures 
 
 
  
• 
Inclusion of new secondary efficacy endpoint 
measurement during the newly added second 
year of subject participation 
• 
Updated terminology to multimodal imaging 
as CFP is not the only imaging modality used 
to measure retinal anatomical measurements 
 
 
 
 
 


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Protocol Version 
Change 
Justification 
•
Inclusion of FA assessment
•
FA included as an assessment to verify
subjects do not have CNV at baseline or
conversion to CNV during the study.
•
Addition that all unscheduled FA images to
be sent to CRC
•
Additional OCT-A
•
OCT-A imaging added, if required, to
identify potential CNV conversion during the
study
•
Clarification of OCT modalities
•
The differing OCT modalities have been
clarified: OCT-A (for monitoring of CNV
conversion), OCT macula 
 to
provide clarity to investigational sites and to
add further timepoints if required by the
Investigator to detect any safety changes on
the retina, 
 any other
safety-related changes
•
Randomisation to either eye (if
both eligible) removed
•
Genotyping ICF
•
The eye with worse visual acuity will be
selected, if both eyes are eligible to help
safeguard vision in the better seeing eye
•
Separate Genotyping ICF created to fulfil
genotyping requirements prior to performing
full screening assessments for eligible
subjects
•
Pre-surgical ophthalmic  checks
•
Clarification regarding the extent of pre- 
surgical ophthalmic examination
•
AE Reporting language
•
Removal of reference to PRL
identification prior to surgery
•
Safety reporting requirements updated to
collect all AEs from date of signed consent
•
The retinotomy site has been relocated to
outside the vascular arcades. The revised
retinotomy location will not encroach on the
Preferred Retinal Locus (PRL) and therefore
the requirement to identify the PRL has been
removed
•
Throughout the protocol
•
Alignment of use of consistent dosing
nomenclature from “Dose 1” and “Dose 2” to
“low dose [
]” and “high dose [
vg]” respectively
•
Administrative inconsistences removed and
language clarified. As these are
minor revisions, they have not been
summarised
V5.0, 03 JUN 2021  
•
Inclusion/Exclusion Criterion
•
Inclusion criterion #6 and exclusion criterion
#1 altered to allow inclusion of patients with
CNV/wet AMD in fellow eye
•
Stratification of subjects with
fellow eye CNV
•
Subjects with fellow eye CNV will be
stratified across all three treatment groups:
high-dose, low-dose and control


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PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
Protocol Version 
Change 
Justification 
 
• 
Corrected the imaging modality 
for retinal anatomical measures  
• 
Clarification of CNV assessment with OCT, 
OCT-A, or FA and added text to refer to the 
imaging manual  
 
• 
Clarification of OCT-A 
certification 
• 
Removal of erroneous text stating OCT-A 
certification is not required 
 
• 
Study drug distribution site 
language updated 
• Updated text to clarify that IMP will be 
despatched directly to sites from an approved 
local/regional distribution vendor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
• 
Administrative changes 
• 
Correction of text related to causality 
assessment of adverse events associated with 
surgical procedures rather than study 
procedures 
• 
Correction of document name for 
justification and definition of the serum CFI 
threshold 
• 
Correction of erroneous footnote number at 
Early Termination Visit 
 
 
 
• 
Sponsor address updated 
V6.0, 06 DEC 2022 
 
• 
Study design has been amended so 
that Part 1 provides an evaluation of 
CFI rare variant GA subjects with 
the low and high dose of GT005 
compared with untreated control, 
and Part 2 evaluates the broad 
genetic GA population with the low 
dose of GT005 compared with 
untreated control.  The overall 
study 
sample 
size 
has 
been 
increased to approximately 202. 
• 
In its current form, the study is unlikely to 
achieve enrolment, and therefore its overall 
scientific objective, in a reasonable timeframe. 
This is due to challenges encountered in 
recruiting GA patients with a CFI rare variant 
genotype, which accounts for approximately 
3% of the overall GA population. Hence the 
study has been adjusted to include Part 2 with 
a more recruitable population of GA patients 
with a broad genetic background. The 
modification of the study population is 
justified based on emerging data which 
strengthens the hypothesis that complement-
targeted therapies have potential to treat a 
genetically broad GA population. With this 
amendment, the primary objective of the study 
remains unchanged; subjects will continue to 
be genotyped as part of the screening 
assessments for the study, and analysis of the 
effect of GT005 according to genetically 
defined subgroups (including the original 
population of CFI rare variants) is still 
planned  




GYROSCOPE THERAPEUTICS 
PAGE 15 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
Protocol Version 
Change 
Justification 
• 
Updated 
Study 
Objectives 
in 
Synopsis and Section 2 secondary 
 to be 
reported through Week 96 
• 
Clarified the analysis timepoints for 
secondary 
 to be 
reported until the end of study   
 
• 
Updated the CFI rare variant 
genetic Inclusion Criterion 8 to 
relate to Part 1 of the study only 
 
 
 
 
 
• 
Updated Exclusion Criterion 1 to 
exclude 
those 
with 
Stargardt 
disease/retinal dystrophies 
 
 
 
 
 
• 
Updated Exclusion Criterion 11 to 
exclude 
investigational 
and 
approved GA products at study 
entry 
in 
the 
study 
eye 
or 
systemically 
• 
Inclusion Criterion 8, CFI rare variant 
genotypes, will only be applicable to Part 1 
of the study. Subjects in Part 2 will not 
require a genotyping subgroup classification 
to enter the study, as subjects with GA, 
secondary to AMD, irrespective of genotype 
will be allowed to enrol into Part 2 
• 
Updated Exclusion Criterion 1 to align with 
other clinical study protocols and to formally 
exclude subjects with another retinal disease, 
other 
than 
GA, 
secondary 
to 
AMD. 
Previously, these subjects were excluded, 
however, it has now been made clear in the 
protocol’s eligibility criteria 
 
• 
In order to preserve the integrity of the clinical 
study, investigational and/or approved GA 
treatments have been excluded from use either 
systemically and in the study eye within the 
timeframe specified 
 
• 
Updated the Synopsis and Section 9 
Statistical Methods in line with the 
change in sample size and study 
design 
• 
The following sections were 
expanded/edited: Sample size determination, 
removed statement that all statistical tests 
will be at the nominal 0.05 one-sided level 
since no formal testing has been decided. 
More information and detail relating to the 
planned statistical analysis has been added to 
the protocol to provide evidence for 
maintaining the statistical integrity and 
robustness of the study design as currently 
approved by Health Authorities (HA) 




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PAGE 17 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
Protocol Version 
Change 
Justification 
•
Updated 7.4.2 Adverse Events and
footnote 13 to clarify that any
additional safety assessments may
be collected to follow up on AEs
•
In order to ensure subjects’ safety and
wellbeing in the study, Investigators could
conduct additional safety tests at their clinical
discretion 
to 
evaluate/monitor 
AEs.
Accordingly, the text has been updated to
define and provide further clarity to this
original intent
•
•
•
Additional safety assessment with
FAF at Week 5
•
Included an additional safety assessment post
GT005 delivery using FAF at Week 5
•
Included new text under footnote 1,
Schedule of Assessments and
Section 6.1.1, Screening Visit 1:
Local or Surgical, to state that:
other 
assessments 
may 
be
performed at the investigator’s
discretion if the 8-week screening
window passes
•
Added standard ophthalmic exam
to the list of screening assessments
that should be repeated for all
subjects if the 8-week screening
window passes
•
Additionally, included rescreening
guidance within 8-weeks and after
8-weeks
•
To ensure that we can collect this or any other
assessment, if needed when the 8-week
screening window passes, the text has been
updated to allow this flexibility
•
For safety reasons added standard ophthalmic
exam to the list of screening assessments that
should be repeated for all subjects if the 8-
week screening window passes
•
To ensure optimal operational management of
the study, provided clarification that if a
subject is rescreened within the 8-week
screening period, the site staff need to repeat
only the haematology/biochemistry, standard
ophthalmic exam and visual acuity (BCVA
and LLVA) assessment provided all other
original results were acceptable
Further, if a subject is rescreened after the 8-
week 
screening 
period, 
all 
screening
assessments should be repeated except for
genotyping and serum CFI
•
Included new footnote 11 under
Schedule of Assessments and in
Section 6.1.9 Visit 6, 
optional for all subjects treated with
GT005
•


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PAGE 18 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
Protocol Version 
Change 
Justification 
•
Increased 
number 
of 
investigational sites from 40 to 
approximately 60 
•
Increased the number of global sites to
approximately 60 to support recruitment in
approximately 202 subjects
Updated footnote 3 under the Schedule 
of Assessments and Section 6.1.3.2 
Surgery Day 1  
•
Clarified that in the event GT005
dosing 
was 
deferred 
during
surgery, the time from surgery may
be rescheduled within 10 weeks of
the original surgery date if agreed
by the Sponsor Medical Monitor
•
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)
•
In the event that GT005 treatment is deferred,
guidance has been provided
•
Updated recent information under
Section 1.6.1.1 Risks associated
with GT005 and ensured that the
new 
information 
was 
also
summarised under Section 1.6.3
Risk Benefit Analysis
•
The Risks associated with GT005 Section has
been aligned with the current version of the
Investigator’s Brochure (IB)
•
Updated 
Section 
4.6 
Discontinuation/Withdrawal 
and 
Section 4.3 Screen Failures and 
Replacements  and provided an 
alternative to stopping participation 
entirely to subjects who were 
randomised to GT005 and do not 
want to receive treatment with 
GT005 and opt to have less 
assessments and data collected as 
part of the study 
•
To collect additional subject-level data and to
preserve the integrity of trial data during the
statistical analysis, additional guidance has
been 
provided 
on 
the
discontinuation/withdrawal from the study
 
 
 
 
 
 
 
 
 
•
 
 
 
 
 
 
 
 
 
 
•
Updated Section 6.1.1 Screening
guidance for subjects in Part 1 and
Part 2. The genotyping assessment
in Part 2 can be performed at the
same time as other screening
assessments
•
To ensure optimal operational management of
the study, subjects in Part 2 can have
genotyping 
and 
all 
other 
screening
assessments performed at the same visit (since
subjects do not need to wait for genotyping
confirmation for study entry)


GYROSCOPE THERAPEUTICS 
PAGE 19 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
Protocol Version 
Change 
Justification 
• 
Updated Section 6.1.5 Surgery Day 
1 and 7.1 Demographic and 
Screening Assessments so subjects 
can provide consent to live-
streaming of the surgery  
• 
Subjects randomised to GT005 will be asked 
if they are willing to consent to have 
livestreaming of the intraocular surgical 
procedure for training and 
monitoring 
purposes, upon the subject providing consent 
• 
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 
• 
Signatory updated 
 
Abbreviations: AEs=adverse events; AESI=adverse event of special interest; AMD=age-related macular degeneration; 
CFI=complement factor I; CNV=choroidal neovascularisation; CRC=Central Reading Centre; EU=European Union; 
FA=fluorescein angiography; GA=geographic Atrophy; IB=Investigational Brochure; ICF=informed consent form; 
IMP=investigational medical product; MHRA=Medicines and Healthcare products Regulatory Agency; OCT= optical 
coherence tomography; OCT-A= optical coherence tomography-angiography; PRL=preferred retinal locus; RoW=rest 
of world; RPE=retinal pigment epithelium.; SAEs=serious adverse events; USA=United States of America; V=version. 
 
 


GYROSCOPE THERAPEUTICS 
PAGE 20 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
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 non-compliance will be documented. 


GYROSCOPE THERAPEUTICS 
PAGE 21 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
SPONSOR:  
Gyroscope Therapeutics 
INVESTIGATIONAL MEDICINAL PRODUCT: 
GT005: A recombinant 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: 
EXPLORE: A Phase 2, outcomes assessor-masked, multicentre, randomised 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 age-related macular degeneration. 
PROTOCOL NO:  
GT005-02 (EXPLORE) 
INDICATION:  
GT005 is under development for the treatment of geographic atrophy (GA) secondary to age-
related macular degeneration (AMD). 
INVESTIGATOR STUDY SITES:  
Approximately 60 study 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:  
Age-related macular degeneration 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 GA 
Chakravarthy 2010. At the time of writing, 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. Variants in genes of complement factors involved 
in the alternative pathway (Complement Factor H, Complement Factor I (CFI), Complement 
Factor B, and Complement component 3) have been found in AMD patients Fritsche 2016. 
These results suggest that mutations in these genes strongly correlate with the likelihood of 
developing AMD Fritsche 2013; Fritsche 2016.  
Study Population:  
This study is composed of two parts: Part 1 and Part 2.  
Part 1 of the protocol will selectively enrol subjects with GA who have either a CFI rare 
variant genotype associated with low serum CFI, or with a previously unreported CFI rare 
variant genotype that have tested to have low serum CFI.   
Part 2 of the protocol will enrol subjects with GA across a broad, non-selective genetic 
background, irrespective of genotype, until approximately 202 subjects are randomised in 
the study overall.  


GYROSCOPE THERAPEUTICS 
PAGE 22 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
Rare Variant Genetic Population (Part 1): Additional studies have found that rare genetic 
variants in CFI (defined by a minor allele frequency <1%) are associated with increased risk 
of advanced AMD, with one study showing that low serum CFI levels together with the 
presence of rare CFI variants is associated with an increased risk of development of advanced 
AMD 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. 
 
 
 
 
 
 
 
 
 
 
 CFI rare variant genotypes previously associated with low serum 
CFI or subjects carrying an unreported CFI rare variant genotype that have tested to have a 
low serum CFI for study entry.   
Part 1 of the study will close for enrolment once all appropriate approvals for protocol V6.0 
are in place; subsequently, subjects with GA and a CFI rare variant genotype should then be 
entered into Part 2 of the study.  
Broad Genetic Population (Part 2): 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].  
Part 2 is designed to evaluate whether administering CFI will be effective in down-regulating 
a hyperactive complement system across all GA patients from a broad genetic population, 
irrespective of genotype, and if this intervention will have a therapeutic effect on disease 
progression.  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]. 
  
DOSE RATIONALE:  
 
 
 
  
OBJECTIVES:  
The overall objectives of the study are to evaluate the safety and efficacy (anatomical and 
functional visual outcomes) of two doses of GT005 in genetically defined subjects with GA 
due to AMD.  
 
 
 


GYROSCOPE THERAPEUTICS 
PAGE 23 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
OBJECTIVES 
ENDPOINTS 
Primary 
• To evaluate the effect of GT005 on the 
progression of GA in subjects with GA 
due to AMD 
• The change from baseline to Week 48 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 






GYROSCOPE THERAPEUTICS 
PAGE 26 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
Subjects allocated to untreated control will be followed by the local or surgical investigative 
site. The pooled untreated control group will provide a reference group to the GT005 
treatment groups.   
Subsequent follow-up visits at Weeks 12, 24, 36, 48, 72, and 96 (Visits 6, 7, 8, 9, 10, and 11) 
will be conducted for both GT005 and untreated control subjects. GT005 treated subjects will 
have an additional visit at Week 8 (Visit 5). Visit 11 will be during Week 96 (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. 
NUMBER OF SUBJECTS: 
Approximately 202 subjects are planned, with subjects randomised to one of two GT005 
dose groups (low dose [
 vg] and high dose 
 vg]) in Part 1 and low dose in Part 2. 
Within each part of the study subjects will be allocated to GT005 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. 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) 
4. Have GA lesion(s) total size between or equal to 1.25mm2 to 17.5mm2 in the study eye 
5. The GA lesion(s) 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: 
a. Non-exudative/sub-clinical fellow eye CNV identified at Screening, or 
b. Known history of fellow eye CNV with either 2 years since diagnosis or with 
no active treatment required in 6 months prior to Screening 
7. Have a BCVA of 24 letters (6/95 and 20/320 Snellen acuity equivalent) or better, using ETDRS 
charts, in the study eye 
8. Part 1 Only: Subjects carrying a CFI rare variant genotype (minor allele frequency of ≤ 
1%) previously associated with low serum CFI or subjects carrying an unreported CFI 
rare variant genotype that have tested to have a low serum CFI 
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. 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. Subjects who have a clinical diagnosis of Stargardt Disease or other retinal dystrophies, 
confirmed by the central reading centre 
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 


GYROSCOPE THERAPEUTICS 
PAGE 27 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
5. History of intraocular surgery in the study eye within 12 weeks prior to Screening (Visit 
1). Yttrium aluminium garnet capsulotomy is permitted if performed >10 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 in the study eye; 
uncontrolled intraocular pressure (IOP) despite the use of more than two topical agents; 
a history of glaucoma-filtering or valve surgery  
8. Axial myopia of greater than -8 dioptres in the study eye  
9. 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 
10. Have a contraindication to the specified protocol corticosteroid regimen 
11. Have received any investigational and/or approved product(s) 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 in the study 
eye or systemically 
12. Have received a gene or cell therapy at any time 
13. Are unwilling to use two forms of contraception (one of which being a barrier method) 
for 90 days post-dosing, if relevant 
14. 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 
DOSING OF THE INVESTIGATIONAL PRODUCT 
The study investigational product, GT005, is supplied to the surgical site as a vial of frozen 
sterile liquid. GT005 is an aqueous suspension of recombinant AAV2 vector particles in 
 
 GT005 is administered at room temperature as a single-time subretinal 
injection into the study eye of subjects allocated to GT005. 
Surgical procedure 
The surgical procedure for subretinal administration of GT005 is based on standardised 
methodology. It is conducted by an appropriately qualified Vitreoretinal Surgeon in an 
operating room under local anaesthesia. Other anaesthetic options may be considered by the 
Surgeon as appropriate for the subject. The duration of the surgery is approximately 1 hour.  
Subjects allocated to treatment are injected with GT005 via a single-time administration, in 
a procedure involving one or more GT005 administration bleb(s). 
 
 
 
 
The bleb(s) usually flatten within approximately 24 hours. The 
detailed procedure is described in the Surgical Manual. 
DURATION OF TREATMENT AND FOLLOW-UP 
All subjects randomised to receive GT005 will receive a single-time subretinal injection. All 
subjects, those receiving GT005 and those allocated to untreated control, will be followed 
for 96 weeks. After the final follow-up visit, all GT005 treated subjects will be invited to 
participate in a long-term follow-up study to assess safety and efficacy over time. 
REFERENCE TREATMENT: 
The pooled untreated control group will provide a reference group to the GT005 treatment 
groups.  
STATISTICAL METHODS: 


GYROSCOPE THERAPEUTICS 
PAGE 28 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
Sample Size and Statistical Power 
Untreated control mean GA change at 48 weeks was assumed to be 2.1 mm2 with SD=1.3 
mm2. Up to ~10−12% of subjects are expected to discontinue treatment and not provide the 
target 48 week observation. 
 
 
 
 
 
 
 
 
Analysis Sets 
The Full Analysis Set (FAS) will include all subjects who are randomised to GT005 or 
untreated control. A Safety Analysis Set (SAF) will include all subjects who are randomised 
to GT005 or untreated control, and have at least one post-baseline observation. 
Efficacy Assessments 
The primary endpoint, change from baseline to Week 48 in GA area, will be compared 
between treatments via least squares means from analysis of covariance (ANCOVA). Details 
of the model specifications and data imputation approaches will be specified in the Statistical 
Analysis Plan (SAP). Other continuous efficacy endpoints will be analysed similarly using 
mixed model repeated measures (MMRM). 
Categorical and binary endpoints will be summarised by counts and percentages by dose. No 
statistical inferential testing is planned for all endpoints since this is an exploratory Phase 2 
study. 
 
 
 
 
.   
Safety Assessments 
Safety evaluations include AEs, ophthalmic imaging and examinations, BCVA and Low 
Luminance Visual Acuity for LLD (ETDRS) score (assessed as both an efficacy and safety 
endpoint), vital signs, laboratory safety (biochemistry and haematology), and 
 
AEs will be summarised in two parts: systemic events and ocular events. For systemic events, 
data will be displayed according to treatment received (untreated, low dose [
 vg] and 
high dose [
 vg]). Ocular events will be displayed according to treatment allocation 
(including GT005 dose group 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, 
intra-ocular pressure, etc.) and BCVA scores, will be summarised in the same manner as 
ocular efficacy variables, dependant on data type. 
Interim Analyses 
The analysis based on the Week 48 data will be the primary efficacy analysis for this study. 


GYROSCOPE THERAPEUTICS 
PAGE 29 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0 06 DEC 2022 
CONFIDENTIAL 
 
 
The database including all Week 48 data will be locked once all enrolled subjects from Part 
1 and Part 2 have completed the Week 48 visit or terminated the study prior to Week 48. 
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. 
Additional interim analyses may be considered to help inform internal development decision 
points for GT005, in which case the details will be pre-specified in the SAP prior to 
conducting the analysis. 
MONITORING COMMITTEES 
Data Monitoring Committee 
The Data Monitoring Committee (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 Independent Statistics Centre (ISC) as per the 
DMC Charter to ensure safety of the subjects. Only the DMC and ISC will be unmasked to 
Part 1 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 and to perform the clinical outcome analyses.  
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. 
 


GYROSCOPE THERAPEUTICS 
PAGE 30 OF 128 
PROTOCOL GT005-02 (EXPLORE): V6.0, 06 DEC 2022 
CONFIDENTIAL 
 
 
Table 1: Schedule of Assessments: Subjects Allocated to GT005 
Location 
Local or Surgical Site 
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 
Screening
1 
Randomisation 
Day 1 (Dosing) 
Day 2 
Day 3 Week 
1 
Week 
2 
Week 
5 
Week 
84 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
Week 
72 
Week 
96/EoS  
Pre-
surgery2 Surgery 
Post-
surgery3 
Window 
-8 weeks 
 
 
 
+ 1 
day 
± 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 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical history 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test6 
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 level7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery and dosing of 
GT005 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events13 
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 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmic examination 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-surgical ocular safety 
check 
 
 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFP  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
FAF 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
OCT-Macula 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 


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Location 
Local or Surgical Site 
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 
Screening
1 
Randomisation 
Day 1 (Dosing) 
Day 2 
Day 3 Week 
1 
Week 
2 
Week 
5 
Week 
84 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
Week 
72 
Week 
96/EoS  
Pre-
surgery2 Surgery 
Post-
surgery3 
Window 
-8 weeks 
 
 
 
+ 1 
day 
± 3 
days 
±3 
days 
±7 
days 
+3/-7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 days 
OCT-A 
X15 
 
 
 
 
 
X16 
Fluorescein angiography 
X15 
 
 
 
 
 
X16 
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  
 
 
X19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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; FA=fluorescein angiography; FAF=fundus autofluorescence; FRI=functional reading 
independence; LLD=low luminance difference; LLVA= low luminance visual acuity; MAIA=macular integrity assessment; MNRead=assessment of reading performance; OCT=optical coherence 
tomography; Tel=telephone; VFQ=visual function 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 8 week 
screening period has elapsed, standard ophthalmic exam, haematology/biochemistry and BCVA/LLVA should be repeated prior to surgery; other assessments may be performed at the 
investigator’s discretion. If a subject is rescreened within 8 weeks of the original screening visit date, 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 after 8 weeks of the original screening visit date, all screening 
assessments should be repeated with the exception of genotyping and serum CFI.  
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. 
In the event that GT005 administration is deferred during the surgical procedure (e.g. due to an adverse event) the administration surgery may be rescheduled within 10 weeks of the original 
surgery date 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. 
4. 
Study assessments at Week 8 may be conducted at +3/-7 days of the study visit. 
5. 
Randomisation will occur following confirmation of eligibility; subjects will be informed via telephone call of the randomisation outcome. 
6. 
Only for women of child-bearing potential. 
7. 
To be completed only if not previously performed at a Sponsor-approved laboratory. 
 
 
 
  
 
 
.  


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Location 
Local or Surgical Site 
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 
Screening
1 
Randomisation 
Day 1 (Dosing) 
Day 2 
Day 3 Week 
1 
Week 
2 
Week 
5 
Week 
84 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
Week 
72 
Week 
96/EoS  
Pre-
surgery2 Surgery 
Post-
surgery3 
Window 
-8 weeks 
 
 
 
+ 1 
day 
± 3 
days 
±3 
days 
±7 
days 
+3/-7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 days 
 
 
12. To be collected only if termination occurs after Visit 4 (Week 5) and before Visit 8 (Week 36). 
13. AEs should be captured from the date of signing the informed consent form. Additional assessments may be conducted, as needed, to allow for safety assessment. 
14. 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. 
15. CNV assessment at screening/prior to surgery 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.  
16. OCT-A and/or FA may be performed during the study period if clinically indicated, for example, if a subject converts to wet AMD. 
 
 
 
 
 
 
 
 
19. 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 
(ALL) 
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/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 
X 
 
 
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 
Fluorescein angiography 
X6 
 
 
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; FA=fluorescein angiography; FAF=fundus autofluorescence; FRI=functional reading independence; 
LLD=low luminance difference; LLVA=low luminance visual acuity; MAIA=macular integrity assessment; MNRead=reading performance; OCT=optical coherence 
tomography; Tel=telephone; VFQ=visual function 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 8-week screening period has elapsed, standard ophthalmic exam, haematology/biochemistry and BCVA/LLVA should be repeated prior to surgery; other assessments 
may be performed at the investigator’s discretion. If a subject is rescreened within 8 weeks of the original screening visit date, 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 after 
8 weeks of the original screening visit date, all screening assessments should be repeated with the exception of genotyping and serum CFI. 


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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 the date of 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 FA. Further details 
are provided in the Central Imaging Manual.  
7. 
OCT-A and/or FA may be performed during the study period if clinically indicated, for example, if a subject converts to wet AMD. 
 
 
 
 
 
 
 
 
 


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1. BACKGROUND INFORMATION 
A full description of the indication, investigational medicinal product (IMP), preclinical and 
clinical data available for GT005 is provided in the Investigator’s 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 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 Preclinical Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A detailed description of the preclinical data is provided in the IB. 
1.4 Clinical Studies 
A single first-in-human study evaluating the safety, dose response and efficacy of three doses 
of GT005 administered by subretinal injection to subjects presenting with GA due to AMD is 
ongoing.  
1.5 Study Rationale 
1.5.1 The Complement Cascade 
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. Variants in genes of complement factors involved in 
the alternative pathway (Complement Factor H, CFI, Complement Factor B, and Complement 
component 3 C3) have been found in AMD patients Fritsche 2016. The results of a number 
of genome-wide association studies suggest that mutations in these genes strongly correlate 
with the likelihood of developing AMD Fritsche 2013; Fritsche 2016. Additional studies have 
found that some rare genetic variants of CFI (defined by a minor allele frequency <1%) are 
associated with increased risk of advanced AMD, with one study showing that low serum CFI 
levels together with the presence of rare CFI variants is associated with an increased risk of 
development of advanced AMD Seddon 2013; Kavanagh 2015; Geerlings 2017.   
1.5.2 Rare Variant Genetic Population (Part 1) 
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, reducing the progression of the disease. The subset of GA patients with CFI rare variant 
genotype associated with a low serum CFI may demonstrate a larger response to treatment that 
supplements CFI locally, correcting the effects of their complement gene mutation. AAV2 
vector-based CFI gene transfer (GT005) provides a sustained expression of human CFI in AMD 


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patients’ eyes and is expected to result in down-regulation of the alternative complement 
pathway. 
Part 1 will only consider CFI rare variant genotypes previously associated with low serum CFI 
or subjects carrying an unreported CFI rare variant genotype that have tested to have a low 
serum CFI for study entry.   
Part 1 of the study will close for enrolment once all appropriate approvals for protocol V6.0 are 
in place; subsequently, subjects with GA and a CFI rare variant genotype should then be entered 
into Part 2 of the study.  
 
1.5.3 Broad Genetic Population (Part 2) 
Part 2 of the EXPLORE Phase II clinical study aims to assess the safety and efficacy of GT005 
in a broad population of GA subjects, regardless of genotype. 
 
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]. Rare, functionally damaging variants in CFH, CFB and C3 
strongly predispose to AMD [Raychaudhuri 2011; Seddon 2013; Zhan 2013; Saksens 2016]. 
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]. 
 
Part 2 is designed to evaluate whether administering CFI will be effective in down-regulating 
a hyperactive complement system across all GA patients from a broad genetic population and 
if this intervention will have a therapeutic effect on disease progression. 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].  
 
1.5.4 Dose Rationale 
 
 
 
 
 
 
  
 
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. It has been demonstrated that normal levels of CFI in plasma and vitreous humor are 


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28,366 and 691 ng/mL, respectively Mandava 2019. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
1.6 Risk/Benefit Assessment 
A summary of data and guidance to the Investigator is provided in the IB. 
1.6.1 Potential Risks 
The risks associated with this study can be divided into those related to the GT005 product, the 
surgical delivery of GT005, and study procedures. 
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, 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
The potential risks associated with gene therapy are related to intraocular inflammation, 
immunogenicity, developmental risks, germ line transmission, and environmental risks as 
discussed below. 


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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 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, 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. 
 
 
 
 
 
 
 
 
 
 
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. 
 
 


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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. GT005 is considered to pose negligible risk to humans, animals, and the environment. 
 
 
   
Retinal Pigment Epithelium (RPE) Changes 
Pigmentary changes have been noted in the RPE of some subjects receiving GT005 via 
subretinal delivery (Refer to the IB for further information). These changes are limited to the 
bleb area and in most cases were first seen at Week 12 and are identifiable on FAF. In a minority 
of cases an area of depigmentation can also be seen on colour fundus photography (CFP).  
 
1.6.1.2 Risks Associated with the Surgical Procedure and Study Procedures 
The surgical technique employed for this clinical study has been developed for and successfully 
used for the choroideremia subretinal gene therapy clinical studies MacLaren 2014; Xue 
2017. Risk mitigation 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: 
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 adverse events (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 


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(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 GT005 
study and assessed as likely to require cataract surgery during the 12-month study period will 
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 48 visit. 
Intraocular pressure elevation is a risk associated with vitrectomy procedures [Chang 
2006] and 
periocular or 
topical steroids [Kersey 2006]. In 
publicly 
available 
safety 
data, voretigene neparvovec (Luxturna®), had reports of elevation in intraocular pressure in 8 
of 81 eyes treated (10%). Subjects will have intraocular pressure (IOP) checked at every visit to 
ensure adequate monitoring and therapies 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.  
1.6.2 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 
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 visual loss. 
1.6.3 Risk Benefit Analysis 
GT005 is currently being evaluated in an ongoing Phase 1/2 clinical study and therefore the 
potential risks are based on clinical data from an ongoing dose escalation safety study, 
preclinical data, and available scientific knowledge of AAV2 vectors carrying different 
transgenes for the treatment of various retinal conditions without significant AEs related to 
these Drug Products MacLaren 2014; Russell 2017; Heier 2017; Voretigene Neparvovec FDA 
ACM 2017]. 
 
 
 
 
 


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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 
further developed and successfully used 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 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 safety and efficacy (anatomical and 
functional visual outcomes) of two doses of GT005 in genetically defined subjects with GA 
due to AMD. 
 
OBJECTIVES 
ENDPOINTS 
Primary 
• To evaluate the effect of GT005 
on the progression of GA in 
subjects with GA due to AMD 
• The change from baseline to Week 48 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 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 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 
functioning questionnaire-25 (VFQ-25) through 
Week 96 


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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 
parameters 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, subjects, 
investigators, 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 at centralised surgical sites for the 
administration of GT005. For women of child-bearing potential a second pregnancy test will be 
performed at Visit 2. GT005 is administered as a single-time subretinal injection into the study 
eye.
 
 
Following the subretinal injection, GT005 subjects may be maintained 
in the clinic overnight up to 24 hours to assess any AEs resulting from the surgery. 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; Table 2.   
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. All subjects will be assessed for the 
occurrence of AEs at each visit and will undergo functional visual and retinal imaging, 
anatomical assessments, and biological sampling as per the schedule of assessments Table 1; 
Table 2. 
Subjects allocated to untreated control will be followed by the local investigative or surgical 
site. The pooled untreated control group will provide a reference group to the GT005 treatment 
groups.   
 
 
Subsequent follow-up visits at Weeks 12, 24, 36, 48, 72, and 96 (Visits 6, 7, 8, 9, 10, and 11) 
will be conducted for both GT005 and untreated control subjects at the local investigative or 
surgical sites. Visit 11 will be during the Week 96 (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.  
 
 
 
This study includes an untreated control group for comparison. 




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A permuted-block randomisation method will be used to obtain an approximately 2:1 ratio 
between treatment with GT005 and the untreated control group(s) for each dose group within 
each stratum.  
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. 
3.4.3 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 receiving GT005 and those allocated to untreated control, will be followed 
for 96 weeks. After the final follow-up visit or early termination visit, all GT005 treated subjects 
will be invited to participate in an extension study (ORACLE) for long-term follow-up to assess 


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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 (AESIs) 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, or 
• 
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) 
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) 
4) 
Have GA lesion(s) total size between or equal to 1.25mm2 to 17.5mm2 in the study eye 
5) 
The GA lesion(s) 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: 
a. 
Non-exudative/sub-clinical fellow eye CNV identified at Screening, or 
b. 
Known history of fellow eye CNV with either ≥2 years since diagnosis or with no 
active treatment required in 6 months prior to Screening 
7) 
Have a BCVA of 24 letters (6/95 and 20/320 Snellen acuity equivalent) or better, using 
ETDRS charts, in the study eye 
8) 
Part 1 Only: Subjects carrying a CFI rare variant genotype (minor allele frequency of 
≤1%) previously associated with low serum CFI or subjects carrying an unreported CFI 
rare variant genotype that have tested to have a low serum CFI 
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. 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)   
4.2 Exclusion Criteria 
Subjects will NOT be included in the study if they meet any of the following criteria: 
1) 
Subjects who have a clinical diagnosis of Stargardt Disease or other retinal dystrophies, 
confirmed by the central reading centre 
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 Screening (Visit 
1). Yttrium aluminium garnet capsulotomy is permitted if performed >10 weeks prior 
to Visit 1 


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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 in the study eye; 
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 dioptres in the study eye  
9) 
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 
10) 
Have a contraindication to specified protocol corticosteroid regimen 
11) 
Have received any investigational and/or approved product(s) 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 in the study 
eye or systemically 
12) 
Have received a gene or cell therapy at any time 
13) 
Are unwilling to use two forms of contraception (one of which being a barrier method) 
for 90 days post-dosing, if relevant 
14) 
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 
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/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.  
 
Subjects who are withdrawn from the study after randomisation will not be replaced. The reason 
for the subject’s withdrawal from the study will be recorded in the electronic case report form 
(eCRF).  
Subjects who are randomised to GT005 treatment but do not subsequently get dosed, should be 
offered the option to continue in the study following the same visit schedule as those who are 
allocated to the untreated control arm [Table 2].  The reason for not receiving GT005 should be 
recorded in the eCRF. 


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4.4 Randomisation Criteria 
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 or 2 years postmenopausal) 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. 
 
As GT005 is a gene therapy, subjects should be made aware that once surgery has taken place, 
they can withdraw from the study but cannot withdraw from the study treatment.  
If appropriate, subjects who are considering withdrawing from the study should be offered the 
option to continue in the study with less intensive assessments, as an alternative to complete 
discontinuation from the study. If the subject is willing to continue with less intensive visits, 
this should be recorded in the subject’s medical record and the eCRF, and the following 
minimum data should be collected at clinic visits or via telephone/email contact (preferably 
according to the study visit schedule): 
• New treatments and/or change in concomitant treatments 
• Adverse Events 
If the contact is performed via telephone, this should ideally be done directly with the subject, 
or alternatively with another person pre-designated by the subject to convey information on 
their behalf. 


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If agreed between the subject and the Investigator, additional data may also be collected at these 
visits, according to the study visit schedule and with consideration to the key primary and 
secondary endpoints for the study. 
  
If the subject completely withdraws from the study, the reason for discontinuation/withdrawal 
of subjects must be determined by the Investigator and recorded in the subject’s medical record 
and in the 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 
• Study cancellation by the Sponsor 
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). As 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, subject to consent, be enrolled in a separate long-term follow-up 
study (ORACLE). The long-term follow-up study will evaluate the long-term safety and 
durability of GT005 after the final follow-up visit at Week 96 or early termination visit. 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 is 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. 
For Part 1, 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. Masking to the doses in Part 1 will be 
maintained at the site level (subjects, masked site personnel and masked monitors) until the end 
of the study. For Part 2, designated unmasked study member(s) is (are) not required. 
All expired GT005 should be recorded in the accountability records and will be destroyed 
locally, as per local guidelines once final accountability is completed. Details regarding the 
handling and preparation of GT005 are detailed in the Pharmacy Manual.    
5.2 Formulation, 
Appearance, 
Packaging 
and 
Labelling 
(include 
comparator 
information) 
GT005 is 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 the appropriate Competent Authority regulations. 
 
 
 
 
  
 
 
 
5.3 Product Preparation, Storage, and Dispensing 
GT005 post-administration measures regarding disposables are detailed in the Pharmacy 
Manual. 
 
 
 
 
 
   




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 The 
randomisation process is defined in Section 3.4.   
Additional measures to minimise bias include standardised methodologies across participating 
sites, and similar visit/assessment schedule for treated/untreated subjects. 
5.6 Concomitant Medication/Therapy Rescue Medication  
5.6.1 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) and 
Section 5.6.2 Prohibited Medication. If the fellow (non-study) eye requires treatment for GA, 
it may be treated at the discretion of the investigator. Fellow eye treatment will be captured in 
the eCRF. The fellow eye must be monitored according to routine clinical practice and AEs 
captured in the eCRF. 
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. 
5.6.2 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. 
The treatments displayed in Table 3 below are not allowed after Visit 1 (screening).  
 
 
 
 
 
 
 
 


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Table 3: Prohibited Medications for Study Eye Only 
Medication  
Prohibition 
period for GT005 
arm  
Prohibition period 
for untreated control 
arm 
Action taken 
Investigational GA 
medication  
Week 96  
Week 96  
Record in eCRF and 
continue with study 
visits until end of 
study 
Approved GA 
medication 
Week 96 
Week 48  
Record in eCRF and 
continue with study 
visits until end of 
study 
 
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 (see Section 5.6.1).   
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 received 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 also 
approved 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 all 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 
6.1.1 Screening (Visit 1: Local or Surgical Site) 
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 EXPLORE 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 EXPLORE 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.  
For Part 1 only: Where prior genotyping has been performed on subjects as aforementioned, 
and the subject is shown to carry a CFI rare variant that meets inclusion requirements, then the 
complete screening visit (Visit 1) can take place. 
If a subject has been genotyped at an alternative laboratory and shown to carry a CFI rare variant 
that meets inclusion requirements, then the complete screening visit (Visit 1) can take place, 
however an additional sample for confirmation of genotype must be taken at this time to 
confirm the finding. A separate informed consent form (ICF) will be used to obtain permission 
to perform the confirmation of genotype. This consent may be performed and obtained 
remotely, if required. The subject may not continue past Visit 1 until genetic confirmation has 
been obtained. 


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For those subjects who have not previously been genotyped, and who fulfil Inclusion Criteria 
1, 2, and 3, consent for genotyping and a genotyping sample should be obtained prior to 
performing any other screening assessments (Visit 1). A separate ICF will be used to obtain 
permission to perform the genotyping. This consent may be performed and obtained remotely, 
if required. The subject can then proceed to perform the remaining screening assessments once 
genetic confirmation has been obtained. 
Where necessary, and to facilitate the completion of all screening assessments, Visit 1 can occur 
over a number of days.  
Screening Assessments 
For Part 1 only (as described above), genotyping may be performed first and only subjects that 
are found to have the genetic variant of interest will be invited back to complete the remaining 
screening assessments. 
For Part 2 only, genotyping is performed as part of the overall screening assessments, since all 
subjects are genetically eligible to participate in this study.  
 
The screening assessments (Visit 1) will determine the full 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. 
 
The following screening assessments are required for ALL subjects: 
• Demographics 
• Medical/surgical history 
• Concomitant medication 
• Genotyping (only required if not already available from a Sponsor-approved laboratory. 
Genotyping results will be received to confirm eligibility prior to other screening 
activities in Part 1 only)   
• Pregnancy test (for women of child-bearing potential only) 
• AEs 
• Vital signs 
• Biochemistry/haematology 
• Serum CFI level (only required if not already available from a Sponsor-approved 
laboratory) 
 
 
• Ophthalmic examination* 
• CFP 
• FAF 
• OCT macula 


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• 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 ETDRS* 
• Low luminance visual acuity (LLVA) using ETDRS for LLD* 
• MNRead 
• VFQ-25 
• FRI Index 
*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, haematology/biochemistry, 
standard ophthalmic exam and BCVA/LLVA should be repeated; other assessments may be 
performed at the investigator’s discretion. 
6.1.2 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 
6.1.3 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: pre-
surgery, surgery, and post-surgery assessments. 


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6.1.3.1 Pre-surgery (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 
• Vital signs 
• AEs 
 
 
 
 
• Pre-surgical ocular safety check to verify there are no new ocular adverse events 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 administration surgery may be rescheduled within 10 weeks 
of the original surgery date 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 assessments are required during surgery: 
 
 
• AEs 
• Concomitant medications 
 
 
 
 
 
The procedure for the administration of GT005 is described in Section 5.4 and in the Surgical 
Manual.  
 
 
  
 
Post-surgery – Day 2 (Surgical Site) 
The following assessments are required one day post-surgery: 


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• Concomitant medication 
 
 
• Vital signs 
• AEs/ 
• Ophthalmic examination 
 
 
• OCT macula 
6.1.4 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 
6.1.5 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) 
6.1.6 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 


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6.1.7 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 local site 
Investigator and the Surgeon. 
Subjects allocated to untreated control will receive a telephone call from their local 
investigative site 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/haematology 
 
  
• Ophthalmic examination 
• OCT macula 
 
  
• BCVA using ETDRS 
• CFP  
• FAF 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
6.1.8 Visit 5, Week 8 (Local or Surgical Site) 
Visit 5 (Week 8) assessments listed below will only apply to subjects randomised to GT005: 
• Concomitant medication 
• AEs 
• Ophthalmic examination 
 
 
• BCVA using ETDRS 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 


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6.1.9 Visit 6, Week 12 (Local or Surgical Site) 
The following assessments will be performed for ALL subjects unless otherwise specified: 
• Concomitant medication 
 
 
• AEs 
 
 
 
• Biochemistry/haematology 
 
 
• Ophthalmic examination 
• FAF 
• 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) 
 
 
 
 
6.1.10 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/haematology 
 
 
 
 
• Ophthalmic examination 
• FAF 


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• OCT macula 
 
 
 
 
 
• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• MNRead 
• VFQ-25 
• FRI Index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
6.1.11 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 
• MNRead 
• VFQ-25 
• FRI Index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 


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6.1.12 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/haematology 
 
 
 
 
 
 
• AEs 
• Ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
 
 
 
 
 
• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• MNRead 
• VFQ-25 
• FRI Index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
6.1.13 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/haematology 
• AEs 
• Ophthalmic examination 


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• CFP 
• FAF 
• OCT macula 
 
 
 
 
 
• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• MNRead 
• VFQ-25 
• FRI Index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
6.1.14 Visit 11, Week 96/End of Study and Early Termination Visit (Local or Surgical 
Site) 
The following assessments will be performed for ALL subjects unless otherwise specified: 
• Concomitant medication 
• Vital signs 
• Biochemistry/haematology 
 
 
 
 
 
 
 
 
 
• AEs 
• Ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
 
 


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• BCVA using ETDRS 
• LLVA using ETDRS for LLD 
• MNRead 
• VFQ-25 
• FRI Index 
• OCT-A and/or FA if clinically indicated (if a subject converts to wet AMD) 
 
 
 
 
 
6.1.15 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 
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 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 Gyroscope sponsored 
study or during the EXPLORE screening period. Informed consent will include permission for 
genotyping (genotyping and serum CFI evaluation are not required for subjects who have these 
from another Gyroscope study) and a consent from each subject or legal representative to enrol 
into EXPLORE 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 EXPLORE 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 EXPLORE, 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 ICF will be given to the participant. The original signed form 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, sex, at baseline 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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For those subjects who have not previously been genotyped, and who fulfil Inclusion Criteria 
1, 2, and 3, consent for genotyping and a genotyping sample should be obtained prior to 
performing any other screening assessments (Visit 1). Where necessary, and to help fulfill this 
requirement, Visit 1 can occur over a number of days. 
7.2 Concomitant Medication 
 
7.2.1 
 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.   
7.3.1 Ophthalmic Examination 
Ophthalmological examinations in both eyes will be performed as follows: anterior segment 
examination via slit lamp biomicroscopy, intraocular pressure 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. Intraocular pressure 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. 
7.3.2 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.  
7.3.3 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; the CRC will 
transfer the data to the data management group and/or Independent Statistics Centre (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).   


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7.3.4 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 
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). 
7.3.5 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 images 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 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 images are to be taken).  
7.3.6 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 which is an eligibility exclusion 
criterion. Other imaging modalities as described in the Central Imaging Manual may also 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.   
7.3.7 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 nanometres, 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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7.3.9 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 Snellen result is >2 lines (BCVA equivalent to 10 letters), worse than the previous BCVA 
ETDRS score, then a BCVA with ETDRS assessment must be repeated. If the BCVA with 
EDTRS results is ≤2 lines worsened compared to the previous BCVA with ETDRS, record the 
subject's 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. 
 
7.3.10 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 and 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.   
7.3.11 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. 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. The LLD is calculated 
as the difference between BCVA and LLVA.  
7.3.12 Reading Performance 
Monocular (study eye separate from contralateral eye) Reading Speed will be assessed by the 
Minnesota Low-Vision Reading Test (MNRead Acuity Test) Appendix 17.2. The reading test 
will be provided in the native language of the participating subject. 
7.3.13 Visual Function Questionnaire  
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 (NEI-VFQ) 
Appendix 17.3.  


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7.3.14 Functional Reading Independence Index 
The FRI index is a patient-reported outcome measure developed specifically for use in GA 
patients. 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 
[Appendix 17.5]. 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. 
7.4 Safety 
7.4.1 Vital Signs 
Vital signs including heart rate, temperature, and blood pressure will be measured. Blood 
pressure (systolic and diastolic) is to be measured in triplicate after 5 minutes rest in a sitting 
position. The same method should be used throughout the study. Heart rate will be assessed as 
a single measurement.   
7.4.2 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. AEs are collected from the time written informed 
consent is provided until end of the study. Additional imaging safety assessments may be 
collected at any visit, as needed, in order to follow-up on any AEs. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
7.4.3 Pregnancy Test 
Females of child-bearing potential are defined as those who have experienced menarche 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).  




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* eGFR will be calculated using the CKD-EPI (chronic kidney disease epidemiology collaboration) formula. 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
EXPLORE screening period. 
 
 
 
 
 Justification and definition of 
rare variant genotypes (minor allele frequency of ≤ 1%) previously associated with low serum 
CFI will be provided in the document ‘Definition of CFI Genotype Eligibility for Clinical 
Studies for GT005’. 
  
 
 


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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 
An 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 


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(i.e. not associated with the development of a new AE or worsening of a pre-existing condition) 
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.
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
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 
8.4.1 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.   


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Severe: Interferes significantly with subject's usual function. 
AE severity will be assessed at the site by the Investigator or a medically qualified designee. 
8.4.2 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 
8.4.3 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. 
8.4.4 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 
8.4.5 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 


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8.5 Reporting Requirements 
8.5.1 Serious Adverse Events and Adverse Events of Special Interest 
All SAEs and AESIs, regardless of treatment group or suspected relationship to IMP or surgical 
procedures, 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 
report is submitted by telephone, this must be followed by detailed written reports using the 
relevant form. 
Any 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. 
Any AE/SAE with a suspected causal relationship to IMP administration occurring at any other 
time after completion of the study must be promptly reported. 
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/AESIs 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: 
 


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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.  
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, 
where possible, sufficient information should be 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, 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 


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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 subjects withdraw from the study due to an AE/SAE/AESI, every effort should be made to 
follow-up on any ongoing AEs. Any subject treated with GT005 should receive appropriate 
medical follow-up. 
8.9 Reporting to Competent Authorities/IECs/IRBs/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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9 
STATISTICS METHODS  
9.1  Sample Size Determination 
The mean GA change at 48 weeks in the untreated control group was assumed to be 2.1 mm2 
as was reported by Holz 2018, with SD=1.3 mm2.   
The following hypotheses are considered: 
H0L: µL - µC = 0, HAL: µL - µC < 0 
H0H: µH - µC = 0, HAH: µH - µC < 0 
Where µL , µH and µC represent the unknown true mean GA change on FAF at 48 weeks in the 
GT005 low dose [
], GT005 high dose [
] and pooled untreated control, respectively. 
 
 
 
 
 
 
 Including the additional subjects that are already randomised to the 
high dose group (approximately 10 subjects) in Part 1, the overall sample size is approximately 
202. 
9.2 Analysis Populations Definitions 
The Full Analysis Set (FAS) will include all subjects who are randomised to GT005 or untreated 
control. The Safety Analysis Set (SAF) will include all subjects who are randomised to the 
GT005 or control group and provide at least one post baseline observation. 
9.3 Significance Testing and Estimations 
Type 1 error (alpha) is set at 0.05 one-sided and estimates of outcome parameters will be 
accompanied by 90% confidence intervals to be consistent with the Type 1 error level. No 
multiplicity adjustment will be applied since this is an exploratory study.  
9.4 Statistical/Analytical Methods 
9.4.1 Demographics and Baseline Characteristics 
Demographic and baseline characteristics including age, race, ethnicity, sex, as well as baseline 
GA lesion size, will be summarised with descriptive statistics or counts and percentages of 
subjects as appropriate by treatment and in total for each defined analysis population. 
9.4.2 Efficacy Assessments 
The primary endpoint, change from baseline to Week 48 in GA area, will be compared between 
treatments via least squares means from analysis of covariance (ANCOVA). The primary 
estimand will focus on the effect of different doses of GT005 on GA change on FAF at Week 
48 and account potential unfavourable effects of GT005. The primary estimand includes the 
following components: 
• Population: subjects with GA secondary to AMD 
• Variable: Change from baseline in GA lesion size on FAF at Week 48 


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• Treatment: the randomised treatment of the investigational therapy GT005 
• Intercurrent events: defined in Table 5 below: 
 
Table 5: Intercurrent events and corresponding primary data handling strategies 
Intercurrent event 
Data handling strategy 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Details of the model specifications and further details on data imputation approaches will be 
described in the SAP. Other continuous efficacy endpoints will be analysed similarly using 
mixed model repeated measures (MMRM).  
 
 
 
  
Categorical and binary endpoints will be summarised by counts and percentages by dose. No 
statistical inferential testing is planned for any endpoint since this is an exploratory Phase 2 
study. 
9.4.3 Safety Assessments 
Safety evaluations include AEs, ophthalmic imaging and examinations, BCVA (ETDRS) score 
(assessed as both an efficacy and safety endpoint), vital signs, laboratory safety (biochemistry 
and haematology), 
 
 


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AEs will be summarised in two parts: systemic events and ocular events. For systemic events, 
data will be displayed according to treatment received (low dose [
vg], high dose [
 
vg], and untreated). Ocular events will be displayed according to treatment allocation (including 
GT005 dose group) and study eye (study eye and contralateral eye).  
All AEs (overall, by seriousness, by severity, by relationship) recorded throughout the study 
will be reported following classification according to the Medical Dictionary for Regulatory 
Activities (MedDRA) 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, intra-
ocular pressure, etc.) and BCVA scores will be summarised in the same manner as ocular 
efficacy variables, dependant on data type. 
 
 
 
 
 
.   
9.4.5 Interim Analyses 
The analysis based on the Week 48 data will be the primary efficacy analysis for this study. 
The database including all Week 48 data will be locked once all enrolled subjects have 
completed the Week 48 visit or terminated the study prior to Week 48. 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. 
Additional interim analyses may be considered to help inform internal development decision 
points for GT005, in which case the details will be pre-specified in the SAP prior to conducting 
the analysis. 
9.4.6 Data Monitoring Committee 
The DMC will review the unmasked data as defined in the DMC Charter to ensure safety of the 
subjects and to inform the Sponsor on efficacy outcome trigger criteria to inform business 
strategy outside of this clinical study. There is no intention to stop this study for an early 
efficacy conclusion, so there is no impact of the Type 1 error. An ISC will conduct these interim 
analyses. The DMC and ISC will be unmasked to study data during the conduct of the study.  
The DMC is an independent committee that will be comprised 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. 
9.4.7 Handling missing data 
Missing or censored data will be handled in accordance with the handling data strategy for 
intercurrent events as described in Table 5. The details of the statistical approaches for missing 
and/or censored data imputation will be described in the SAP and may include additional 
missing 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, 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 system 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 is always 
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 investigative 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/institution should have written and dated 
approval/favourable opinion from the IEC/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/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
After IEC/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/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
13.2 
Subject Information and Consent 
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. Written 
informed consent will be obtained from each subject before any study related procedures or 
assessments are performed.  
The Sponsor will provide a sample informed consent form. The final version controlled form 
must be agreed to by the Sponsor, and the IEC/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/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. 
The Investigator should, with the consent of the subject, inform the subject’s primary physician 
about their participation in the clinical study. 


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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 requested by FDA 21 CFR Part 
54. 
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 required to complete Form FDA 3454. 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 or 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 or 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 eCRF. 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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February 2020]. 
Provost N, et al. Biodistribution of rAAV vectors following intraocular administration: 
evidence for the presence and persistence of vector DNA in the optic nerve and in the brain.  
Mol Ther 2005;11:275–83. 
Raychaudhuri A, et al. A rare penetrant mutation in CFH confers high risk of age-related 
macular degeneration. Nat Genet 2011;43:1232–1236. 
Russell S, et al.  Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients 
with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 
3 trial.  Lancet 2017;390:849–860.  
Saksens NTM, et al. Rare genetic variants associated with development of age-related macular 
degeneration. JAMA Ophthalmol 2016;134:287–293. 
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. 
Xue K, et al. Technique of retinal gene therapy: delivery of viral vector into the subretinal space. 
Eye 2017;31:1308–1316. 


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Zhan X, et al. Identification of a rare coding variant in complement 3 associated with age-
related macular degeneration. Nat Genet 2013;45:1375–1379. 


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17 APPENDICES 
17.1 
AREDS 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 10x 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. 
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) 


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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. 
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. 


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




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17.4 Vitreous Haze Grading Scale 
 
 
 


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SAP_001.pdf: 
Clinical Development 
CPPY988A1 
CPPY988A12202 (GT005-02) / NCT04437368 
EXPLORE: A Phase 2, Outcomes Assessor-Masked, Multicenter, 
Randomized 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 Age-Related 
Macular Degeneration 
Statistical Analysis Plan (SAP)  
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
13-Jun-2024
Number of pages: 
30 
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) 
24-
Jan-
2024 
Prior 
to 
DB 
lock 
Creation of 
final 
version 
N/A - First version 
N/A 
 


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Table of contents 
Table of contents ..................................................................................................................................... 3 
List of abbreviations ............................................................................................................................... 5 
1 
Introduction ............................................................................................................................................. 6 
1.1 
Study design .............................................................................................................................. 6 
1.2 
Study objectives, endpoints and estimands ............................................................................... 8 
1.2.1 
Primary estimand(s) .............................................................................................. 10 
2 
Statistical methods ................................................................................................................................ 10 
2.1 
Data analysis general information ........................................................................................... 10 
2.1.1 
General definitions ............................................................................................... 10 
2.2 
Analysis sets ............................................................................................................................ 12 
2.2.1 
Subgroup of interest .............................................................................................. 12 
2.3 
Subject disposition, demographics and other baseline characteristics .................................... 12 
2.3.1 
Subject disposition ................................................................................................ 12 
2.3.2 
Demographics and other baseline characteristics ................................................. 13 
2.3.3 
Medical history ..................................................................................................... 13 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, compliance) ........... 14 
2.4.1 
Study treatment ..................................................................................................... 14 
2.4.2 
Prior, concomitant and post therapies ................................................................... 14 
2.5 
Analysis supporting primary objective(s) ................................................................................ 14 
2.5.1 
Primary endpoint(s) .............................................................................................. 14 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................................... 15 
2.5.3 
Handling of intercurrent events ............................................................................ 15 
2.5.4 
Handling of missing values not related to intercurrent event ............................... 15 
2.5.5 
Sensitivity analyses ............................................................................................... 15 
2.5.6 
Supplementary analyses ....................................................................................... 15 
2.6 
Analysis supporting secondary objectives ............................................................................... 16 
2.6.1 
Secondary endpoint(s) .......................................................................................... 16 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................................... 16 
2.6.3 
Handling of missing values/censoring/discontinuations ....................................... 18 
2.7 
Safety analyses ........................................................................................................................ 18 
2.7.1 
Adverse events (AEs) ........................................................................................... 18 
2.7.2 
Deaths ................................................................................................................... 20 
2.7.3 
Loss in best corrected visual acuity ...................................................................... 20 
2.7.4 
Laboratory data ..................................................................................................... 20 
2.7.5 
Other safety data ................................................................................................... 21 
2.8 
Pharmacokinetic endpoints ...................................................................................................... 21 
2.9 
PD and PK/PD analyses .......................................................................................................... 21 
2.10 
Patient-reported outcomes ....................................................................................................... 21 


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 23 
 
 24 
3 
Sample size calculation ......................................................................................................................... 25 
4 
Change to protocol specified analyses .................................................................................................. 26 
5 
Appendix ............................................................................................................................................... 26 
5.1 
Imputation rules ....................................................................................................................... 26 
5.1.1 
AE date imputation ............................................................................................... 26 
5.1.2 
Concomitant medication date imputation ............................................................. 28 
5.2 
AEs coding/grading ................................................................................................................. 30 
5.3 
Laboratory parameters derivations .......................................................................................... 30 
5.4 
Statistical models ..................................................................................................................... 30 
5.4.1 
Analysis supporting primary objective(s) ............................................................. 30 
5.5 
Rule of exclusion criteria of analysis sets ............................................................................... 30 
 


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List of abbreviations 
 
 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AMD 
Age-related Macular Degeneration 
BCVA 
Best Corrected Visual Acuity 
CFI 
Complement factor I 
CFP 
Color Fundus Photography 
CI 
Confidence Interval 
CNV 
Choroidal neovascularisation 
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  
FRI 
Functional Reading Independence 
GA 
Geographic atrophy 
IRT 
Interactive Response Technology 
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  
RPE 
Retinal Pigment Epithelium  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TAb 
Total (or binding) Antibodies 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
VFQ-25 
Visual Function Questionnaire-25 
 
 


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1 
Introduction 
The EXPLORE study (CPPY988A12202) is being terminated early as Novartis has made the 
decision to stop the current clinical development program for GT005 in subjects with 
geographic atrophy 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 analysis planned in/changed from the study protocol, and to provide detailed 
statistical methods that will be used for the EXPLORE Clinical Study Report (CSR).  
A 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. Data will be analyzed according 
to the data analysis plan described in this document that will be incorporated into the CSR. 
This SAP is based on the EXPLORE Clinical Study Protocol V6.0, dated 6 December 2022. 
1.1 
Study design 
This is a Phase 2, outcomes assessor-masked, multicenter, randomized 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 age-related macular degeneration (AMD).  
Approximately 202 subjects are planned to be randomized to GT005 or the untreated control 
group. 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 a 
previous Gyroscope sponsored study, or during the EXPLORE screening period. Data from 
subjects screened in another Gyroscope sponsored study at the same investigative site as 
EXPLORE 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 EXPLORE, they will be classed 
as Screen Failures for this study and may be considered for entry into another Gyroscope 
sponsored study. 
Following consent, subjects will undergo ophthalmic and clinical assessments to determine 
eligibility for inclusion in the study. The consent process and screening assessments will occur 
at either the subject’s local or surgical investigative site. A proportion of the study sites will be 
designated as centralized surgical sites. 
On confirmation of eligibility, subjects in Part 1, will be randomized to one of two dose groups 
(low dose [
 vg] or high dose 
 vg]). Within each part of the study, subjects will be 
allocated to GT005 or untreated control based on a 2:1 scheme (Figure 1-1). Once Part 1 
enrolment is completed, and the last active subject completes screening and either screen fails 
or is randomized, then Part 2 can commence. In Part 2, subjects will be randomized to one of 
two treatment groups (low dose 
] or untreated control) in a 2:1 scheme.  






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• 
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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1.2.1 
Primary estimand(s) 
The primary estimand will focus on the effect attributable to different doses of GT005 on GA 
change on FAF at Week 48 in subjects who have not received alternative GA medications or 
therapies in the study eye. 
The primary estimand is described by the following attributes: 
1. Population: Subjects with GA secondary to AMD. Details on the target population are 
defined by the study inclusion and exclusion criteria. 
2. Variable: Change from baseline in GA lesion size (mm2) based on FAF at Week 48 
3. Treatment: The randomized treatment (different doses) of the investigational therapy 
GT005 delivered through transvitreal subretinal injection. 
4. Summary Measure: The treatment difference of the variable means between GT005 
and untreated control, represented as % relative to untreated control. 
5. Intercurrent events and data handling strategy: defined in Table 1-2. 
Table 1-2 
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 missing at random (MAR) 
2 
Statistical methods 
2.1 
Data analysis general information 
The analyses will be performed by the Contract Research Organization (CRO) using SAS 9.4.  
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 the treatment group unless otherwise specified. Where appropriate, 
point estimates and confidence intervals (CI) of treatment group differences will be provided. 
2.1.1 
General definitions  
2.1.1.1 
Study treatment  
The following treatment groups will be presented: 
• Untreated control  
• Low dose GT005 (
 vg) 
• High dose GT005 (
 vg) 


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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 (if applicable)  
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. 
2.1.1.4 
Unscheduled visits 
For unscheduled visits, the analysis visits will be derived with windowing where appropriate 
(e.g., Visit 3 ± 3 days) as per the protocol. For scheduled visits, the analysis visits will be the 
actual (reported) visit number. 
Data collected at unscheduled visits will not be used in ‘by-visit’ tabulations, graphs or analyses 
unless it can be mapped to a missed scheduled visit with the window specified per the protocol. 
If multiple unscheduled visits are allocated to the same missed scheduled visit: 
• The unscheduled visit closest to the missed scheduled visit will be used 
• If there are multiple unscheduled visits with the same distance to the missed scheduled 
visit, the latest one will be used 
For analyses showing abnormalities, data from unscheduled visits will be considered 
individually, without mapping to a main visit.  
For analyses based on all post-baseline values such as averages over a given period summaries 
of maximum/minimum values, data collected at unscheduled visits will be included.  
All data collected at unscheduled visits will be listed. 


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2.1.1.5 
Missing baseline and post-baseline data  
Missing baseline data will not be imputed. 
Observations with values ‘not done’, ‘not evaluable’, ‘not applicable’ will be treated as missing 
values. 
In case of multiple entries for the same assessment are observed within one visit, the latest 
assessment value will be used. 
2.1.1.6 
Alternative GA medications or therapies 
Avacincaptad pegol (Izervay) and pegcetacoplan (Syfovre) via intravitreal injection are Food 
and Drug Administration approved treatments for GA and are permittable alternative GA 
treatments in this study.  
2.2 
Analysis sets  
The All-Enrolled Set includes all patients who signed informed consent. This analysis set will 
be used to summarize subject disposition. 
The Full Analysis Set (FAS) will include all subjects who are randomized to GT005 or 
untreated control. The FAS will be used for the analysis of efficacy and safety data.    
The number and percentage of subjects within each of the above analysis sets will be 
summarized. 
2.2.1 
Subgroup of interest 
Not Applicable. 
2.3 
Subject disposition, demographics and other baseline 
characteristics 
2.3.1 
Subject disposition 
Subject disposition will be summarized separately by treatment group and in total for the All-
Enrolled Set: the number and percentage of screen failures (including the primary reason for 
screen failure), subjects enrolled, randomized, randomized and treated with GT005, completed 
study, discontinued the study prematurely (including the primary reason for premature study 
discontinuation). 
A listing of subjects who discontinued study earlier than the planned end-of-study will be 
provided by treatment group for the FAS. This listing will identify the last visit completed and 
when the study was discontinued including the primary reason.   
In addition, protocol deviations (PDs) will be listed and summarized by the number and 
percentage of subjects with each deviation category for the FAS. 


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2.3.2 
Demographics and other baseline characteristics 
Demographic and baseline characteristics including age, race, (self-reported and genetically 
defined) ethnicity, sex, and AMD genetic subgroup will be summarized with descriptive 
statistics or counts and percentages of subjects as appropriate by treatment group and in total 
for FAS. 
Summary statistics will be presented for the study eye if they are baseline ocular characteristics. 
Listings for demographic and ocular baseline characteristics will be provided.  
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. These outputs will be based 
on the FAS. 


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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 
allocated to one of the two GT005 doses. The surgical procedure for subretinal administration 
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. 
A listing for surgical and dose administration records will 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-baseline visits and 
continued into the treatment period. 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 arms, 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 evaluate 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 48 in GA area as measured by FAF.  


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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. 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, three interaction terms (assessment visit and 
treatment group, assessment visit and GA area at the baseline, GA area at the baseline and 
treatment group) as the fixed effect and subject as a random effect. 
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 groups. A line plot for the estimated LSM 
with 90% CI by visit and treatment groups will also be provided. 
As this study is being terminated, statistical modeling as described above and/or summary tables 
will be provided as appropriate based on data availability.  
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 48 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 
In the case of missing data occurring in other scenarios, i.e. independent of intercurrent events 
defined in Table 1-2, 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. 




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• The 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. 
4.a Change in best corrected visual acuity (BCVA) Score via the early treatment for diabetic 
retinopathy (ETDRS) chart through Week 96  
• The change in BCVA through Week 96 will be estimated among treatment groups 
via least squares means from a 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 least-squares 
mean (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 groups. A line plot for the estimated LSM with 90% CI by visit 
and treatment groups will also be provided. All BCVA assessments will be listed by 
treatment group, site, and subject.  
4.b Change in low luminance difference (LLD) via the ETDRS chart through Week 96 
• The LLD and the changes from baseline will be summarized based on observed data 
by assessment visits and treatment group. All LLD assessments will be listed by 
treatment group, site, and subject. 
5.a Change in reading performance as assessed by Minnesota low-vision reading test 
(MNRead) chart through Week 96  
• The Maximum reading speed (MRS) for each eye as assessed by MNRead Chart and 
the 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.  


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5.b Change in functional reading independence (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 on the visual function questionnaire-25 (VFQ-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. 
As this study is being terminated, statistical modeling and/or summary tables for corresponding 
endpoints will be provided as appropriate based on data availability. 
2.6.3 
Handling of missing values/censoring/discontinuations 
Missing data handling of secondary analyses for different 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. 
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 






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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 
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  
 


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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 
“All of the time” to sub-
question f…  
Impute “yes" for sub-question e 
and score according to 
algorithm  
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 sub-scales 
and composite scores and changes from baseline will be calculated and summarized by 
assessment visits. 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 


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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 
Dependency 
20, 23 and 24 
Driving 
15c, 16 and 16a 
Color vision 
12 
Peripheral vision 
10 
The composite score is the average of the 11 subscales shown in Table 2-5. It will be set to 
missing if at least six of the subscales are missing. 


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Partial Adverse Event 
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 ) 
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. 


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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). 
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 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.  


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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). 
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 


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5.1.2.4 
Other imputations 
Not applicable. 
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 subjects to be excluded 
All Enrolled Set 
Not signed the informed consent 
Full Analysis Set 
Not randomized