Clinical trial NCT05063734
Conditions: Diabetes Mellitus Diabetic Retinopathy Diabetic Macular Edema
Sponsor: Oxurion
Start date: 2021-08-27; Completion date: 2022-06-29
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is conducted to select the THR-687 dose level (Part A of the study) and to assess the efficacy and safety of the selected dose level compared to aflibercept (Part B of the study).

Detailed description:
In Part A, approximately 12 subjects are planned to be randomized (1:1 allocation) to THR-687 1.2mg and THR-687 2.0mg.

In Part B, in the cohort of Treatment Naïve subjects are planned to be randomized (2:1 allocation) to THR-687 selected dose level from Part A and Aflibercept 2.0mg.

In Part B, in the cohort of Previously Treated subjects are planned to be randomized (1:1 allocation) to THR-687 selected dose level from Part A and Aflibercept 2.0mg.

All subjects in the study will receive study treatment in one selected study eye only.

Arms: arm 1: None arm 2: None arm 3: Due to the discontinuation of the study after Part A, the dose level for Part B has not been selected arm 4: None arm 5: Due to the discontinuation of the study after Part A, the dose level for Part B has not been selected arm 6: None
Interventions: intervention 1: THR-687 dose level 1 intervention 2: THR-687 dose level 2 intervention 3: THR-687 selected dose level intervention 4: Aflibercept
Intervention descriptions: intervention 1: 3 intravitreal injections of THR-687 dose level 1, 1 month apart intervention 2: 3 intravitreal injections of THR-687 dose level 2, 1 month apart intervention 3: 3 intravitreal injections of THR-687 selected dose level, 1 month apart, possibly followed by a 4th intravitreal injection with the same dose level of THR-687 at Month 3, or Month 4, or Month 5, if any of the PRN criteria are met. intervention 4: 3 intravitreal injections of aflibercept, 1 month apart, possibly followed by a 4th intravitreal injection with aflibercept at Month 3, or Month 4, or Month 5, if any of the PRN criteria are met.

Protocol documents:
Prot_SAP_000.pdf: 
 
Cover Page 
Protocol_THR-687-002_Version 2.0_07-Sep-2021 
 
 
 
 
 
 
 
 
 
 
 
 
DOCUMENT TYPE 
Study Protocol 
PROTOCOL TITLE: 
A Phase 2, randomised, multicentre 
study to assess the dose level of multiple 
THR-687 injections and to evaluate the 
efficacy and safety of THR-687 versus 
aflibercept for the treatment of diabetic 
macular oedema (DME) 
PROTOCOL NUMBER: 
THR-687-002 
CLINICALTRIALS.GOV IDENTIFIER: 
NCT05063734 
PROTOCOL VERSION: 
Version 2.0 
PROTOCOL DATE 
07-Sep-2021 


CLARIFICATION NOTE 
Study THR-687-002 was designed as a 2-part study. Part A was the randomised, 
dose-selection part of the study assessing 2 dose levels of THR-687. The objective of 
Part A of the study was to select the THR-687 dose level to be compared to aflibercept 
in Part B, which was the randomised, active-controlled part of the study.  
THR-687 dose level selection was to be based on a benefit-risk assessment conducted by 
the Oxurion Steering Committee, when all subjects in Part A completed the Month 3 
visit. However, while the benefit-risk assessment showed that THR-687 was safe and 
well-tolerated at all dose levels tested, there was insufficient evidence of efficacy on the 
key outcome measures (Best-Corrected Visual Acuity and Central Subfield Thickness). 
The study was therefore not advanced to Part B. 


 
Protocol 
Protocol_THR-687-002_Version 2.0_07-Sep-2021 
 
CONFIDENTIAL 
 
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Based on Transcelerate BioPharma CPT October 2020 Release 
TITLE PAGE 
Protocol Title: 
A Phase 2, randomised, multicentre study to assess the dose level of multiple THR-687 
injections and to evaluate the efficacy and safety of THR-687 versus aflibercept for the treatment 
of diabetic macular oedema (DME)  
Short Title: 
A study to evaluate THR-687 treatment for diabetic macular oedema 
Protocol Number:  
THR-687-002 
Acronym:  
INTEGRAL 
Protocol Version History: 
Version 1.0: 02-Apr-2021 
Version 2.0 (Amendment 1): 07-Sep-2021 
Compound: 
THR-687 
Study Phase:  
Phase 2 
Sponsor Name:  
Oxurion NV 
Legal Registered Address:  
Gaston Geenslaan 1 
B-3001 Leuven 
Belgium  
Regulatory Agency Identifier Numbers: 
IND: 133843 
EudraCT: 2020-000362-42 


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SPONSOR SIGNATURE PAGE 
 
 
 
 
PROTOCOL VERSION AND DATE: 
Version 2.0 (Amendment 1): 07-Sep-2021 
 
 
 
 
A Phase 2, randomised, multicentre study to assess the dose level of multiple THR-687 
injections and to evaluate the efficacy and safety of THR-687 versus aflibercept for the treatment 
of diabetic macular oedema (DME) 
 
 
 
 
Sponsor Signatory: 
 
 
 
 
 
Petra Kozma-Wiebe, MD, PhD 
Head of Clinical Development 
 
Date 
 
 
 
Medical Monitor Name and Contact Information can be found in the study-specific 
manual. 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................10 
1.1. 
Synopsis ......................................................................................................................10 
1.1.1. 
Protocol Title ..............................................................................................................10 
1.1.2. 
Brief Title ....................................................................................................................10 
1.1.3. 
Study Rationale ...........................................................................................................10 
1.1.4. 
Study Population .........................................................................................................10 
1.1.5. 
Objectives ...................................................................................................................10 
1.1.6. 
Endpoints and Main Estimand for the Primary Endpoint ...........................................11 
1.1.7. 
Overall Design ............................................................................................................13 
1.1.8. 
Number of Subjects (Planned) ....................................................................................13 
1.1.9. 
Study Treatment Arms ................................................................................................13 
1.1.10. 
Investigational Medicinal Product Allocation ............................................................14 
1.1.11. 
Study Duration ............................................................................................................15 
1.1.12. 
Masking ......................................................................................................................15 
1.1.13. 
Committees .................................................................................................................15 
1.2. 
Study Scheme .............................................................................................................16 
1.3. 
Schedules of Activities ...............................................................................................17 
1.3.1. 
Schedule of Activities – Part A of the Study ..............................................................17 
1.3.2. 
Schedule of Activities – Part B of the Study ..............................................................20 
2. 
INTRODUCTION ......................................................................................................23 
2.1. 
Study Rationale ...........................................................................................................23 
2.2. 
Background .................................................................................................................23 
2.2.1. 
Diabetic Macular Oedema ..........................................................................................23 
2.2.2. 
Current Treatment Options .........................................................................................24 
2.2.3. 
THR-687 .....................................................................................................................25 
2.2.3.1. 
Nonclinical Data .........................................................................................................26 
2.2.3.2. 
Clinical Data ...............................................................................................................26 


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2.3. 
Benefit-Risk Assessment ............................................................................................28 
2.3.1. 
Benefit Assessment .....................................................................................................28 
2.3.2. 
Risk Assessment .........................................................................................................29 
2.3.2.1. 
Potential Risks Related to the Investigational Medicinal Products ............................29 
2.3.2.2. 
Potential Risks Related to the Intravitreal Injection Procedure ..................................29 
2.3.2.3. 
Potential Risks Related to Other Study Procedures ....................................................29 
2.3.2.4. 
Measures to Minimise the Risk for the Subjects in the Study ....................................31 
2.3.3. 
Overall Benefit-Risk Conclusion ................................................................................31 
3. 
OBJECTIVES, ENDPOINTS AND MAIN ESTIMAND FOR THE 
PRIMARY ENDPOINT .............................................................................................32 
3.1. 
Objectives ...................................................................................................................32 
3.1.1. 
Part A ..........................................................................................................................32 
3.1.1.1. 
Primary Objective .......................................................................................................32 
3.1.1.2. 
Other Objectives .........................................................................................................32 
3.1.2. 
Part B ..........................................................................................................................32 
3.1.2.1. 
Primary Objective .......................................................................................................32 
3.1.2.2. 
Other Objectives .........................................................................................................32 
3.2. 
Endpoints and Main Estimand for the Primary Endpoint ...........................................32 
3.2.1. 
Part A ..........................................................................................................................32 
3.2.1.1. 
Key Endpoints to Assess Benefit-Risk .......................................................................32 
3.2.1.2. 
Other Endpoints ..........................................................................................................33 
3.2.2. 
Part B ..........................................................................................................................33 
3.2.2.1. 
Primary Endpoint and Main Estimand; Rx Naïve Subjects ........................................33 
3.2.2.2. 
Secondary Endpoints ..................................................................................................33 
3.2.2.3. 
Exploratory Endpoints ................................................................................................33 
4. 
STUDY DESIGN .......................................................................................................35 
4.1. 
Overall Design ............................................................................................................35 
4.2. 
Scientific Rationale for Study Design ........................................................................37 
4.2.1. 
Rationale for the Study Population .............................................................................37 
4.2.2. 
Rationale for the THR-687 Dose Levels ....................................................................37 
4.2.3. 
Rationale for the Control Arm ....................................................................................38 
4.2.4. 
Rationale for the Dosing Regimen .............................................................................38 
4.2.5. 
Rationale for the Primary Endpoint ............................................................................38 


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4.3. 
Study Definitions ........................................................................................................39 
5. 
STUDY POPULATION .............................................................................................40 
5.1. 
Inclusion Criteria ........................................................................................................40 
5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Lifestyle Considerations .............................................................................................43 
5.4. 
Screen Failures ............................................................................................................43 
6. 
STUDY TREATMENTS AND CONCOMITANT MEDICATIONS AND 
INTERVENTIONS .....................................................................................................44 
6.1. 
Study Treatments ........................................................................................................44 
6.1.1. 
Considerations Related to Study Treatment Administration ......................................44 
6.1.2. 
Part A ..........................................................................................................................44 
6.1.3. 
Part B ..........................................................................................................................45 
6.1.3.1. 
PRN Criteria for 4th Injection with Investigational Medicinal Product ......................46 
6.2. 
Storage, Preparation, Administration and Accountability ..........................................46 
6.2.1. 
Storage ........................................................................................................................46 
6.2.2. 
Preparation and Administration ..................................................................................47 
6.2.2.1. 
General Information ....................................................................................................47 
6.2.2.2. 
Preparation and Administration ..................................................................................47 
6.2.3. 
Study Eye Post-Injection Assessment ........................................................................49 
6.2.4. 
Accountability .............................................................................................................50 
6.3. 
Measures to Minimise Bias: Randomisation and Masking ........................................50 
6.3.1. 
Randomisation and Investigational Medicinal Product Kit Number 
Allocation ...................................................................................................................50 
6.3.2. 
Masking ......................................................................................................................51 
6.3.2.1. 
Part A ..........................................................................................................................51 
6.3.2.2. 
Part B ..........................................................................................................................51 
6.3.2.3. 
Emergency Unmasking ...............................................................................................51 
6.4. 
Study Treatment Compliance .....................................................................................52 
6.5. 
Continued Access to Study Treatment after the End of the Study .............................52 
6.6. 
Treatment of Overdose ...............................................................................................52 
6.7. 
Concomitant Medications and Interventions ..............................................................52 
6.7.1. 
Recording of Prior and Concomitant Medications (Including Intravitreal 
Injections) ...................................................................................................................52 


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6.7.2. 
Recording of Prior and Concomitant Interventions ....................................................53 
6.7.3. 
Rescue Treatment .......................................................................................................53 
7. 
WITHDRAWAL FROM REPEAT INJECTION WITH IMP AND 
DISCONTINUATION FROM THE STUDY ............................................................54 
7.1. 
Withdrawal from Repeat Injection with IMP .............................................................54 
7.2. 
Discontinuation from the Study ..................................................................................55 
7.3. 
Lost to Follow-up .......................................................................................................55 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................57 
8.1. 
Efficacy Assessments .................................................................................................57 
8.1.1. 
Best-Corrected Visual Acuity .....................................................................................57 
8.1.2. 
Spectral Domain Optical Coherence Tomography .....................................................58 
8.1.3. 
Fluorescein Angiography ............................................................................................58 
8.1.4. 
Colour Fundus Photography .......................................................................................58 
8.1.5. 
Optical Coherence Tomography Angiography ...........................................................58 
8.1.6. 
National Eye Institute 25-Item Visual Function Questionnaire .................................58 
8.2. 
Safety Assessments .....................................................................................................59 
8.2.1. 
Full Ophthalmic Examination .....................................................................................59 
8.2.2. 
Best-Corrected Visual Acuity .....................................................................................59 
8.2.3. 
HbA1c .........................................................................................................................59 
8.2.4. 
Pregnancy Testing ......................................................................................................59 
8.3. 
Adverse Events and Serious Adverse Events .............................................................60 
8.3.1. 
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events ...........................................................................................................60 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................60 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................61 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................61 
8.3.5. 
Pregnancy ...................................................................................................................61 
8.3.5.1. 
Women of Childbearing Potential ..............................................................................61 
8.3.5.2. 
Men of Reproductive Potential ...................................................................................62 
8.4. 
Pharmacokinetics ........................................................................................................62 
8.5. 
Genetics ......................................................................................................................63 
8.6. 
Immunogenicity Assessments ....................................................................................63 
8.7. 
Medical Resource Utilisation and Health Economics ................................................63 


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9. 
STATISTICAL CONSIDERATIONS .......................................................................64 
9.1. 
Statistical Hypotheses .................................................................................................64 
9.1.1. 
Multiplicity Adjustment..............................................................................................64 
9.2. 
Analysis Sets ...............................................................................................................65 
9.3. 
Statistical Analyses .....................................................................................................65 
9.3.1. 
General Considerations ...............................................................................................65 
9.3.1.1. 
Procedure for Accounting for Missing Data ...............................................................65 
9.3.1.2. 
Analytical Methods Used in Part A ............................................................................66 
9.3.1.3. 
Analytical Methods Used in Part B ............................................................................66 
9.3.2. 
Efficacy Analyses .......................................................................................................67 
9.3.2.1. 
Primary Endpoint and Estimand Analysis; Rx Naïve Subjects (Part B) ....................67 
9.3.2.2. 
Other Endpoints Analysis ...........................................................................................67 
9.3.3. 
Safety Analyses ..........................................................................................................67 
9.3.4. 
Other Analyses ............................................................................................................67 
9.4. 
Sequence of Analyses .................................................................................................67 
9.5. 
Sample Size Determination ........................................................................................67 
9.6. 
Committees .................................................................................................................68 
9.6.1. 
Safety Monitoring Committee ....................................................................................68 
9.6.2. 
Steering Committee ....................................................................................................69 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................71 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................71 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................71 
10.1.2. 
Financial Disclosure ...................................................................................................71 
10.1.3. 
Informed Consent Process ..........................................................................................72 
10.1.4. 
Data Protection ...........................................................................................................72 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................73 
10.1.6. 
Data Quality Assurance ..............................................................................................73 
10.1.7. 
Source Documents ......................................................................................................74 
10.1.8. 
Study / Site Termination .............................................................................................74 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................75 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting ............................76 


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10.3.1. 
Definition of an Adverse Event ..................................................................................76 
10.3.2. 
Definition of a Serious Adverse Event .......................................................................77 
10.3.3. 
Recording, Assessment and Follow-Up of Adverse Events and Serious 
Adverse Events ...........................................................................................................78 
10.3.4. 
Reporting of Serious Adverse Events .........................................................................80 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................81 
10.4.1. 
Definition of Woman of Childbearing Potential ........................................................81 
10.4.2. 
Definition of Highly Effective Birth Control Methods ..............................................82 
10.4.3. 
Collection of Pregnancy Information .........................................................................82 
10.4.3.1. 
Female Subjects who Become Pregnant .....................................................................82 
10.4.3.2. 
Male Subjects with Partners who Become Pregnant ..................................................82 
10.5. 
Appendix 5: Abbreviations .........................................................................................83 
11. 
REFERENCES ...........................................................................................................85 
 
 


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LIST OF TABLES 
Table 1: 
Schedule of Activities – Part A of the Study ..............................................................17 
Table 2: 
Schedule of Activities – Part B of the Study ..............................................................20 
Table 3: 
Study Treatments (Part A) ..........................................................................................44 
Table 4: 
Study Treatments (Part B) ..........................................................................................45 
Table 5: 
PRN Criteria ...............................................................................................................46 
Table 6: 
Rescue Criteria ............................................................................................................53 
Table 7: 
Analysis Sets ...............................................................................................................65 
Table 8: 
Protocol-Required Laboratory Tests...........................................................................75 
Table 9: 
Optional Laboratory Test ............................................................................................75 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
1.1.1. 
Protocol Title 
A Phase 2, randomised, multicentre study to assess the dose level of multiple THR-687 
injections and to evaluate the efficacy and safety of THR-687 versus aflibercept for the treatment 
of diabetic macular oedema (DME) 
1.1.2. 
Brief Title 
A study to evaluate THR-687 treatment for diabetic macular oedema 
1.1.3. 
Study Rationale 
Study THR-687-002 is the first study in which multiple intravitreal (IVT) injections of THR-687 
will be administered in humans. The study is composed of 2 parts (also refer to the study 
scheme): 
• Part A is conducted to select the THR-687 dose level to be assessed in Part B.  
• Part B is conducted to evaluate the efficacy and safety of the selected THR-687 dose 
level from Part A, compared to aflibercept.  
1.1.4. 
Study Population 
Subjects with central-involved DME (CI-DME): 
• Part A will be conducted in subjects who are treatment-naïve for DME in the study 
eye (i.e. eyes that have not been treated with anti-VEGFs, intravitreal corticosteroids, 
or any investigational product for DME) (further referred to as ‘Rx naïve subjects’). 
• Part B will be conducted both in Rx naïve subjects, and in subjects who received 
prior treatment for DME in the study eye (further referred to as ‘previously treated 
subjects’). 
1.1.5. 
Objectives 
Part A 
Primary Objective 
The primary objective of this part of the study is to select the THR-687 dose level (1.2mg or 
2.0mg) to be further assessed in Part B. Dose level selection will be based on a benefit-risk 
assessment conducted when all subjects completed the Month 3 visit. 
Refer to the Key Endpoints to Assess Benefit-Risk for the related endpoints. 
Other Objectives 
The other objectives of this part of the study are the same as those defined for Part B. 


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Part B 
Primary Objective 
The primary objective of this part of the study is to assess the difference in treatment effect 
between THR-687 and aflibercept, in terms of the change from Baseline in best-corrected visual 
acuity (BCVA) at Month 3, in Rx naïve subjects. 
Refer to the Primary Endpoint and Main Estimand for the related endpoint and the main 
estimand. 
Other Objectives 
• To assess the efficacy of multiple IVT injections of THR-687 over-time 
• To assess the safety of multiple IVT injections of THR-687 over-time  
Refer to the Secondary and the Exploratory Endpoints for the related endpoints. 
1.1.6. 
Endpoints and Main Estimand for the Primary Endpoint 
Part A 
Key Endpoints to Assess Benefit-Risk 
• Incidence of ocular and non-ocular adverse events (AEs) and serious adverse events 
(SAEs) 
• Development of severe intraocular inflammation: ≥ 2+ inflammation on any of the 
intraocular inflammation grading scales (grading of anterior chamber cells, grading of 
anterior chamber flare, Nussenblatt chart for vitreous inflammation grading) 
• Incidence of BCVA decrease of ≥ 10 ETDRS letter score from Baseline, by study 
visit 
• Change from Baseline in BCVA ETDRS letter score, by study visit 
• Change from Baseline in central subfield thickness (CST), based on spectral domain 
optical coherence tomography (SD-OCT), as assessed by the central reading centre 
(CRC), by study visit 
Other Endpoints 
All applicable endpoints defined in Part B will also be assessed in an exploratory manner for 
Part A (if not already part of the key endpoints to assess benefit-risk).  
Part B 
Primary Endpoint and Main Estimand; Rx Naïve Subjects 
• The primary endpoint is defined as the change from Baseline in BCVA ETDRS letter 
score, at Month 3 
The main estimand for the primary endpoint is defined as the difference between the 
2 study treatment arms in the mean change from Baseline in BCVA ETDRS letter 
score at Month 3, using the Full Analysis Set (FAS), whereby the intercurrent event 


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‘initiation of rescue treatment’ will be handled using the while-on-treatment strategy 
i.e. after initiation of rescue treatment, the last available value of BCVA prior to the 
intercurrent event will be carried forward. Other intercurrent events, including death 
or discontinuation from the study due to an AE related to the investigational 
medicinal product (IMP), will be handled by carrying forward the last available 
assessment prior to the event.  
Secondary Endpoints  
• Weighted average of the change from Baseline in BCVA ETDRS letter score from 
Day 8 through Month 3 using the trapezoidal rule (area under the curve [AUC]) 
• Change from Baseline in BCVA ETDRS letter score, by study visit 
• Change from Baseline in CST, based on SD-OCT, as assessed by the CRC, by study 
visit 
• Incidence of ocular and non-ocular AEs and SAEs, from first injection up to the end 
of the study 
Exploratory Endpoints 
• Proportion of subjects with categorical changes from Baseline in BCVA ETDRS 
letter score (loss of ≥ 5, ≥ 10 and ≥ 15 ETDRS letters; gain of ≥ 5, ≥ 10 and 
≥ 15 ETDRS letters), by study visit  
• Proportion of subjects with BCVA ≥ 69 ETDRS letters (Snellen equivalent 20/40 or 
better), among subjects with BCVA ≥ 69 ETDRS letters at Day 1 and among subjects 
with BCVA < 69 ETDRS letters at Day 1, by study visit 
• Proportion of subjects with a 4th injection with IMP at Month 3, at Month 4, at 
Month 5, or who did not require a 4th injection with IMP 
• Time between 3rd injection with IMP and 4th injection with IMP or initiation of rescue 
treatment (whichever comes first) 
• Time to first rescue treatment  
• Proportion of subjects withdrawn from repeat injection with IMP and reason for 
withdrawal 
• Proportion of subjects with an improvement of ≥ 2 steps on the ETDRS Severity 
Scale from Baseline, based on colour fundus photography, as assessed by the CRC, 
by study visit 
• Changes from Baseline in ischaemia and leakage assessments, based on fluorescein 
angiography, as assessed by the CRC, by study visit 
• Changes from Baseline in vascular density and foveal avascular zone area, based on 
optical coherence tomography angiography (OCTA), as assessed by the CRC, by 
study visit, in subjects at sites that have the required type of equipment 


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• Change from Baseline in National Eye Institute 25-Item Visual Function 
Questionnaire (NEI VFQ-25) total and subscale scores, by study visit, in subjects in 
selected countries 
• THR-687 plasma levels by Day 3, in subjects who provide consent, at sites that 
perform the sampling 
• Development of severe intraocular inflammation: ≥ 2+ inflammation on any of the 
intraocular inflammation grading scales (grading of anterior chamber cells, grading of 
anterior chamber flare, Nussenblatt chart for vitreous inflammation grading), by study 
visit 
1.1.7. 
Overall Design 
This is a Phase 2, multicentre study composed of 2 parts (also refer to the study scheme): 
• Part A is the randomised, single-masked, dose-selection part of the study assessing 
2 dose levels of THR-687.  
• Part B is the randomised, double-masked, active-controlled part of the study with a 
single dose level of THR-687 (selected from Part A) and aflibercept as comparator. 
Randomisation in Part B will only be initiated after dose level selection by the 
Steering Committee, which will be based on a benefit-risk assessment conducted 
when all subjects in Part A have completed the Month 3 visit. 
1.1.8. 
Number of Subjects (Planned) 
Part A 
It is planned to randomise approximately12 subjects (approximately 6 subjects per dose level).  
Part B 
It is planned to randomise approximately 291 subjects in total, including: 
• Approximately 231 Rx naïve subjects (approximately 154 subjects will receive 
THR-687 [selected dose level from Part A] and approximately 77 subjects 
aflibercept).   
• Approximately 60 previously treated subjects (approximately 30 subjects will receive 
THR-687 [selected dose level from Part A] and approximately 30 subjects 
aflibercept). 
1.1.9. 
Study Treatment Arms 
Part A 
Approximately 12 subjects are planned to be randomised (1:1 allocation) to: 
• THR-687 1.2mg. Approximately 6 subjects are planned to receive IVT THR-687 
1.2mg at Day 1, Month 1 and Month 2. 
• THR-687 2.0mg. Approximately 6 subjects are planned to receive IVT THR-687 
2.0mg at Day 1, Month 1 and Month 2. 


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Part B 
Approximately 231 Rx naïve subjects are planned to be randomised (2:1 allocation), stratified by 
study eye CST (as assessed by the CRC) at Screening and by study eye BCVA at Day 1, to: 
• THR-687 (selected dose level from Part A). Approximately 154 subjects are 
planned to receive IVT THR-687 (selected dose level from Part A) at Day 1, 
Month 1 and Month 2, possibly followed by a 4th injection with the same dose level 
of THR-687 at Month 3, or Month 4, or Month 5, if any of the pro re nata (PRN) 
criteria are met.  
• Aflibercept 2mg. Approximately 77 subjects are planned to receive IVT 
aflibercept 2mg at Day 1, Month 1 and Month 2, possibly followed by a 4th injection 
with aflibercept 2mg at Month 3, or Month 4, or Month 5, if any of PRN criteria are 
met. 
Approximately 60 previously treated subjects are planned to be randomised (1:1 allocation), 
stratified by study eye BCVA at Day 1, to: 
• THR-687 (selected dose level from Part A). Approximately 30 subjects are planned 
to receive IVT THR-687 (selected dose level from Part A) at Day 1, Month 1 and 
Month 2, possibly followed by a 4th injection with the same dose level of THR-687 at 
Month 3, or Month 4, or Month 5, if any of the PRN criteria are met.  
• Aflibercept 2mg. Approximately 30 subjects are planned to receive IVT 
aflibercept 2mg at Day 1, Month 1 and Month 2, possibly followed by a 4th injection 
with aflibercept 2mg at Month 3, or Month 4, or Month 5, if any of PRN criteria are 
met. 
1.1.10. 
Investigational Medicinal Product Allocation 
Part A 
Eligible subjects will be randomised to receive either THR-687 2.0mg or THR-687 1.2mg 
(1:1 allocation), using an interactive web response system (IWRS).  
Part B 
Eligible Rx naïve subjects will be randomised to receive either THR-687 (selected dose level 
from Part A) or aflibercept 2mg (2:1 allocation), using an IWRS. Randomisation will be 
stratified by: 
• Study eye CST at Screening (< 400µm versus ≥ 400µm, on SD-OCT, as assessed by 
the CRC), and 
• Study eye BCVA at Day 1 (≤ 63 ETDRS letters versus > 63 ETDRS letters). 
Eligible previously treated subjects will be randomised to receive either THR-687 (selected dose 
level from Part A) or aflibercept 2mg (1:1 allocation), using an IWRS. Randomisation will be 
stratified by study eye BCVA at Day 1 (≤ 63 ETDRS letters versus > 63 ETDRS letters).  


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1.1.11. 
Study Duration 
Part A 
For each treated subject, the study duration will be 6 months from the first injection. 
Part B 
For each treated subject, the study duration will be 8 months from the first injection. 
1.1.12. 
Masking 
Part A 
The randomised, dose-selection part of the study will be conducted in a single-masked manner.   
In addition, to ensure objective assessment: 
• Masked BCVA assessor(s) will be assigned at each site to perform BCVA 
assessments. 
• The CRC in charge of the grading of the ophthalmic images and the laboratories in 
charge of the protocol-related laboratory assessments will be masked to IMP 
assignment. 
Part B 
The randomised, active-controlled part of the study will be conducted in a double-masked 
manner.  
In order to preserve the masking, IMP handling and administration will be performed by 
unmasked study personnel. IMP preparation must occur outside the subject’s view, and the 
subject should be asked to direct his / her gaze away at all times. 
1.1.13. 
Committees 
A Safety Monitoring Committee (SMC) will be established, composed of members of relevant 
functional areas who are not involved in the day-to-day execution, management or monitoring of 
the study.  
A Steering Committee will be established to select the dose level of THR-687 that will be 
assessed in Part B. The Steering Committee will be composed of members of relevant functional 
areas who are not involved in the day-to-day execution, management or monitoring of the study. 


 
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1.2. 
Study Scheme 
 
* The benefit-risk assessment will be conducted by the Steering Committee when all subjects in Part A have completed the Month 3 visit. 
** Subjects will receive a 4th IVT injection with the IMP allocated at the time of randomisation, the first time any of the PRN criteria are met at Month 3, or 
Month 4, or Month 5 (each subject will receive maximum 4 injections with IMP in total). 
BCVA = best-corrected visual acuity; D = Day; IVT = intravitreal; M = Month; mg = milligram; N = number; PRN = pro re nata; Rando = randomisation; 
Rx = treatment 


 
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1.3. 
Schedules of Activities 
1.3.1. 
Schedule of Activities – Part A of the Study 
Table 1: 
Schedule of Activities – Part A of the Study 
Contact Number 
Visit 1 
Visit 2 a Optional 
Visit b 
Visit 3 Visit 4 a Visit 5 a 
Visit 6 
Visit 7 
Visit 8 
Visit 9 / 
End of 
Study 
Unscheduled 
Visit c 
Timing 
Visit window 
Scree-
ning d  
Day 1 
Up to 28d  
post-V1 
Day 3 
Day 8 
±3d 
Month 1 
Day 29 
±4d 
Month 2 
Day 57 
±4d 
Month 3 
Day 85 
±4d 
Month 4 
Day 113 
±4d 
Month 5 
Day 141 
±4d 
Month 6 
Day 169 
±4d 
Any time 
during the 
study 
Assessment  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography e, medical and ocular 
history 
X (1) 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medications and 
interventions 
X (2) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test f 
X (3) 
X 
 
 
X 
X 
X 
X 
X 
 
 
Blood pressure measurement 
X (4) 
X 
 
 
 
 
 
 
 
 
 
Ophthalmic assessments: 
   BCVA (ETDRS letter score) 
X g (5) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
   Full ophthalmic examination h 
X g (6) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
   SD-OCT 
X g (7) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
   Colour fundus photography 
X g (8) 
 
 
 
 
 
X 
 
 
X 
 
   Fluorescein angiography 
X g (9) 
 
 
 
 
 
X 
 
 
 
 
   OCTA i 
X g  
 
 
 
 
 
X 
 
 
X 
 
Biological samples: 
   Blood sampling for HbA1c (∼2 mL) j 
X (10) 
 
 
 
 
 
X 
 
 
X 
 
   Blood sampling for THR-687 plasma 
levels (∼2 mL) k 
 
X l 
X 
 
 
 
 
 
 
 
 


 
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Contact Number 
Visit 1 
Visit 2 a Optional 
Visit b 
Visit 3 Visit 4 a Visit 5 a 
Visit 6 
Visit 7 
Visit 8 
Visit 9 / 
End of 
Study 
Unscheduled 
Visit c 
Timing 
Visit window 
Scree-
ning d  
Day 1 
Up to 28d  
post-V1 
Day 3 
Day 8 
±3d 
Month 1 
Day 29 
±4d 
Month 2 
Day 57 
±4d 
Month 3 
Day 85 
±4d 
Month 4 
Day 113 
±4d 
Month 5 
Day 141 
±4d 
Month 6 
Day 169 
±4d 
Any time 
during the 
study 
Assessment  
   Study eye aqueous humour sampling m 
 
X 
 
 
 
 
X 
 
 
 
 
IMP kit number allocation 
 
X 
 
 
X 
X 
 
 
 
 
 
Assess list of criteria leading to 
withdrawal from repeat injection with 
IMP n 
 
 
 
 
X 
X 
 
 
 
 
 
IMP administration (study eye) 
 
X 
 
 
X 
X 
 
 
 
 
 
Study eye post-injection assessment o 
 
X 
 
 
X 
X 
 
 
 
 
 
AE and SAE monitoring and reporting 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
a Assessments scheduled during injection visits must be performed prior to the IMP injection, except for the study eye post-injection assessment including 
monitoring and recording of post-injection AEs and SAEs and post-injection concomitant medications (if applicable). 
b Optional visit for subjects who consent to blood sampling for THR-687 plasma levels. 
c Unscheduled visits for clinical reasons may be conducted at any time during the study as per the Investigator’s clinical judgement. The assessments indicated in 
this table must be performed during all unscheduled visits conducted for clinical reasons. Other assessment may be performed as deemed necessary depending 
on the reason for the unscheduled visit. 
d At Screening, the subject’s eligibility for study participation will be determined by checking all inclusion and exclusion criteria. It is mandatory to start with the 
non-invasive screening assessments before performing any of the invasive screening assessments, and it is recommended to do the eligibility assessment in the 
numerical order as indicated between brackets in Table 1. If a subject fails one of the in- / exclusion criteria, the subject will be a screen failure and no further 
assessments will be done. Certain in- / exclusion criteria need to be confirmed by the CRC / the central laboratory as specified in Section 5. Only if the subject 
is deemed eligible based on the Investigator's assessment at Screening, must the images / blood sample(s) be provided to the CRC / the central laboratory for 
confirmation of eligibility. 
e Year of birth, age, sex, ethnicity and race (race and / or ethnicity will not be collected in countries where this is not permitted by the regulatory authority / 
IEC / IRB). 
f Only for women of childbearing potential. Highly sensitive urine pregnancy test at all indicated visits UNLESS a serum pregnancy test is required by local 
regulations or the IRB / IEC, in which case a blood sample for serum pregnancy testing (∼3.5mL) will be collected at Screening and a highly sensitive urine 
pregnancy test will be done at the other visits. 
g Performed in both eyes. Ophthalmic assessments without this footnote are performed in the study eye only. 
h Full ophthalmic examination including slit lamp examination, IOP assessment and dilated fundus examination. 
i Only at sites that have the required type of OCTA equipment. 


 
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j To be shipped as whole blood (no processing).  
k Only at sites that perform the sampling, in subjects who provide consent. To be processed to plasma. 
l Sample to be taken at 2 hours (± 15 minutes) after the injection with IMP. 
m Only at sites that perform aqueous humour sampling, in subjects who provide consent. 
n Refer to Section 7.1 for the list of criteria for withdrawal from repeat injection with IMP.  
o The study eye post-injection assessment will include verification of optic nerve perfusion within a few minutes after the injection, as well as an IOP assessment 
done within 30±15 minutes after the injection. Refer to Section 6.2.3 for more detailed information.  
Light grey coloured visits indicate injection visits. The dark grey coloured visit indicates unscheduled visits.  
AE = adverse event; BCVA = best-corrected visual acuity; d = days; HbA1c = glycated haemoglobin A; IMP = investigational medicinal product; 
mL = millilitre; OCTA = optical coherence tomography angiography; SAE = serious adverse event; SD-OCT = spectral domain optical coherence tomography 


 
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1.3.2. 
Schedule of Activities – Part B of the Study 
Table 2: 
Schedule of Activities – Part B of the Study 
Contact Number 
Visit 1 Visit 2 a Optio-
nal  
Visit b 
Visit 3 Visit 4 a Visit 5 a Visit 6 a Visit 7 a Visit 8 a Visit 9 
Visit 10 Visit 11/ 
End of 
Study 
Un-
scheduled 
Visit c 
Timing 
Visit window 
Scree-
ning d  
Day 1 
Up to 28d 
post-V1 
Day 3 Day 8 
±3d 
Month 1 
Day 29 
±4d 
Month 2 
Day 57 
±4d 
Month 3 
Day 85 
±4d 
Month 4 
Day 113 
±4d 
Month 5 
Day 141 
±4d 
Month 6 
Day 169 
±4d 
Month 7 
Day 197 
±4d 
Month 8 
Day 225 
±4d 
Any time 
during the 
study 
Assessment  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography e, medical and 
ocular history f 
X (1) 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications and interventions 
X (2) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test g 
X (3) 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood pressure measurement 
X (4) 
X 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmic assessments: 
   BCVA (ETDRS letter score) 
X h (5) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   Full ophthalmic examination i 
X h (6) 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   SD-OCT 
X h (7) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   Colour fundus photography 
X h (8) 
 
 
 
 
 
X 
 
 
X 
 
X 
 
   Fluorescein angiography 
X h (9) 
 
 
 
 
 
 
 
 
 
 
X 
 
   OCTA j 
X h  
 
 
 
 
 
X 
 
 
X 
 
X 
 
NEI VFQ-25 k 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Biological samples: 
   Blood sampling for HbA1c 
(∼2 mL) l 
X (10) 
 
 
 
 
 
X 
 
 
 
 
X 
 


 
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Contact Number 
Visit 1 Visit 2 a Optio-
nal  
Visit b 
Visit 3 Visit 4 a Visit 5 a Visit 6 a Visit 7 a Visit 8 a Visit 9 
Visit 10 Visit 11/ 
End of 
Study 
Un-
scheduled 
Visit c 
Timing 
Visit window 
Scree-
ning d  
Day 1 
Up to 28d 
post-V1 
Day 3 Day 8 
±3d 
Month 1 
Day 29 
±4d 
Month 2 
Day 57 
±4d 
Month 3 
Day 85 
±4d 
Month 4 
Day 113 
±4d 
Month 5 
Day 141 
±4d 
Month 6 
Day 169 
±4d 
Month 7 
Day 197 
±4d 
Month 8 
Day 225 
±4d 
Any time 
during the 
study 
Assessment  
   Blood sampling for THR-687 
plasma levels (∼2 mL) m 
 
X n 
X 
 
 
 
 
 
 
 
 
 
 
   Study eye aqueous humour 
sampling o 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
IMP kit number allocation 
 
X 
 
 
X 
X 
(X) p  
(X) p 
(X) p 
 
 
 
 
IMP administration (study eye) q  
 
X 
 
 
X 
X 
(X) p 
(X) p 
(X) p 
 
 
 
 
Assess PRN criteria r 
 
 
 
 
 
 
X 
(X) 
(X) 
 
 
 
 
Assess list of withdrawal criteria 
from repeat injection with IMP s 
 
 
 
 
X 
X 
(X) p 
(X) p 
(X) p 
 
 
 
 
Study eye post-injection 
assessment t 
 
X 
 
 
X 
X 
(X) p 
(X) p 
(X) p 
 
 
 
 
AE and SAE monitoring and 
reporting 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Assessments scheduled during injection visits must be performed prior to the IMP injection, except for the study eye post-injection assessment including 
monitoring and recording of post-injection AEs and SAEs and post-injection concomitant medications (if applicable). 
b Optional visit for subjects who consent to blood sampling for THR-687 plasma levels. 
c Unscheduled visits for clinical reasons may be conducted at any time during the study as per the Investigator’s clinical judgement. The assessments indicated in 
this table must be performed during all unscheduled visits conducted for clinical reasons. Other assessment may be performed as deemed necessary depending 
on the reason for the unscheduled visit. 
d At Screening, the subject’s eligibility for study participation will be determined by checking all inclusion and exclusion criteria. It is mandatory to start with the 
non-invasive screening assessments before performing any of the invasive screening assessments, and it is recommended to do the eligibility assessment in the 
numerical order as indicated between brackets in Table 2. If a subject fails one of the in- / exclusion criteria, the subject will be a screen failure and no further 
assessments will be done. Certain in- / exclusion criteria need to be confirmed by the CRC / the central laboratory as specified in Section 5. Only if the subject 
is deemed eligible based on the Investigator's assessment at Screening, must the images / blood sample(s) be provided to the CRC / the central laboratory for 
confirmation of eligibility. 
e Year of birth, age, sex, ethnicity and race (race and / or ethnicity will not be collected in countries where this is not permitted by the regulatory authority / IEC / 
IRB). 


 
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f For previously treated subjects, ocular history will include visual acuity and retinal thickness measurements done prior to study entry 
g Only for women of childbearing potential. Highly sensitive urine pregnancy test at all indicated visits UNLESS a serum pregnancy test is required by local 
regulations or the IRB / IEC, in which case a blood sample for serum pregnancy testing (∼3.5mL) will be collected at Screening and a highly sensitive urine 
pregnancy test will be done at the other visits. 
h Performed in both eyes. Ophthalmic assessments without this footnote are performed in the study eye only. 
i Full ophthalmic examination including slit lamp examination, IOP assessment and dilated fundus examination. 
j Only at sites that have the required type of OCTA equipment. 
k Only in selected countries. 
l To be shipped as whole blood (no processing).  
m Only at sites that perform the sampling, in subjects who provide consent. To be processed to plasma. 
n Sample to be taken at 2 hours (± 15 minutes) after the injection with IMP. 
o Only at sites that perform aqueous humour sampling, in subjects who provide consent. 
p Only if the 4th injection with IMP is administered at this visit. 
q IMP handling and administration will be performed by an unmasked study personnel. 
r Subjects will receive a 4th IVT injection with the IMP allocated at the time of randomisation, the first time any of the PRN criteria are met at Month 3, 4, or 5 
(each subject will receive maximum 4 injections with IMP in total).  
s Refer to Section 7.1 for the list of criteria for withdrawal from repeat injection with IMP.  
t The study eye post-injection assessment will include verification of optic nerve perfusion within a few minutes after the injection, as well as an IOP assessment 
done within 30±15 minutes after the injection. Refer to Section 6.2.3 for more detailed information.  
Light grey coloured visits indicate IMP injection visits. Visits with hatch pattern indicate visits at which a 4th injection with IMP will be administered the first 
time any of the PRN criteria are met (each subject will receive maximum 4 injections with IMP in total). The dark grey coloured visit indicates unscheduled 
visits. 
AE = adverse event; BCVA = best-corrected visual acuity; d = days; HbA1c = glycated haemoglobin A; IMP = investigational medicinal product; 
IVT = intravitreal; mL = millilitre; NEI VFQ-25 = National Eye Institute 25-Item Visual Function Questionnaire; OCTA = optical coherence tomography 
angiography; PRN = pro re nata; SAE = serious adverse event; SD-OCT = spectral domain optical coherence tomography 


 
 
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2. 
INTRODUCTION 
2.1. 
Study Rationale 
THR-687 was administered for the first time in humans in the Phase 1 study THR-687-001 
(ClinicalTrials.gov Identifier: NCT03666923). The subjects in this study had CI-DME with a 
history of response to prior anti-VEGF and / or corticosteroid treatment and remained responsive 
to treatment in the opinion of the Investigator. It was an open-label study with a 
3+3 dose-escalation design. Subjects received a single IVT injection of one of 3 different dose 
levels of THR-687 and were followed up for 3 months after the injection. The study showed that 
a single IVT injection of THR-687 was safe and well-tolerated at all dose levels tested. In 
addition, preliminary efficacy in terms of BCVA gain from Baseline was observed (refer to 
Section 2.2.3.2 for more information). The results of the Phase 1 study support the further 
clinical development of THR-687 for the treatment of DME. 
Study THR-687-002 is the first study in which multiple IVT injections of THR-687 will be 
administered in humans. The study is composed of 2 parts (also refer to the study scheme): 
• Part A is conducted to select the THR-687 dose level to be assessed in Part B.  
• Part B is conducted to evaluate the efficacy and safety of the selected THR-687 dose 
level from Part A, compared to aflibercept.  
2.2. 
Background 
2.2.1. 
Diabetic Macular Oedema 
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus 
and the leading cause of blindness in working-age adults in the United States, Europe, and 
increasingly worldwide. A meta-analysis done on studies published between 2015 and 2018 
estimated the global prevalence of DR at 27.0% of patients with diabetes (Thomas et al., 2019). 
A higher prevalence was observed in patients with type 1 diabetes compared to those with type 2 
diabetes. Regional and ethnic differences in the DR prevalence rates exist. The prevalence of DR 
was estimated at 20.6% of patients with diabetes in Europe, 21.9% in North America & the 
Caribbean, 12.5% in South East Asia (lowest prevalence rate) and 36.2% in the Western Pacific 
Region (highest prevalence rate). DME, which is characterised by exudation and accumulation of 
extracellular fluid in the macula secondary to an increase in vascular permeability, is a major 
cause of the vision loss associated with DR. In the same meta-analysis, the global prevalence of 
DME was estimated at 4.6% of patients with diabetes. Regional differences in the DME 
prevalence rate were also observed. The prevalence of DME was estimated at 1.2% of patients 
with diabetes in Europe and at 2.5% in North America & The Caribbean (lowest prevalence 
rates), as compared to 9.1% in the Western Pacific Region and 21.5% in Africa (highest 
prevalence rates) (Thomas et al., 2019). The prevalence of DME is expected to rise further due 
to the increasing prevalence of diabetes, ageing of the population and increased life expectancy: 
the number of adults aged 20 – 79 years with diabetes worldwide was estimated at 463 million in 
2019 and is expected to increase to 700 million by 2045 (International Diabetes Federation, 
2019). 


 
 
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2.2.2. 
Current Treatment Options 
Refer to Schmidt-Erfurth et al., 2017 (Europe) and the Diabetic Retinopathy Preferred Practice 
Pattern, 2019 (United States) for guidelines on DME management. 
Before the era of the anti-VEGF agents, focal / grid laser using small, light-intensity laser burns 
(50-100µm in diameter) to micro-aneurysms / diffuse area of thickening in a grid pattern has 
been the standard-of-care treatment for DME. Different studies demonstrated the benefit of 
focal / grid laser photocoagulation over no treatment in terms of the prevention of vision loss (for 
a review, refer to Romero-Aroca et al., 2014). Complications such as loss of central vision, 
central scotomas and decreased colour vision have however been associated with the procedure. 
In addition, focal laser burns have been observed to expand over time. More recently, 
subthreshold micropulse laser has been developed as a treatment that avoids damaging the inner 
neurosensory retina, thereby reducing potential complications. There is emerging evidence to 
suggest that similar efficacy outcomes can be achieved with micropulse laser as compared to 
conventional laser (for a review, refer to Scholz, Altay and Fauser, 2017). On the other hand, 
while photocoagulation treatment reduces the risk of visual loss and works over a long timescale, 
recovery of vision is much harder to achieve with laser treatment than with anti-VEGF 
treatments. Therefore, the indication of focal / grid laser is now limited to the treatment of 
patients with non-centre-involved DME. In addition, it can be used as an adjunctive option to 
pharmacological therapies as deferred laser surgery treatment may ultimately decrease the need 
for repeated anti-VEGF injections. 
Pharmacologic agents are available for the treatment of DME: 
• Since the marketing approval of ranibizumab for the treatment of DME, anti-VEGF 
agents have become the first-line standard-of-care treatment for CI-DME. VEGF is a 
potent vasopermeability factor contributing to the macular thickening and visual 
impairment associated with DME. Anti-VEGF compounds decrease angiogenesis and 
vascular permeability, causing regression of neovascularisation and reduction of 
oedema. Several clinical studies have shown that anti-VEGF treatment is more 
effective than focal / grid laser treatment at decreasing CST and improving vision 
patients with CI-DME (for a review, refer to Bahrami et al., 2016). AEs related to 
anti-VEGF treatment are rare and mostly related to the need for repeated IVT 
injections over a prolonged period of time (Boyer et al., 2013). Many DME patients 
however, up to 40%, do not adequately respond to anti-VEGF treatment in terms of 
BCVA and / or CST improvement (Bressler et al., 2016; Bressler et al., 2018 
Gonzalez et al., 2016; Korobelnik et al., 2014).  
• Inflammation plays an important role in the pathogenesis of DME. Cytokines and 
chemokines released by leukocytes in the blood significantly increase vascular 
permeability leading to more fluid build-up under the retina. Corticosteroid therapies 
can inhibit inflammatory mediators. Several clinical studies have shown that 
corticosteroids are effective in decreasing CST and improving vision in DME 
(Boyer et al., 2014; Campochiaro et al., 2011; Elman et al., 2010). While the 
treatment burden of corticosteroid implants is much lower than that of anti-VEGF 
agents, IVT corticosteroids are associated with increased risks of cataract 
development and elevation of intraocular pressure (IOP). Overall, the use of IVT 


 
 
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corticosteroids in patients with DME is therefore reserved as a second-line therapy in 
those who respond poorly to IVT anti-VEGF therapy and is contraindicated in 
patients with underlying glaucoma. 
Considering that up to 40% of the patients do not adequately respond to anti-VEGF treatment 
(first line treatment) and the restrictions related to the available second line treatments, there is 
an important clinical need for additional treatments for DME. 
2.2.3. 
THR-687 
THR-687 is a small molecule directed against integrin receptors that inhibits interactions 
between specific integrins and their ligands. Integrins constitute a family of transmembrane cell 
surface receptors that can mediate cell-cell and cell-extracellular matrix interactions. Integrins 
play an important role in various biological processes including cell differentiation, adhesion, 
shape, migration, motility, invasion, proliferation, and survival. Because of their role in these 
biological processes, integrins also play an important role in various pathological conditions. 
Integrins are obligate heterodimeric receptors consisting of a non-covalently bound α and 
β subunit. Different combinations of the 18 α and the 8 β known subunits constitute the family of 
24 heterodimeric integrin members recognised thus far. The integrin family of receptors can be 
broadly classified into 4 different categories depending on their ligand recognition pattern: 
1) RGD binding, 2) collagen binding, 3) laminin binding and 4) leukocyte binding types of 
integrins (also refer to Figure 1). 
Figure 1: 
The Integrin Family 
 
Taken from Barczyk, Carracedo and Gullberg, 2010 
THR-687 has been shown to antagonise mainly RGD-binding integrins, including αvβ3, αvβ5 and 
α5β1. These integrins have been shown to play an important role in retinal angiogenesis and 
vascular permeability. Interaction of integrins with the extracellular matrix can lead to 
neovascularisation of the retinal surface, which can eventually extend towards the vitreous 


 
 
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region. Immunohistological staining on human retinal tissues derived from proliferative diabetic 
retinopathy (PDR) patients has shown that actively proliferating vascular endothelial cells 
express αvβ3 and αvβ5, which are not highly expressed in quiescent endothelial cells 
(Friedlander et al., 1996; Ning et al., 2008). In addition, αvβ3 and β3 have been shown to be 
expressed in fibrovascular epiretinal membranes from patients with active PDR in the fibrotic 
stage (Abu El-Asrar, Missotten and Geboes, 2010; Ning et al., 2008), while α5 has been shown to 
be overexpressed in a laser-induced mouse model of choroidal neovascularisation (CNV) 
(Umeda et al., 2006). In line with this, several nonclinical studies have demonstrated that 
inhibition of integrins attenuates leukostasis and retinal vascular permeability (Iliaki et al., 2009; 
Rao et al., 2010; Santulli et al., 2008). Antagonism of αvβ3 and αvβ5 prevented retinal 
neovascularisation but did not harm pre-existing blood vessels (Friedlander et al., 1996; 
Hammes et al.,1996; Lahdenranta et al., 2007; Santulli et al., 2008), while inhibition of α5β1 
inhibited endothelial cell proliferation and produce regression of choroidal neovascular 
membranes in different animal models (Ramakrishnan et al., 2006; Umeda et al., 2006). 
By antagonising these integrin receptors, THR-687 is hence expected to inhibit 
neovascularisation and vascular leakage. Given its multifaceted mechanisms of action, THR-687 
is a promising drug candidate for the treatment of retinal vascular diseases. 
2.2.3.1. 
Nonclinical Data 
The available nonclinical data support the potential of THR-687 1.2mg and THR-687 2.0mg as 
safe treatment options for DME. Refer to the Investigator’s Brochure for a description of the 
available nonclinical data. 
2.2.3.2. 
Clinical Data 
The first clinical study with THR-687 (study THR-687-001) has been completed. The objective 
of this Phase 1 study was to evaluate the safety of a single IVT injection of 3 dose levels of 
THR-687. A total of 12 subjects were treated in the study: 3 subjects with THR-687 0.3mg, 
3 with THR-687 0.8mg and 6 with THR-687 2.0mg.* The subjects were followed up for 
3 months after the injection.  
A single IVT injection with THR-687 was safe and well tolerated at all dose levels tested. No 
dose-limiting toxicities, SAEs or AEs leading to discontinuation from the study were reported.  
Overall, 9 AEs in the study eye were reported in 5/12 (41.7%) subjects, and 4 of these AEs in 
3/12 (25.0%) subjects were deemed treatment-related by the Investigator: 
• The treatment-related AEs were 2 events of Conjunctival Haemorrhage (reported for 
1 subject who received THR-687 0.3mg and for 1 subject who received 
THR-687 0.8mg), Intraocular Pressure Increased (reported for 1 subject who received 
THR-687 0.3mg) and Eye Pain (reported for 1 subject who received THR-687 
2.0mg). All AEs that were deemed treatment-related by the Investigator were mild in 
severity and resolved within 28 days without treatment.  
• The other (non-treatment-related) events reported in the study eye were Ocular 
Hypertension, Vision Blurred (1 event each) and Diabetic Retinal Oedema (3 events).  


 
 
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All AEs reported in the study eye were considered associated with the IVT injection procedure, 
underlying disease progression or concomitant diseases, and not with THR-687 itself. 
While the objective of the Phase 1 study was to evaluate the safety of a single IVT injection of 
THR-687, preliminary efficacy in terms of BCVA gain from Baseline was observed. Overall, 
across study treatment arms: 
• A rapid onset of action was observed: at 1, 7 and 14 days after the injection, the mean 
(standard deviation [SD]) gain were 3.1 (3.18), 7.2 (4.88) and 7.7 (5.16) ETDRS 
letters, respectively. 
• The effect was the highest at 1 month after the injection, with a mean (SD) gain of 
9.2 (6.38) ETDRS letters.  
• The effect was maintained up to the end of the study: at Month 3, the mean (SD) gain 
was 8.3 (6.77) ETDRS letters. 
In all study treatment arms, mean gains in BCVA from Baseline were shown at all study visits. 
At each visit, the largest mean gain in BCVA from Baseline was observed for the highest dose 
level (THR 687 2.0mg). At this dose level, the mean gains in BCVA from Baseline were 4.3, 9.8, 
11.2, 10.8 and 12.5 ETDRS letters at 1 day, 7 days, 14 days, 1 month and 3 months after the 
injection, respectively. 
Overall, across dose levels, a marginal impact on CST was observed until 1 month after the 
injection, with a mean (SD) decrease of -35.8 (91.89) µm at Month 1. After that, the mean CST 
increased to the value at Baseline, with a mean (SD) change from Baseline of +4.1 (115.63) µm 
at Month 3. As for BCVA, the largest effects on decrease in CST from Baseline were observed 
for the highest dose level (THR-687 2.0mg). 
Refer to the Investigator’s Brochure for a more detailed description of the available clinical data. 
* In study THR-687-001, the dose levels reflected the content of all THR-687 as chloride salt. In 
this study, the dose levels reflect the amount of THR-687 free base (THR-687 active form). A 
conversion table is presented below: 
Dose Level Indicating THR-687 Free Base 
Form (Active THR-687) 
Dose Level Indicating THR-687 Salt Form  
(All THR-687) 
THR-687 0.3mg 
THR-687 0.4mg 
THR-687 0.8mg 
THR-687 1.0mg 
THR-687 1.2mg 
THR-687 1.5mg 
THR-687 2.0mg 
THR-687 2.5mg 
mg = milligram 


 
 
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2.3. 
Benefit-Risk Assessment 
2.3.1. 
Benefit Assessment 
It is expected that the study treatments offer benefit to the subjects in the study: 
• THR-687: The results of the Phase 1 study with THR-687 in previously treated 
subjects with CI-DME showed that a single IVT injection of THR-687 was safe and 
well-tolerated. In addition, mean gains in BCVA from Baseline were observed at all 
dose levels tested.  
• Aflibercept (Part B): Aflibercept is an approved first-line, standard-of-care 
treatment for DME.  
− Most of the subjects will be naïve to treatment with aflibercept in the study eye. 
Per label, aflibercept treatment is to be initiated with 1 injection per month for 
5 consecutive injections. Considering the treatment schedule foreseen in this 
study, aflibercept will not be administered per label for the majority of the 
subjects in the comparator arms. At the same time, it is expected that aflibercept 
will offer benefit in the dosing regimen used in the study. Indeed, as described in 
Section 4.2.4, 70 – 80% of the maximum effect of aflibercept on visual acuity 
improvement was observed at 1 month after the 3 first monthly injections 
(Korobelnik et al., 2014).  
− Some of the subjects will have been previously treated with aflibercept in the 
study eye. This will include subjects who responded well to the treatment, and 
who are hence expected to benefit from continued treatment, as well as subjects 
who did not respond optimally to the treatment with aflibercept. It is however 
expected that also this latter type of subjects can benefit from the treatment with 
aflibercept in the study, as it has been shown that continued treatment with 
aflibercept in patients who do not optimally respond to the treatment, does not 
preclude the possibility of future development of a better response. As an 
example, a post-hoc analysis of the Diabetic Retinopathy Clinical Research 
Network (DRCR.net) Protocol T on the 31.6% of eyes treated with aflibercept 
that had persistent DME (i.e. with CST > 250µm at each completed study visit) 
through 24 weeks of treatment (i.e. after 3 – 6 injections with aflibercept) showed 
that continued aflibercept treatment through 2 years resulted in long-term 
improvement of visual acuity (51.4% of the eyes with persistent DME at Week 24 
had a gain of ≥2 lines from Baseline at Year 2), and in resolution of DME (in eyes 
with persistent DME at Week 24, the probability for chronic persistent DME at 
Year 2 was 44.2%) (Bressler et al., 2018). 
Another benefit of study participation is that the subjects will be closely followed up for the 
duration of the study, including a BCVA assessment and a full ophthalmic examination at each 
study visit (except for the optional blood sampling visit), as well as regular ocular imaging 
including SD-OCT, colour fundus photography and fluorescein angiography. 


 
 
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An indirect benefit of study participation is that this study may contribute to the development of 
a new DME treatment. In addition, this study may realise overall advancement of medical and 
scientific knowledge that may benefit patients in the future. 
2.3.2. 
Risk Assessment 
2.3.2.1. 
Potential Risks Related to the Investigational Medicinal Products 
Potential Risks Related to Intravitreal THR-687 
This is the second clinical study in which THR-687 will be administered in humans. Given the 
limited human experience with THR-687, it is currently not possible to classify any AE, apart 
from AEs related to the IVT injection procedure, as expected.  
A single IVT injection with THR-687 was safe and well-tolerated at all dose levels tested in the 
Phase 1 study THR-687-001. The AEs that were reported in the study eye were considered 
associated with the IVT injection procedure, underlying disease progression or concomitant 
diseases, and not with THR-687 itself (also refer to Section 2.2.3.2). 
Potential Risks Related to Intravitreal Aflibercept  
Refer to the Eylea® (aflibercept) label for information regarding the potential risks related to 
aflibercept. 
2.3.2.2. 
Potential Risks Related to the Intravitreal Injection Procedure 
The risk of complications from the IVT injection itself is low. Complications associated with 
IVT injections include eye pain, intraocular haemorrhage, ocular infection, transient increase in 
IOP, retinal detachment and floaters (Aiello et al., 2004; Avery et al., 2014; 
Charalampidou et al., 2011; Jager et al., 2004).  
The prevalence of endophthalmitis, retinal detachment and intraocular haemorrhage after IVT 
injections is estimated to be 0.2%, 0.9% and 1.3% per IVT injection, respectively 
(Jager et al., 2004). Nevertheless, careful attention to aseptic conditions, injection technique and 
appropriate post-injection monitoring are essential because uncommon injection-related 
complications may potentially lead to permanent vision loss. 
2.3.2.3. 
Potential Risks Related to Other Study Procedures 
Anaesthetic Eye Drops 
Allergic reactions to anaesthetic eye drops are rare, but include itching, lid swelling and eye 
redness. Another risk associated with these drops is scratching of the cornea due to rubbing of 
the numbed eye. Study subjects must therefore be instructed not to rub their eyes until the 
anaesthetic wears off (about 15 minutes). 
Pupil Dilation 
Pupil dilation will lead to the pupils remaining dilated for several hours. This may result in light 
sensitivity and blurred vision (especially for near tasks). Study subjects must be told not to drive 


 
 
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while their pupils are dilated. Allergic reactions are rare but include eyelid swelling and eye 
redness. 
Tonometry 
If contact tonometry is used for IOP measurement, there is a small risk for corneal scratching 
(abrasion). 
Fluorescein Angiography 
Fluorescein will be injected in the systemic circulation, which may cause pain at the injection 
site and which carries a small risk of bleeding, bruising and / or infection at the injection site. 
Other side effects may include nausea, vomiting, gastrointestinal distress, headache, syncope and 
hypotension. In addition, the fluorescein may lead to temporary, limited darkening of the skin 
and urine.  
In very rare cases, a severe allergic reaction can occur, which can cause breathing problems and 
exceptionally lead to death. For this reason, people with a history of drug reaction or allergy will 
be carefully monitored. 
Blood Draw 
Blood draw carries a small risk of pain, excessive bleeding, fainting or light-headedness, 
haematoma under the skin at the site of the needle insertion and a rare risk of infection. 
Anterior Chamber Paracentesis 
Anterior chamber paracentesis is widely performed in the management of uveitis, particularly in 
diagnosing infective causes. It is also commonly used to immediately lower pathological 
elevation of IOP. Anterior chamber paracentesis is a generally safe procedure; the incidence of 
complications is low when caution is exercised. Reported complications include allergy to 
povidone iodine, inadvertent injection of air into the anterior chamber, trauma to the cornea, iris 
or lens, hyphaemia, severe inflammation, infection or endophthalmitis (Azuara-Blanco and Katz, 
1997; Cheung, Durrani and Murray, 2004; Helbig et al., 1995; Trivedi, Denniston and Murray, 
2011; Van der Lelij and Rothova, 1997). In 3 retrospective case series, a total of 361, 560 and 
301 patients undergoing anterior chamber paracenteses were assessed, respectively 
(Kitazawa et al., 2017; Trivedi, Denniston and Murray, 2011; Van der Lelij and Rothova, 1997). 
No long-term serious post-operative complications were reported in any of the studies. 
Trivedi et al reported 4 complications out of 560 patients (0.7%): 2 cases of inadvertent injection 
of air that resolved spontaneously, 1 anterior capsule touch due to sudden eye movement that 
was self-healing and 1 allergic reaction to povidone iodine. None of the patients reported pain 
(Trivedi, Denniston and Murray, 2011). Van der Lelij et al reported small hyphaemia in 5 out of 
72 patients who were examined 30 minutes after the puncture. The depth of the anterior chamber 
of all evaluated patients was restored at the time of examination (Van der Lelij and Rothova, 
1997). 


 
 
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2.3.2.4. 
Measures to Minimise the Risk for the Subjects in the Study 
To minimise the risks for the subjects in the study, the following measures will be taken: 
• For each subject, each AE will be recorded from the time of providing consent until 
the end of his / her participation in the study. At each study visit (except for the 
optional blood sampling visit at Day 3), the study personnel will inquire about 
medical complaints, and a full ophthalmic examination (including slit lamp 
examination, IOP assessment and dilated fundus examination) and BCVA assessment 
will be performed. In addition, regular ocular imaging will be performed, including 
SD-OCT, colour fundus photography and fluorescein angiography. 
• A list of withdrawal criteria from repeat injection with IMP is provided (refer to 
Section 7.1). If for a subject, any of these criteria apply at the time of planned repeat 
injection, he / she will not receive further injection(s) with IMP but will continue 
study participation (apart from injection-related procedures) to ensure a complete 
follow-up. In addition, the Investigator may withdraw study subjects from repeat 
injection from IMP at his / her discretion.  
• Criteria for rescue treatment are provided (refer to Section 6.7.3). When a subject 
who will receive no further injections with IMP experiences a worsening of DME in 
the study eye, rescue (standard-of-care) treatment can be administered as deemed 
necessary by the Investigator if one of the criteria for rescue treatment is met. These 
subjects will continue study participation to ensure a complete follow-up. 
• As this is the first study assessing multiple IVT injections of THR-687, an SMC will 
be established. The SMC will be empowered to make recommendations on further 
study conduct. Refer to Section 9.6.1 for more information on the SMC. 
2.3.3. 
Overall Benefit-Risk Conclusion 
Considering the measures taken to minimise the risk for the subjects in the study, the Sponsor 
believes that the potential risks associated with study participation are justified by the anticipated 
benefits that may be afforded to the subjects in the study, and to patients with DME in general. 


 
 
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3. 
OBJECTIVES, ENDPOINTS AND MAIN ESTIMAND FOR THE 
PRIMARY ENDPOINT 
3.1. 
Objectives 
3.1.1. 
Part A 
3.1.1.1. 
Primary Objective 
The primary objective of this part of the study is to select the THR-687 dose level (1.2mg or 
2.0mg) to be further assessed in Part B. Dose level selection will be based on a benefit-risk 
assessment conducted when all subjects completed the Month 3 visit. 
Refer to Section 3.2.1.1 for the related endpoints. 
3.1.1.2. 
Other Objectives 
The other objectives of this part of the study are the same as those defined for Part B. 
3.1.2. 
Part B 
3.1.2.1. 
Primary Objective 
The primary objective of this part of the study is to assess the difference in treatment effect 
between THR-687 and aflibercept, in terms of the change from Baseline in BCVA at Month 3, in 
Rx naïve subjects. 
Refer to Section 3.2.2.1 for the related endpoint and the main estimand. 
3.1.2.2. 
Other Objectives 
• To assess the efficacy of multiple IVT injections of THR-687 over-time 
• To assess the safety of multiple IVT injections of THR-687 over-time  
Refer to Section 3.2.2.2 and to Section 3.2.2.3 for the related endpoints. 
3.2. 
Endpoints and Main Estimand for the Primary Endpoint 
3.2.1. 
Part A 
3.2.1.1. 
Key Endpoints to Assess Benefit-Risk 
• Incidence of ocular and non-ocular AEs and SAEs 
• Development of severe intraocular inflammation: ≥ 2+ inflammation on any of the 
intraocular inflammation grading scales (grading of anterior chamber cells, grading of 
anterior chamber flare, Nussenblatt chart for vitreous inflammation grading) 
• Incidence of BCVA decrease of ≥ 10 ETDRS letter score from Baseline, by study 
visit 
• Change from Baseline in BCVA ETDRS letter score, by study visit 


 
 
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• Change from Baseline in CST, based on SD-OCT, as assessed by the CRC, by study 
visit 
3.2.1.2. 
Other Endpoints 
All applicable endpoints defined in Part B will also be assessed in an exploratory manner for 
Part A (if not already part of the key endpoints to assess benefit-risk).  
3.2.2. 
Part B 
3.2.2.1. 
Primary Endpoint and Main Estimand; Rx Naïve Subjects 
• The primary endpoint is defined as the change from Baseline in BCVA ETDRS letter 
score, at Month 3 
The main estimand for the primary endpoint is defined as the difference between the 
2 study treatment arms in the mean change from Baseline in BCVA ETDRS letter 
score at Month 3, using the FAS, whereby the intercurrent event ‘initiation of rescue 
treatment’ will be handled using the while-on-treatment strategy i.e. after initiation of 
rescue treatment, the last available value of BCVA prior to the intercurrent event will 
be carried forward. Other intercurrent events, including death or discontinuation from 
the study due to an AE related to IMP, will be handled by carrying forward the last 
available assessment prior to the event. 
3.2.2.2. 
Secondary Endpoints  
• Weighted average of the change from Baseline in BCVA ETDRS letter score from 
Day 8 through Month 3 using the trapezoidal rule (AUC) 
• Change from Baseline in BCVA ETDRS letter score, by study visit 
• Change from Baseline in CST, based on SD-OCT, as assessed by the CRC, by study 
visit 
• Incidence of ocular and non-ocular AEs and SAEs, from first injection up to the end 
of the study 
3.2.2.3. 
Exploratory Endpoints 
• Proportion of subjects with categorical changes from Baseline in BCVA ETDRS 
letter score (loss of ≥ 5, ≥ 10 and ≥ 15 ETDRS letters; gain of ≥ 5, ≥ 10 and 
≥ 15 ETDRS letters), by study visit  
• Proportion of subjects with BCVA ≥ 69 ETDRS letters (Snellen equivalent 20/40 or 
better), among subjects with BCVA ≥ 69 ETDRS letters at Day 1 and among subjects 
with BCVA < 69 ETDRS letters at Day 1, by study visit 
• Proportion of subjects with a 4th injection with IMP at Month 3, at Month 4, at 
Month 5, or who did not require a 4th injection with IMP 
• Time between 3rd injection with IMP and 4th injection with IMP or initiation of rescue 
treatment (whichever comes first) 


 
 
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• Time to first rescue treatment  
• Proportion of subjects withdrawn from repeat injection with IMP and reason for 
withdrawal 
• Proportion of subjects with an improvement of ≥ 2 steps on the ETDRS Severity 
Scale from Baseline, based on colour fundus photography, as assessed by the CRC, 
by study visit 
• Changes from Baseline in ischaemia and leakage assessments, based on fluorescein 
angiography, as assessed by the CRC, by study visit 
• Changes from Baseline in vascular density and foveal avascular zone area, based on 
OCTA, as assessed by the CRC, by study visit, in subjects at sites that have the 
required type of equipment 
• Change from Baseline in NEI VFQ-25 total and subscale scores, by study visit, in 
subjects in selected countries 
• THR-687 plasma levels by Day 3, in subjects who provide consent, at sites that 
perform the sampling  
• Development of severe intraocular inflammation: ≥ 2+ inflammation on any of the 
intraocular inflammation grading scales (grading of anterior chamber cells, grading of 
anterior chamber flare, Nussenblatt chart for vitreous inflammation grading), by study 
visit 


 
 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
• Overall Design: This is a Phase 2, multicentre study composed of 2 parts (also refer 
to the study scheme). 
Part A is the randomised, single-masked, dose-selection part of the study assessing 
2 dose levels of THR-687.  
Part B is the randomised, double-masked, active-controlled part of the study with a 
single dose level of THR-687 (selected from Part A) and aflibercept as comparator. 
Randomisation in Part B will only be initiated after dose level selection by the 
Steering Committee, which will be based on a benefit-risk assessment conducted 
when all subjects in Part A have completed the Month 3 visit. 
• Number of Subjects (Planned): 
In Part A, it is planned to randomise approximately 12 subjects (approximately 
6 subjects per dose level).  
In Part B, it is planned to randomise approximately 291 subjects in total, including: 
− Approximately 231 Rx naïve subjects (approximately 154 subjects will receive 
THR-687 [selected dose level from Part A] and approximately 77 subjects 
aflibercept).   
− Approximately 60 previously treated subjects (approximately 30 subjects will 
receive THR-687 [selected dose level from Part A] and approximately 
30 subjects aflibercept). 
• Study Treatment Arms: 
Part A: Approximately 12 subjects are planned to be randomised (1:1 allocation) to: 
− THR-687 1.2mg. Approximately 6 subjects are planned to receive IVT 
THR-687 1.2mg at Day 1, Month 1 and Month 2. 
− THR-687 2.0mg. Approximately 6 subjects are planned to receive IVT 
THR-687 2.0mg at Day 1, Month 1 and Month 2. 
Part B:  
Approximately 231 subjects are planned to be randomised (2:1 allocation), stratified 
by study eye CST (as assessed by the CRC) at Screening and by study eye BCVA at 
Day 1, to: 
− THR-687 (selected dose level from Part A). Approximately 154 subjects are 
planned to receive IVT THR-687 (selected dose level from Part A) at Day 1, 
Month 1 and Month 2, possibly followed by a 4th injection with the same dose 
level of THR-687 at Month 3, or Month 4, or Month 5, if any of the PRN criteria 
are met.  


 
 
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− Aflibercept 2mg. Approximately 77 subjects are planned to receive IVT 
aflibercept 2mg at Day 1, Month 1 and Month 2, possibly followed by a 
4th injection with aflibercept 2mg at Month 3, or Month 4, or Month 5, if any of 
the PRN criteria are met. 
Approximately 60 previously treated subjects are planned to be randomised 
(1:1 allocation), stratified by study eye BCVA at Day 1, to: 
− THR-687 (selected dose level from Part A). Approximately 30 subjects are 
planned to receive IVT THR-687 (selected dose level from Part A) at Day 1, 
Month 1 and Month 2, possibly followed by a 4th injection with the same dose 
level of THR-687 at Month 3, or Month 4, or Month 5, if any of the PRN criteria 
are met.  
− Aflibercept 2mg. Approximately 30 subjects are planned to receive IVT 
aflibercept 2mg at Day 1, Month 1 and Month 2, possibly followed by a 4th 
injection with aflibercept 2mg at Month 3, or Month 4, or Month 5, if any of PRN 
criteria are met. 
• Investigational Medicinal Product Allocation: 
Part A: Eligible subjects will be randomised to receive either THR-687 1.2mg or 
THR-687 2.0mg (1:1 allocation), using an IWRS.  
Part B: Eligible Rx naïve subjects will be randomised to receive either 
THR-687 (selected dose level from Part A) or aflibercept 2mg (2:1 allocation), using 
an IWRS. Randomisation will be stratified by: 
− Study eye CST at Screening (< 400µm versus ≥ 400µm, on SD-OCT, as assessed 
by the CRC), and 
− Study eye BCVA at Day 1 (≤ 63 ETDRS letters versus > 63 ETDRS letters). 
Eligible previously treated subjects will be randomised to receive either 
THR-687 (selected dose level from Part A) or aflibercept 2mg (1:1 allocation), using 
an IWRS. Randomisation will be stratified by study eye BCVA at Day 1 
(≤ 63 ETDRS letters versus > 63 ETDRS letters).  
• Study Duration: 
Part A: For each treated subject, the study duration will be 6 months from the first 
injection. 
Part B: For each treated subject, the study duration will be 8 months from the first 
injection. 
• Masking: 
Part A: The randomised, dose-selection part of the study will be conducted in a 
single-masked manner. In addition, to ensure objective assessment: 
− Masked BCVA assessor(s) will be assigned at each site to perform BCVA 
assessments. 


 
 
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− The CRC in charge of the grading of the ophthalmic images and the laboratories 
in charge of the protocol-related laboratory assessments will be masked to IMP 
assignment. 
Part B: The randomised, active-controlled part of the study will be conducted in a 
double-masked manner. In order to preserve the masking, IMP handling and 
administration will be performed by unmasked study personnel. IMP preparation 
must occur outside the subject’s view, and the subject should be asked to direct 
his / her gaze away at all times. 
• Committees: 
An SMC will be established, composed of members of relevant functional areas who 
are not involved in the day-to-day execution, management or monitoring of the study.  
A Steering Committee will be established to select the dose level of THR-687 that 
will be assessed in Part B. The Steering Committee will be composed of members of 
relevant functional areas who are not involved in the day-to-day execution, 
management or monitoring of the study. 
4.2. 
Scientific Rationale for Study Design 
4.2.1. 
Rationale for the Study Population 
This study will include Rx naïve subjects as well as previously treated subjects. 
The main goal is to compare the treatment effect of THR-687 with that of aflibercept in eyes that 
are naïve to treatment for DME (i.e. in eyes that have not been treated with anti-VEGFs, 
intravitreal corticosteroids, or any investigational product for DME; note that prior subthreshold 
micropulse laser and focal / grid laser are allowed provided a washout period of 180 days, as 
specified in Section 5.2). This population will allow for a direct comparison of THR-687 with an 
approved first-line treatment for DME (aflibercept). For that reason, all subject in Part A will be 
Rx naïve (to allow for dose level selection in this population), and the primary endpoint in Part 
B will be assessed on Rx naïve subjects only. 
In addition, subjects who received prior treatment for DME in the study eye will be included in 
Part B to explore the effect of THR-687 in this population. Indeed, considering its multifaceted 
mechanism of action, and as supported by the Phase 1 data, THR-687 is also expected to be 
efficacious in this population. 
4.2.2. 
Rationale for the THR-687 Dose Levels 
In Part A, 2 dose levels of THR-687 will be evaluated to allow for the selection of an efficacious 
dose level with minimal side effects.  
THR-687 2.0mg was selected as the highest dose level to be assessed in Part A, based on the 
results from the Phase 1 clinical study, and from repeated dose toxicity studies in New Zealand 
White (NZW) rabbits and in Göttingen minipigs: 
• As described in Section 2.2.3.2, a single IVT injection of THR-687 at 0.3mg, 0.8mg 
and 2.0mg was safe and well tolerated in the Phase 1 clinical study THR-687-001. 


 
 
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The largest effects on both BCVA and CST were observed at the highest dose level 
(THR-687 2.0mg).  
• In the repeated dose toxicity studies, no observed adverse effect dose level (NOAEL) 
in NZW rabbits was 2.5mg/eye (highest dose level investigated) while the NOAEL in 
Göttingen minipigs was 3.8mg/eye (second highest dose level investigated). 
Considering the volume of the vitreous of the NZW rabbit (∼1.5mL) and the 
Göttingen minipig (∼3mL) versus that of human (∼ 4.36mL), there is a safety margin 
of 3.6 for the NZW rabbit and one of 2.8 for the Göttingen minipig over the clinical 
dose level of 2.0mg. 
THR-687 1.2mg was selected as the other dose level to be assessed in Part A, based on the 
results from the Phase 1 study. Considering that all dose levels assessed in the Phase 1 study 
were safe and well tolerated, and that the largest effects on both BCVA and CST were seen with 
the highest dose level (THR-687 2.0mg), a slightly higher dose level than the middle dose level 
that was assessed in the Phase 1 study, was selected. 
4.2.3. 
Rationale for the Control Arm 
There is no control arm in Part A. 
Treatment with aflibercept will be used as a control in Part B as it is an approved 
standard-of-care treatment for DME.  
4.2.4. 
Rationale for the Dosing Regimen 
In Part A, subjects are planned to receive 3 IVT injections with THR-687, each 1 month apart. 
This dosing regimen is deemed sufficient to evaluate the potential of THR-687 as a treatment for 
DME, given the observation that the effect of anti-VEGF treatments on visual acuity reaches 
70 - 80% of its maximum effect at 1 month after the 3 first monthly injections (Korobelnik et al., 
2014; Mitchell et al., 2011). 
In Part B, subjects are planned to receive 3 IVT injections with IMP, 1 month apart, possibly 
followed by an additional, 4th injection with the allocated IMP at either Month 3, or Month 4, or 
Month 5, if any of the PRN criteria are met (refer to Section 6.1.3.1). This dosing regimen was 
selected for THR-687 in order to provide information on the dosing regimen(s) to be assessed 
during further clinical development (induction / initiation phase [number of loading doses 
required], maintenance phase [durability of the treatment effect]). 
For masking reasons, aflibercept will be administered following the same dosing regimen as that 
for THR-687 described above.  
4.2.5. 
Rationale for the Primary Endpoint 
The primary endpoint of Part B is the change from Baseline in BCVA ETDRS letter score, at 
Month 3.  
BCVA was selected as the primary outcome measure because it is a clinically meaningful 
measure to evaluate the efficacy of a DME treatment.  
Month 3 was selected as the timepoint for the primary endpoint considering that all subjects are 
planned to receive 3 monthly injections (at Day 1, Month 1 and Month 2), i.e. treatment is 


 
 
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standardised up to and including Month 2. From Month 3 onwards, treatment will vary between 
subjects (timing of the PRN injection, confounding effect of rescue treatment). Month 3 will 
hence allow for a clear comparison of the treatment effect of THR-687 and aflibercept.  
4.3. 
Study Definitions 
The study start date is the date on which the first subject signs the informed consent form 
(ICF). 
An enrolled subject is any subject who provided informed consent to participate in the clinical 
study.  
An eligible subject is an enrolled subject who meets all inclusion criteria and does not meet any 
exclusion criteria as defined in Section 5.1 and Section 5.2, respectively. 
A screen failure is an enrolled subject who was not randomised (for any reason, i.e. this may be 
a non-eligible or an eligible subject).  
A treated subject is a subject who received at least one injection with IMP. 
As per International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) E6, an IMP is a pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, including a product with a marketing 
authorisation when used or assembled (formulated or packaged) in a way different from the 
approved form, or when used for an unapproved indication, or when used to gain further 
information about an approved use. The IMPs in this study are THR-687 1.2mg, THR-687 2.0mg 
and aflibercept. 
A withdrawal from repeat injection is a treated subject who does not receive all injections with 
IMP as foreseen in the study protocol. 
A treated subject will be considered lost to follow-up if he / she fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The Baseline value of an assessment is defined as the last non-missing value prior to the first 
administration of IMP.  
Study treatment is the IMP that is planned to be administered to the subjects per the study 
protocol. 
Rescue treatment is any standard-of-care treatment for DME (i.e. anti-VEGF, corticosteroid or 
retinal laser treatment, depending on local practice) administered in the study eye while being in 
the study. 
The end of the study is the date of the last visit of the last subject in the study. 


 
 
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5. 
STUDY POPULATION 
The subjects in the study will be subjects with CI-DME: 
• Part A will be conducted in Rx naïve subjects. 
• Part B will be conducted both in Rx naïve subjects, and in previously treated 
subjects. 
For each subject, only 1 eye will be selected as the study eye. If both eyes are eligible, the eye 
with the lower BCVA will be selected as the study eye. If both eyes are eligible and have the 
same BCVA, the eye with the higher CST, as assessed by the CRC, will be selected as the study 
eye.   
Refer to the study specific manual for a more detailed guidance on the selection of the study eye. 
5.1. 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Written informed consent obtained from the subject prior to screening procedures 
2. Male or female aged 18 years or older at the time of signing the informed consent 
3. Type 1 or type 2 diabetes 
4. BCVA ETDRS letter score ≤ 78 (i.e. Snellen equivalent 20/32 or worse) (Part A), or  
≤ 73 (i.e. Snellen equivalent 20/40 or worse) (Part B), and ≥ 39 (i.e. Snellen equivalent 
20/160 or better) (both study parts), in the study eye 
5. CI-DME with CST ≥ 300µm in men, or ≥ 285µm in women, measured from the retinal 
pigment epithelium (RPE) to the internal limiting membrane (ILM) inclusively, on 
SD-OCT, in the study eye, as assessed by the CRC 
6. Rx naïve study eye with known diagnosis of DME ≤ 12 months prior to screening 
procedures, or previously treated study eye with known diagnosis of DME ≤ 36 months 
prior to screening procedures  
7. BCVA ETDRS letter score ≥ 34 (i.e. Snellen equivalent 20/200 or better) in the fellow 
eye 
 
5.2. 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
1. Macular oedema due to causes other than DME in the study eye (e.g. cataract extraction, 
vitreomacular traction) 
2. Concurrent disease in the study eye, other than DME, that could require medical or 
surgical intervention during the study period or could confound interpretation of the 
results (e.g. cataract, retinal vascular occlusion, retinal break [tear or detachment], 
macular hole, macular or retinal degeneration, CNV of any cause or subretinal 
haemorrhage involving the centre of the fovea) 


 
 
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3. Any condition in the study eye that could confound the ability to detect the efficacy of the 
IMPs (e.g. subretinal fibrosis or scar, vitreomacular traction, epiretinal membrane with 
deformation in the centre 1mm, foveal atrophy, retinal break [tear or detachment], 
macular ischaemia), as assessed by the CRC 
4. Ocular trauma (e.g. corneoscleral laceration, lens subluxation, cryoretinopexy) in the 
study eye within 6 months prior to Day 1  
5. Insufficient pupil dilation that precludes the adequate visualisation of the posterior 
segment of the study eye 
6. ETDRS severity level ≥ 61 (Part A), or ETDRS severity level ≥65 (Part B), on colour 
fundus photograph, in the study eye, as assessed by the CRC 
7. Presence of iris neovascularisation in the study eye 
8. Previous medications / interventions as listed below: 
Medication / Intervention 
Excluded Period prior to Day 1 
Study Eye 
 
Rx naïve subjects  
Previously treated 
subjects a 
Medication:  
Anti-VEGF treatment 
Any time 
90 days 
IVT injection with corticosteroids  
Any time 
180 days 
Ozurdex® (dexamethasone IVT implant) 
Any time 
180 days 
Iluvien® (fluocinolone acetonide IVT 
implant) 
Any time 
Peri-ocular corticosteroid treatment 
90 days 
Topical corticosteroids 
7 days 
Intervention: 
Subthreshold micropulse laser treatment 
180 days 
180 days 
Focal / grid laser photocoagulation 
180 days 
180 days 
Panretinal laser photocoagulation 
Any time 
Glaucoma laser 
90 days 
Vitrectomy, glaucoma tube shunt or 
trabeculectomy, scleral buckle surgery 
Any time 
Any other intraocular surgery 
90 days 
Systemic 
Anti-VEGF treatment  
Any time 
Corticosteroid treatment b 
90 days 
a Previously treated subjects will only be enrolled in Part B.  
b Except for corticosteroid inhalers, which are allowed at any time prior to Day 1. 
IVT = intravitreal; Rx = treatment 


 
 
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9. Planned administration of any of the medications / interventions in the study eye listed in 
the table above, or planned administration of systemic anti-VEGFs or corticosteroids 
(except for corticosteroid inhalers, the planned use of which is allowed), at any time 
during the entire study period  
10. Aphakia or absence of the posterior capsule in the study eye 
11. Anterior chamber intraocular lens (IOL) in the study eye 
12. Uncontrolled glaucoma (IOP ≥ 24mmHg despite treatment with anti-glaucoma 
medication[s]), or controlled glaucoma treated with > 2 anti-glaucoma medications, in the 
study eye 
13. History of or current high myopia (i.e. > 7D, or > 27mm axial length), in the study eye 
14. Previously received THR-687 or any other experimental therapy for DME, in either eye 
15. Any active or suspected ocular or periocular infection, or active intraocular inflammation, 
in either eye (e.g. blepharitis, infectious conjunctivitis, keratitis, scleritis, 
endophthalmitis, uveitis) 
16. Untreated diabetes (i.e. not utilising any diabetes medication) 
17. Glycated haemoglobin A (HbA1c) > 12%, as assessed by the central laboratory 
18. Uncontrolled hypertension in the opinion of the Investigator (e.g. systolic blood pressure 
> 180mmHg and / or diastolic blood pressure > 100mmHg), or any finding in the 
Investigator's opinion suggesting clinically significant hypertensive retinopathy 
19. Known hypersensitivity to the active substance of aflibercept, to the IMPs' excipients, or 
any of the medications that will be used for study procedures  
20. Pregnant or lactating woman (if a serum pregnancy test is required by local regulations or 
the Institutional Review Board [IRB] / Independent Ethics Committee [IEC], pregnancy 
will be assessed by the central laboratory) 
21. Women of childbearing potential not utilising a highly effective birth control method, or 
planning to become pregnant or to discontinue birth control methods, up to the Month 5 
visit (Part A), or up to the Month 8 visit (Part B) 
Refer to Appendix 4 for the definitions of woman of childbearing potential and of highly 
effective birth control methods. 
22. Men of reproductive potential not utilising contraception (where 1 method is barrier at 
the minimum), or planning to discontinue contraceptive , up to and including the Month 5 
visit (Part A), or up and including to the Month 8 visit (Part B) 
23. Myocardial infarction, other acute cardiac event requiring hospitalisation, stroke, 
transient ischaemic attack, or treatment for acute congestive heart failure within 6 months 
prior to Day 1 
24. History and / or current evidence of a systemic medical condition or any other reason that 
may, in the Investigator's opinion, preclude adherence to the scheduled study visits / 
assessments and safe participation in the study 


 
 
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25. Under treatment for a systemic infection 
26. Participation in a clinical study with any investigational product, within 5 times the 
half-life of both the parent drug and relevant metabolites, prior to screening procedures; 
or current participation in another clinical study; or planned participation in another 
clinical study at any time during the entire study period 
 
5.3. 
Lifestyle Considerations 
There are no lifestyle restrictions for study subjects before or during the study. 
5.4. 
Screen Failures 
A screen failure is an enrolled subject (i.e. consented to participate in the study) who does not 
receive any injection with IMP (for any reason, i.e. this may be a non-eligible or an eligible 
subject). A minimal set of information on screen failures is required to ensure transparent 
reporting of screen failures to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities.  
Refer to the study-specific manual for detailed instructions on information to be recorded in the 
electronic case report form (eCRF) for screen failures. 
For screen failures due to reasons that are expected to be temporary, one re-screening visit may 
be organised: 
• If the re-screening visit is conducted up to 4 calendar days after the first Screening, 
the subject does not need to sign a new ICF, will maintain his / her assigned 
subject number, and only the BCVA assessment, the IOP assessment as well as the 
assessment(s) that led to the screen failure need to be repeated. 
• If the re-screening visit is conducted more than 4 calendar days after the first 
Screening, the subject needs to have all screening procedures repeated (including 
signing of a new ICF and assignment of a new subject number). 


 
 
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6. 
STUDY TREATMENTS AND CONCOMITANT MEDICATIONS 
AND INTERVENTIONS 
6.1. 
Study Treatments  
6.1.1. 
Considerations Related to Study Treatment Administration 
At Day 1, only eligible subjects will be administered study treatment. Before each repeat 
injection with IMP (i.e. at Month 1 and Month 2 and, if applicable, before the 4th injection with 
IMP at Month 3, 4 or 5 [in Part B only]), the withdrawal criteria described in Section 7.1 will be 
assessed. Repeat injection with IMP will only be administered to subjects who are not withdrawn 
from repeat injection with IMP. 
6.1.2. 
Part A 
The study treatments that will be administered in Part A are presented in Table 3. 
Table 3: 
Study Treatments (Part A) 
IMP 
THR-687 1.2mg 
THR-687 2.0mg 
Type 
Drug 
Drug 
Product Name 
THR-687 
Diluent 
THR-687 
Formulation 
THR-687 40mg/mL (as 
free base) 
10mM monobasic, 
monohydrate sodium 
phosphate 
Sodium hydroxide for 
pH adjustment 
Water for injection 
 
10mM monobasic, 
monohydrate sodium 
phosphate 
Sodium hydroxide for 
pH adjustment 
Water for injection 
THR-687 40mg/mL (as 
free base) 
10mM monobasic, 
monohydrate sodium 
phosphate 
Sodium hydroxide for 
pH adjustment 
Water for injection 
Presentation 
Clear to slightly 
opalescent, colourless 
to slightly yellow 
Clear to slightly 
opalescent, colourless 
Clear to slightly 
opalescent, colourless 
to slightly yellow 
Volume for Dilution 
0.3mL (vial volume) 
0.2mL 
N/A (no dilution) 
Volume to be 
Administered 
0.05mL (50µL) 
Route of 
Administration 
IVT injection 
Dosing Regimen 
3 injections, each 1 month apart 
Use 
Experimental 
IMP = investigational medicinal product; IVT = intravitreal; mg = milligram; µL = microlitre; mL = millilitre; 
mM = millimolar; N/A = not applicable 
THR-687 will be provided in THR-687 IMP kits, containing a THR-687 and a diluent vial, and 
syringes and needles (CE marked) for withdrawal, dilution (only to be used if dilution is 
required) and injection of THR-687. Refer to the study-specific manual for a detailed packaging 
and labelling description. 


 
 
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6.1.3. 
Part B 
The study treatments that will be administered in Part B are presented in Table 4.  
Table 4: 
Study Treatments (Part B) 
IMP 
THR-687 (selected dose level from Part A) 
Aflibercept 2mg 
Type 
Drug 
Drug 
Product Name 
THR-687 
Diluent a 
Aflibercept 
Formulation 
THR-687 40mg/mL 
(as free base) 
10mM monobasic, 
monohydrate sodium 
phosphate 
Sodium hydroxide for 
pH adjustment 
Water for injection 
 
10mM monobasic, 
monohydrate sodium 
phosphate 
Sodium hydroxide 
for pH adjustment 
Water for injection 
Aflibercept 40mg/mL 
Polysorbate 20 
Sodium dihydrogen phosphate 
monohydrate 
Disodium hydrogen phosphate 
heptahydrate 
Sodium chloride 
Sucrose 
Water for injection 
Presentation 
Clear to slightly 
opalescent, colourless 
to slightly yellow 
Clear to slightly 
opalescent, 
colourless 
Clear, colourless to pale yellow  
Volume for 
Dilution 
0.3mL (vial volume), 
or N/A (no dilution) a 
0.2mL 
N/A (no dilution) 
Volume to be 
Administered 
0.05mL (50µL) 
Route of 
Administration 
IVT injection 
Dosing Regimen 
3 injections, 1 month apart, possibly followed by a 4th injection at Month 3, 
Month 4, or Month 5, the first time any of the PRN criteria are met (see Table 5) 
Use 
Experimental 
Active comparator 
a No dilution will be required if THR-687 2.0mg is the selected dose level. 
IMP = investigational medicinal product; IVT = intravitreal; mg = milligram; µL = microlitre; mL = millilitre; 
mM = millimolar; N/A = not applicable; PRN = pro re nata 
There will be 2 types of kits: 
• THR-687 IMP kits, containing a THR-687 vial and a diluent vial, and syringes and 
needles (CE marked) for withdrawal, dilution (only to be used if dilution is required) 
and injection of THR-687.  
• Aflibercept IMP kits, containing either a pre-filled syringe and an injection needle 
(CE marked); or an aflibercept vial, a syringe, and needles (CE marked) for 
withdrawal and injection of aflibercept.  
Refer to the study-specific manual for a detailed packaging and labelling description. 


 
 
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6.1.3.1. 
PRN Criteria for 4th Injection with Investigational Medicinal Product 
Subjects in Part B will receive a 4th injection with the allocated IMP at Month 3, Month 4, or 
Month 5, the first time either of the PRN criteria in Table 5 are met, as assessed by the 
Investigator.  
Subjects will receive maximum 4 injections with IMP in total, with the last injection 
administered at Month 5 the latest. 
The 4th injection with IMP will be administered if the study eye is still improving in terms of 
BCVA (i.e. if the maximum treatment effect has not been reached yet and the treatment is to be 
continued; 1st PRN criterion in Table 5), or if there is a moderate worsening in terms of BCVA 
and CST from the previously conducted visit (i.e. treatment is needed; 2nd PRN criterion in 
Table 5). Of note, subjects with substantial worsening of DME will be withdrawn from repeat 
injection with IMP and will receive rescue treatment (refer to Section 7.1 and Section 6.7.3, 
respectively).  
If a subject who is eligible to receive the 4th injection with IMP, meets both the PRN criteria 
defined in Table 5 and the rescue criteria defined in Table 6, the PRN criteria will prevail. Such a 
subject will hence receive a 4th injection with the allocated IMP rather than rescue treatment. 
Table 5: 
PRN Criteria 
PRN Criteria 
Rationale 
1. 
≥ 5 ETDRS letter score gain in BCVA from the previously 
conducted study visit, and / or 
≥ 10% decrease in CST from the previously conducted 
study visit 
Eye is improving; maximum 
treatment effect has not been 
reached yet; treatment to be 
continued 
2. 
Loss in BCVA of > 5 to ≤ 10 ETDRS letters from the 
previously conducted study visit, or from the last injection 
with IMP, and / or 
Increase in CST of > 10 to ≤ 20% from previously 
conducted study visit, or from the last injection with IMP, 
based on SD-OCT 
Eye is worsening; treatment needed 
BCVA = best-corrected visual acuity; CST = central subfield thickness; SD-OCT = spectral domain optical 
coherence tomography 
6.2. 
Storage, Preparation, Administration and Accountability 
6.2.1. 
Storage 
The IMPs must be stored refrigerated at +2°C to +8°C (36°F to 46°F) in a secure, 
temperature-controlled and monitored refrigerator with access limited to authorised site 
personnel. If temperature excursions are noted, this must be reported immediately to the 
unmasked study monitor. IMP kits subject to a temperature excursion need to be quarantined 
immediately at the required storage temperature until further instructions. 
From a microbiological point of view, the IMPs must be used immediately after opening of the 
vial(s) / dilution. 


 
 
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6.2.2. 
Preparation and Administration 
6.2.2.1. 
General Information 
To maintain the masking for the study subjects, IMP preparation must occur outside the subject’s 
view, and the subject should be asked to direct his / her gaze away at all times. In addition, in 
Part B, considering the double-masked set-up of this part of the study, IMP preparation and 
administration must be performed by unmasked site personnel. 
The pre-injection and injection procedures, including injection tray assembly and anaesthetic 
preparation, will be performed under controlled aseptic conditions. This will include surgical 
hand disinfection, sterile gloves and disinfection of the peri-ocular skin, eyelid and ocular 
surface (i.e. cleansed with povidone iodine). Adequate anaesthesia will be administered prior to 
the injection as per local clinical practice. Additionally, safety measures will be implemented as 
required per specific institutional policies associated with IVT injections. 
Only subjects enrolled in the study may receive study treatment, and only authorised site 
personnel may administer the injections with IMP.  
6.2.2.2. 
Preparation and Administration 
6.2.2.2.1. THR-687 1.2mg 
1. Take the THR-687 and the diluent vials out of the THR-687 IMP kit.  
2. Visually inspect the THR-687 vial. Only a clear to slightly opalescent, colourless to 
slightly yellow solution can be used. 
3. Remove the protective flip-off cap from the THR-687 vial and discard the flip-off cap 
immediately.  
4. Disinfect the top of the THR-687 vial with an alcohol wipe. 
5. Visually inspect the diluent vial. Only a clear to slightly opalescent, colourless solution 
can be used. 
6. Remove the protective flip-off cap from the diluent vial and discard the flip-off cap 
immediately. 
7. Disinfect the top of the diluent vial with an alcohol wipe. 
8. Using aseptic technique, withdraw the diluent with a 19G needle and one of the 1mL 
syringes provided in the THR-687 IMP kit (incline the vial at approximately 45° to ease 
withdrawal – do not invert the vial). Carefully expel the air and excess diluent from the 
syringe to retain 0.2mL (also refer to Table 3). 
9. Add the indicated volume of diluent into the THR-687 vial. Discard the needle and the 
syringe.  
10. Invert the vial about 4 times until THR-687 and the diluent are mixed.  
11. Visually inspect the vial. Only a solution free from visible particles can be used. 


 
 
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12. Using aseptic technique, withdraw the IMP from the vial with the other 19G needle and 
1mL syringe provided in the THR-687 IMP kit. Discard the needle after withdrawal of 
the vial contents. Do not use this 19G needle for the IVT injection. 
13. Replace the needle with the 30G injection needle provided in the THR-687 IMP kit.  
14. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there 
are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the 
top. 
15. Eliminate all bubbles and expel excess THR-687 from the syringe and adjust the volume 
to the 0.05mL (= 50µL) mark on the syringe (corresponding to THR-687 1.2mg). 
16. Inject 0.05mL (= 50µL) of the IMP into the mid-vitreous of the study eye: 
a. The injection will be made through the pars plana in the inferotemporal quadrant 
3.5-4mm posterior to the limbus. 
b. The needle will be inserted at least 6mm towards the centre of the eye avoiding the 
horizontal meridian. 
c. Use a moderately slow injection technique to allow the IMP to enter the vitreous. 
d. A different scleral site will be used for subsequent injections. 
17. Slowly remove the needle and use a sterile cotton-tip applicator to prevent reflux of both 
the IMP and the vitreous. 
18. Discard the syringe and the needle immediately after the injection. 
19. Put the vials back in their box. Seal the box and store securely for IMP accountability. 
Refer to the study-specific manual for more details. 
6.2.2.2.2. THR-687 2.0mg 
1. Take the THR-687 vial out of the THR-687 IMP kit. The diluent is not needed for the 
administration of THR-687 2.0mg and can stay in the box.  
2. Visually inspect the THR-687 vial. Only a clear to slightly opalescent, colourless to 
slightly yellow solution can be used. 
3. Remove the protective flip-off cap from the THR-687 vial and discard the flip-off cap 
immediately. 
4. Disinfect the top of the THR-687 vial with an alcohol wipe. 
5. Using aseptic technique, withdraw THR-687 from its vial with a 19G needle and one of 
the 1mL syringes provided in the THR-687 IMP kit (incline the vial at approximately 45° 
to ease withdrawal – do not invert the vial). Discard the needle after withdrawal of the 
vial contents. Do not use this 19G needle for the IVT injection. 
6. Replace the needle with the 30G injection needle provided in the THR-687 IMP kit.  
7. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there 
are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the 
top. 


 
 
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8. Eliminate all bubbles and expel excess THR-687 from the syringe and adjust the volume 
to the 0.05mL (= 50µL) mark on the syringe (corresponding to THR-687 2.0mg). 
9. Inject 0.05mL (= 50µL) of the IMP into the mid-vitreous of the study eye: 
a. The injection will be made through the pars plana in the inferotemporal quadrant 
3.5-4mm posterior to the limbus. 
b. The needle will be inserted at least 6mm towards the centre of the eye avoiding the 
horizontal meridian. 
c. Use a moderately slow injection technique to allow the IMP to enter the vitreous. 
d. A different scleral site will be used for subsequent injections. 
10. Slowly remove the needle and use a sterile cotton-tip applicator to prevent reflux of both 
the IMP and the vitreous. 
11. Discard the syringe and the needle immediately after the injection. 
12. Put the vials back in their box. Seal the box and store securely for IMP accountability. 
Refer to the study-specific manual for more details. 
6.2.2.2.3. Aflibercept 2mg 
Refer to the Eylea® (aflibercept) label for instruction on the preparation and administration of 
aflibercept. 
Refer to the study-specific manual for more details. 
6.2.3. 
Study Eye Post-Injection Assessment 
For each injection with IMP, a post-injection assessment must be performed within a few 
minutes after the injection to exclude central retinal artery non-perfusion or other complications, 
and can be repeated as many times as needed at the discretion of the Investigator.  
The study eye must be monitored for elevated IOP within 30±15 minutes after the injection. 
Elevated IOP may occur in the context of the central retinal artery that remains closed for 
approximately 2 minutes with the subject reporting no light perception. Transient greying or 
obscuration of vision following injection is expected and does not need to be treated. If IOP is 
elevated after the injection, IOP must be monitored until the IOP decreases to normal range. 
The following must be done: 
1. Visualise the optic nerve head to verify reperfusion of the central retinal artery  
2. Monitor IOP. Increased IOP may warrant treatment at the discretion of the Investigator 
(e.g. anterior chamber paracentesis).  
3. Verify that the retina is attached and that there is no haemorrhage. 
Instruct subjects that they must avoid rubbing their eye. Also instruct subjects to report any 
symptoms suggestive of infection, bleeding, retinal break (tear or detachment) or increased IOP 
without delay (e.g. eye pain, worsening eye redness, severely blurred or decreased vision, 
increased sensitivity to light, floaters). 


 
 
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6.2.4. 
Accountability 
A full accountability record must be maintained by the authorised study personnel. 
IMPs (both unused and used) must be stored securely. A study monitor will visit the site 
periodically to check inventories and ensure that the IMPs have correctly been administered and 
that all unused products remain intact or are quarantined. After IMP administration is completed 
for all subjects and upon request from the Sponsor, all IMPs must be reconciled by the study 
monitor. Refer to the study-specific manual for practical information on the return / destruction 
of used / unused IMP kits. 
Under no circumstances will the IMPs be used in any manner other than directed by this 
protocol. 
6.3. 
Measures to Minimise Bias: Randomisation and Masking 
6.3.1. 
Randomisation and Investigational Medicinal Product Kit Number Allocation 
In Part A, the target is to randomise approximately 12 subjects to THR-687 1.2mg or THR-687 
2.0mg in a 1:1 allocation ratio (approximately 6 subjects per study treatment arm). 
Six (6) subjects per dose level are considered to provide sufficient information to assess the 
benefit-risk to select a dose level of THR-687 which warrants further investigation in Part B 
(also refer to Section 9.5). Subjects in this part of the study may therefore be replaced if 
insufficient data are collected (e.g. a subject who does not receive 3 injections with IMP and / or 
does not attend the Month 3 visit, if the reason for the missing injection / visit is unrelated to 
IMP safety or efficacy), or if the subject’s data need to be excluded from the analysis. The need 
to replace a subject will be assessed on a case-by-case basis. 
In Part B, the target is to randomise: 
• Approximately 231 Rx naïve subjects to THR-687 (selected dose level from Part A) 
or aflibercept 2mg in a 2:1 allocation ratio (approximately 154 and 77 subjects, 
respectively). Randomisation will be stratified by study eye CST at Screening 
(< 400µm versus ≥ 400µm, on SD-OCT, as assessed by the CRC) and by study eye 
BCVA at Day 1 (≤ 63 ETDRS letters versus > 63 ETDRS letters). 
• Approximately 60 previously treated subjects to THR-687 (selected dose level from 
Part A) or aflibercept 2mg in a 1:1 allocation ratio (approximately 30 subjects per 
study treatment arm). Randomisation will be stratified by study eye BCVA at Day 1 
(≤ 63 ETDRS letters versus > 63 ETDRS letters).  
Eligible subjects will be centrally assigned to randomised study treatment using an IWRS, 
integrated in the eCRF. At Day 1, authorised site personnel will access the subject’s eCRF to 
randomise the subject. 
At each injection visit, IMP kit number allocation will be performed through an IWRS, 
integrated in the eCRF. Authorised site personnel will access the subject’s eCRF to obtain the 
assigned IMP kit number.  
Refer to the study specific manuals for practical information on randomisation and IMP kit 
number allocation. 


 
 
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6.3.2. 
Masking 
Refer to the study specific manuals for practical information on study masking. 
6.3.2.1. 
Part A 
The randomised, dose-selection part of the study will be conducted in a single-masked manner. 
Study subjects will be masked to the IMP assignment, while all site personnel (except for the 
masked BCVA assessor) can be aware of the individual IMP assignment. 
At the same time, to ensure objective assessment of the main study endpoints: 
• Masked BCVA assessor(s) will be assigned at each site to perform BCVA 
assessments. 
• The CRC in charge of the grading of the ophthalmic images and the laboratories in 
charge of the protocol-related laboratory assessments will also be masked to IMP 
assignment. 
6.3.2.2. 
Part B 
The randomised, active-controlled part of the study will be conducted in a double-masked 
manner. The study subjects and the site personnel will be masked to the IMP assignment. The 
CRC in charge of the grading of the ophthalmic images and the laboratories in charge of 
protocol-related laboratory assessments will also be masked to the IMP assignment. 
In order to keep the masking, IMP handling and administration will be performed by unmasked 
study personnel. IMP preparation must occur outside the subject’s view, and the subject should 
be asked to direct his / her gaze away at all times.  
In the event of a quality assurance audit, the auditor(s) will be allowed access to unmasked study 
treatment records at the site to verify that randomisation / IMP kit number allocation has been 
conducted accurately. 
6.3.2.3. 
Emergency Unmasking 
The IWRS (Randomisation and Trial Supply Management [RTSM] system) will be programmed 
with emergency unmasking instructions. In case of an emergency, the Investigator has the sole 
responsibility for determining if unmasking of a subject’s study treatment assignment is 
warranted. Subject safety must always be the first consideration in making such a decision.  
If the Investigator decides that emergency unmasking is warranted, the Investigator must make 
every effort to contact the Sponsor Medical Monitor prior to unmasking a subject’s study 
treatment assignment, unless this could delay emergency treatment for the subject.  
Refer to the study-specific manuals for practical information on emergency unmasking. 
Sponsor safety personnel may unmask the study treatment assignment for any subject with a 
suspected unexpected serious adverse reaction (SUSAR). If the SUSAR requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s study treatment, may be sent to Investigator in accordance with local 
regulations. 


 
 
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6.4. 
Study Treatment Compliance 
Study treatment will be administered on site by authorised, unmasked site personnel. Information 
on IMP preparation and administration (such as the volume used for dilution [if applicable], the 
volume injected intravitreally, as well as the date and the time of the injection), will be recorded 
in the subject’s eCRF.  
Refer to the study-specific manuals for more detailed information. 
6.5. 
Continued Access to Study Treatment after the End of the Study 
Study treatment will be provided by the Sponsor (rescue treatment will not be provided by the 
Sponsor).  
As THR-687 is an investigational drug that has not yet been approved, it will not be available 
outside of the study.  
Subjects should be treated as per standard-of-care after the end of the study. 
6.6. 
Treatment of Overdose 
There is no specific antidote available in case of overdosing with THR-687 or aflibercept. 
Treatment of overdoses will be provided based on the nature of the symptoms. 
Overdosing due to increased injection volume may increase IOP. In case of overdosing due to 
increased injection volume, IOP must be monitored and adequate treatment will be initiated if 
deemed necessary. 
6.7. 
Concomitant Medications and Interventions 
All medications and interventions are allowed during the study, except those listed in Section 5.2 
(in the study eye or systemically), which should ideally be avoided during the entire study period 
as they may confound the study results. However, if there is a worsening of DME in the study 
eye and the subject will receive no further injections with IMP, rescue treatment may be 
administered as described in Section 6.7.3. 
The treatment of underlying diseases, including diabetes, is left to the subject’s medical care 
provider. 
Contact the Medical Monitor if there are any questions regarding prior or concomitant 
medications or interventions (ocular or non-ocular). 
6.7.1. 
Recording of Prior and Concomitant Medications (Including Intravitreal 
Injections) 
At Screening, the Investigator will assess prior medications taken / received by the subject 
(ocular and non-ocular). All prior IVT injections (both eyes) must be recorded in the subject’s 
eCRF. Any other medications taken / received in the 6 months prior to Screening must also be 
recorded in the subject’s eCRF. Vitamins and dietary supplements will not be recorded. 
At each study contact subsequent to Screening, the Investigator will assess any medications 
(ocular and non-ocular) taken / received by the subject and record all in the subject’s eCRF, 


 
 
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including anti-inflammatory and anti-infection eye drops given before or after IVT injections. 
Vitamins and dietary supplements will not be recorded.  
6.7.2. 
Recording of Prior and Concomitant Interventions 
At Screening, the Investigator will assess prior interventions received by the subject (ocular and 
non-ocular). All prior ocular interventions (both eyes) must be recorded in the subject’s eCRF. 
Any non-ocular interventions received in the 6 months prior to Screening must also be recorded 
in the subject’s eCRF.  
At each study contact subsequent to Screening, the Investigator will assess any interventions 
(ocular and non-ocular) received by the subject and record all in the subject’s eCRF. 
6.7.3. 
Rescue Treatment 
As per the study exclusion criteria, subjects will not be eligible for study participation if it is 
planned to administer any of the confounding medications / interventions as listed in Section 5.2, 
at any time during the study period. These medications / interventions should be avoided to be 
able to assess the effect of the IMP.  
However, once a subject will receive no further injections with IMP (either because he /she was 
withdrawn from repeat injection with IMP, or because he / she received all per protocol 
injections with IMP), rescue treatment may be administered as deemed necessary by the 
Investigator if one of the criteria in Table 6 are met, as assessed by the Investigator. Once a 
subject received rescue treatment, he / she may hence not receive any further injections with 
IMP. 
Rescue treatment will consist of standard-of-care treatment for DME and may hence be 
anti-VEGF, corticosteroid or retinal laser treatment depending on local practice. Once rescue 
treatment has been administered to a subject, this treatment can be continued as per standard-of-
care at the discretion of the Investigator. (i.e. irrespective of the rescue criteria). 
Table 6: 
Rescue Criteria 
Rescue Criteria a 
1. 
≥ 10 ETDRS letter score loss in BCVA from Day 1, and 
≥ 20% increase in CST from Day 1, based on SD-OCT 
2. 
BCVA is worse than Day 1, and 
≥ 10 ETDRS letter score loss in BCVA from the previously conducted study visit, and 
≥ 20% increase in CST from previously conducted study visit, based on SD-OCT 
a Once rescue treatment has been administered to a subject, this treatment can be continued as per standard-of-care 
at the discretion of the Investigator. (i.e. irrespective of the rescue criteria). 
BCVA = best-corrected visual acuity; CST = central subfield thickness; SD-OCT = spectral domain optical 
coherence tomography 


 
 
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7. 
WITHDRAWAL FROM REPEAT INJECTION WITH IMP AND 
DISCONTINUATION FROM THE STUDY 
7.1. 
Withdrawal from Repeat Injection with IMP 
A withdrawal from repeat injection with IMP refers to any treated subject who does not receive 
all study treatments as foreseen in the study protocol. Once a subject is withdrawn from repeat 
injection with IMP, the subject will not receive further injections with IMP, however, the subject 
may be treated with rescue treatment, as described in Section 6.7.3. 
In order to ensure a complete follow-up, subjects withdrawn from repeat injection with IMP will 
not be discontinued from the study and will continue all scheduled study visits and procedures, 
with the exception of IMP injection-related procedures (i.e. assessing the criteria leading to 
withdrawal from repeat injection with IMP, IMP kit number allocation, IMP administration and 
study eye post-injection assessment). The masking will be maintained for subjects who are 
withdrawn from repeat injection with IMP. 
The below criteria will be assessed by the Investigator before repeat injection with IMP at 
Month 1 and Month 2 and, if applicable, before the 4th injection with IMP at Month 3, 4, or 5 (in 
Part B only). If any of the criteria apply, no further injections with IMP will be administered, 
unless it is a temporary event, in which case the injection can be postponed until the event is 
resolved, if this is feasible within the protocol-specified study visit window. 
1. Pregnancy, or woman of childbearing potential not adhering to highly effective birth 
control method 
2. Rescue criteria are met and rescue treatment will be or has been administered to the 
subject (refer to Section 6.7.3) 
3. Active or suspected ocular or periocular infection, or active intraocular inflammation, in 
either eye (e.g. blepharitis, infectious conjunctivitis, keratitis, scleritis, endophthalmitis, 
uveitis) 
4. Hypersensitivity reaction to the IMP at the previous injection 
5. Ocular trauma (including corneoscleral laceration, lens subluxation, cryoretinopexy) in 
the study eye 
6. IOP ≥ 30mmHg in the study eye 
7. Retinal break (tear or detachment) in the study eye 
8. Stage 3 or 4 macular hole in the study eye 
9. Subretinal haemorrhage involving the centre of the fovea (as assessed by the Investigator) 
in the study eye 
10. Study eye intraocular surgery (for any reason) since the previous injection with IMP, or 
planned intraocular surgery within the next 28 days 
11. Study eye IVT injection or retinal laser treatment (both for any reason) since the previous 
injection with IMP 


 
 
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In addition to the criteria above, which apply to all subjects in the study, the following criterion 
applies to subjects in Part B only: 
• Subject’s individual treatment assignment has been unmasked by emergency 
unmasking 
Subjects may also be withdrawn from repeat injection with IMP at any time at the discretion of 
the Investigator (e.g. based on significant abnormalities on ophthalmic examination associated 
with the previous injection not listed in the criteria leading to withdrawal from repeat injection). 
7.2. 
Discontinuation from the Study 
A treated subject may discontinue from the study at any time at his / her own request or may be 
discontinued at any time at the discretion of the Investigator for safety, behavioural, or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuation from the study, if possible, an end of study visit should 
be conducted, as shown in the Schedules of Activities (SoAs).  
• All data collected until the date of study discontinuation, including the data collected 
during the End of Study Visit, must be recorded in the subject’s eCRF. The date of 
discontinuation from the study and the exact reason for study discontinuation will 
also be recorded in the subject’s eCRF. 
• If the subject withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.  
• If a subject discontinues from the study, he / she may request destruction of any 
samples taken and not tested. The Investigator must document this in the site study 
records. 
• The Investigator will follow subjects who are discontinued from the study as a result 
of an AE or SAE until the event has resolved, stabilised, is otherwise explained, or 
until the subject is lost to follow-up (also refer to Section 8.3.3). If the discontinuation 
from the study is a result of a pregnancy, the pregnancy will need to be reported and 
followed-up until conclusion (also refer to Section 8.3.5). 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he / she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible, counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and / or should continue in the 
study. 


 
 
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• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to re-gain contact with the subject. These contact attempts must be 
documented in the subject’s source documents. 
• Should the subject continue to be unreachable, he / she will be considered to have 
discontinued from the study.  


 
 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Adherence to the study design requirements is essential and required for study 
conduct. 
• Study procedures and their timing are summarised in the SoAs. Protocol waivers or 
exemptions are not allowed. 
• Unscheduled visits can be conducted at any time during the study. For each 
unscheduled visit, the reason for the visit, the visit date, the procedures performed and 
results obtained need to be recorded in the subject’s eCRF. If an unscheduled visit is 
conducted for clinical reasons, as a minimum the procedures as indicated in the SoAs 
need to be performed. In addition, other assessment may be performed as deemed 
necessary depending on the reason for the unscheduled visit.  
• Immediate safety concerns will be discussed with the Medical Monitor upon 
occurrence or awareness to determine if the subject should continue with or be 
withdrawn from IMP administration. Of note, if emergency unmasking is warranted 
and contacting the Medical Monitor could delay emergency treatment for the subject, 
the Investigator can proceed without contacting the Medical Monitor (refer to 
Section 6.3.2.3). In addition, subjects may be withdrawn from repeat injection with 
IMP at any time at the discretion of the Investigator (also refer to Section 7.1). 
• All in- and exclusion criteria must be checked at Screening to confirm that potential 
subjects meet all inclusion criteria and do not meet any exclusion criteria. 
Standard-of-care procedures done prior to Screening cannot be used for eligibility 
confirmation. The Investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screen failure, as 
applicable. Of note: 
− Some of the in- and exclusion criteria will need to be confirmed by the CRC / the 
central laboratory, as specified in Section 5.1 and Section 5.2. 
− The Investigator will re-confirm eligibility at Day 1 (by checking all criteria that 
can be re-confirmed by the Investigator, including blood pressure measurement, 
highly sensitive urine pregnancy test [for women of childbearing potential], 
BCVA assessment, full ophthalmic examination, recording of concomitant 
medications and interventions, AEs and SAEs) before randomisation. 
8.1. 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoAs. 
8.1.1. 
Best-Corrected Visual Acuity 
BCVA will be reported as ETDRS letter score. BCVA will be assessed by a qualified BCVA 
assessor who will be masked to IMP assignment (refer to Section 6.3.2).  
Refer to the study-specific manual for practical information on BCVA assessment. 


 
 
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8.1.2. 
Spectral Domain Optical Coherence Tomography 
SD-OCT imaging will be used to assess the retina, including CST, centre point thickness, total 
macular volume and other parameters such as presence of intraretinal and subretinal fluid. 
SD-OCT imaging will be performed by a CRC-certified photographer using CRC-certified 
equipment. SD-OCT images will be submitted to and graded by the CRC.  
Refer to the study-specific manuals for practical information on certifications, imaging 
procedures and submission of the images to the CRC. 
8.1.3. 
Fluorescein Angiography 
Fluorescein angiography will be used to assess retinal ischaemia and leakage. Fluorescein 
angiography will be performed by a CRC-certified photographer using CRC-certified equipment. 
Fluorescein angiographs will be submitted to and evaluated by the CRC.  
Refer to the study-specific manuals for practical information on certifications, imaging 
procedures and submission of the images to the CRC. 
8.1.4. 
Colour Fundus Photography 
Colour fundus photography will be used to assess DR severity (ETDRS severity level). Colour 
fundus photography will be performed by a CRC-certified photographer using CRC-certified 
equipment. Colour fundus photographs will be submitted to and graded by the CRC. 
Refer to the study-specific manuals for practical information on certifications, imaging 
procedures and submission of the images to the CRC. 
8.1.5. 
Optical Coherence Tomography Angiography 
OCTA will be used to assess vascular density and foveal avascular zone area. OCTA will be 
done at sites that have the required type of OCTA equipment and that are willing to do the 
imaging. OCTA will be performed by CRC-certified photographers using CRC-certified 
equipment. OCTA images will be submitted to and graded by the CRC.  
Refer to the study-specific manuals for practical information on certifications, imaging 
procedures and submission of the images to the CRC. 
8.1.6. 
National Eye Institute 25-Item Visual Function Questionnaire 
In selected countries, vision-related quality of life will be assessed using the NEI VFQ-25 
(interviewer-administered format), for all subjects . The NEI VFQ-25 interview will be 
administered to all subjects in the selected countries.  
Refer to the study-specific manuals for practical information on the NEI VFQ-25 questionnaire. 


 
 
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8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoAs. 
8.2.1. 
Full Ophthalmic Examination 
Full ophthalmic examination will consist of slit lamp examination, IOP assessment and dilated 
fundus examination. Full ophthalmic examination will be performed by authorised site 
personnel. 
Any clinically significant abnormalities detected during the full ophthalmic examination which 
are present at the time of Screening must also be recorded in the Ocular History section of the 
subject’s eCRF (e.g. all subjects are expected to have a clinically significant abnormal macula in 
the study eye). Any new clinically significant abnormalities that arise after Screening must also 
be recorded in the AE section of the subject’s eCRF.  
8.2.2. 
Best-Corrected Visual Acuity 
BCVA is both a measure of efficacy (gain from Baseline in ETDRS letter score) and safety 
(decrease from Baseline in ETDRS letter score). Refer to Section 8.1.1 for more information. 
8.2.3. 
HbA1c 
Blood samples (approximately 2mL) to asses HbA1c values will be collected. These blood 
samples do not require processing and will be shipped ambiently to the central laboratory for 
determination of the HbA1c value. The reports received from the central laboratory must be filed 
with the source documents.  
Refer to the study-specific manual for more information on blood sampling, storage, shipment 
and result availability. 
The Investigator must review the central laboratory report, document his / her review, and record 
any clinically relevant changes that are more severe than expected for the subject’s condition in 
the AE section of the subject’s eCRF (also refer to Appendix 3). The Investigator will refer the 
subject to his / her medical care provider if treatment is deemed required. 
8.2.4. 
Pregnancy Testing 
Pregnancy testing for women of childbearing potential will be done locally by using the provided 
highly sensitive urine pregnancy tests.  
If serum pregnancy testing is required by local regulations or the IRB / IEC, a blood sample for 
pregnancy testing will be collected at Screening (approximately 3.5mL). This blood sample will 
be processed to serum and shipped to the central laboratory for highly sensitive serum testing. At 
all other visits, pregnancy testing will be done locally by using the provided highly sensitive 
urine pregnancy tests. 
Refer to Section 8.3.5 for additional information regarding pregnancy, and to the study-specific 
manuals for more information regarding pregnancy testing and, if applicable, blood sampling, 
processing and shipment for serum pregnancy testing. 


 
 
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8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 3. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.1. 
Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events 
All AEs and SAEs will be collected from the time the subject provides consent to participate in 
the study until the end of the study (last study visit) for the subject. Any clinically significant 
medical abnormalities that are present before Screening must be recorded in the Medical History 
or the Ocular History section of the subject’s eCRF (as applicable).  
All SAEs will be recorded and reported immediately and under no circumstance can this exceed 
24 hours. SAEs will be reported by completing the SAE form in the subject’s eCRF (also refer to 
Appendix 3). The Investigator (or his / her designee) will complete the SAE form as thoroughly 
as possible and verify the information with the corresponding source documents. The 
Investigator will submit any updated SAE data within 24 hours of it being available. 
If the eCRF system does not work, the Investigator (or his / her designee) will provide the 
information to the Sponsor by completing the paper SAE form, which will be provided to the 
Sponsor by email (pharmacovigilance@oxurion.com) within 24 hours. This back-up system will 
only be used if the eCRF is not working and NOT if the system is slow. As soon as the eCRF is 
working again, the Investigator (or his / her designee) must complete the electronic SAE form. 
Investigators are not obliged to actively seek information on AEs or SAEs after conclusion of the 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he / she deems the event to be 
reasonably related to the study treatment or to study participation, the Investigator must promptly 
notify the Sponsor, either by completing the SAE form in the subject’s eCRF (if still possible), or 
by completing the paper SAE form and providing it to the Sponsor by email 
(pharmacovigilance@oxurion.com). 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
The Investigator will question the subject about any medical complaints (including new medical 
complaints and changes [worsening, improvement or disappearance] of complaints that he / she 
was having). Care must be taken not to introduce bias when detecting AEs and / or SAEs. 
Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire 
about AE occurrences. In addition, AEs or SAEs can be detected by the Investigator by 
performing study assessments (e.g. full ophthalmic examination). 


 
 
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8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial reporting of the AE or the SAE, the Investigator is required to proactively follow 
up on the event as follows: 
• All AEs that lead to discontinuation from the study and all SAEs will be followed up 
until the event has resolved, stabilised, is otherwise explained, or the subject is lost to 
follow-up, whichever occurs first.   
• All other AEs will be followed up until the event has resolved, stabilised, is otherwise 
explained, the subject is lost to follow-up, or the subject has completed the study, 
whichever occurs first. 
Further information on follow-up procedures is provided in Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt reporting of SAEs to the Sponsor is essential so that legal obligations and 
ethical responsibilities towards the safety of the subjects and the safety of a study 
treatment under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs / IECs and Investigators. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB / IEC, if appropriate according to local requirements. 
• Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
8.3.5. 
Pregnancy 
8.3.5.1. 
Women of Childbearing Potential 
• Women of childbearing potential must agree to use a highly effective birth control 
method, up to the Month 5 visit for subjects in Part A, and up to the Month 8 visit for 
subjects in Part B. The Investigator must counsel study subjects about the possible 
untoward effects on the foetus. Since no reproductive or development toxicity studies 
have been performed for THR-687 yet, and as studies in animals with aflibercept 
have shown embryo-foetal toxicity, the Investigator is required to actively follow up 
the subject’s adherence to their birth control method. 
• Women of childbearing potential will only be eligible for study participation after a 
negative highly sensitive pregnancy test at Screening and at Day 1. In addition, a 
highly sensitive pregnancy test will be taken before each repeat injection with IMP. 
Women who are pregnant at that time must be withdrawn from repeat injection with 


 
 
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IMP. These women will not be discontinued from the study and, apart from IMP 
injection-related procedures, will continue all scheduled study visits and procedures 
to ensure complete follow-up. Refer to Section 7.1 for more information on 
withdrawal from repeat injection with IMP. 
• The Investigator will immediately (within 24 hours after receipt or awareness of the 
information) report pregnancies occurring in female subjects, from the time they 
received the first injection with IMP, up to the Month 5 visit for subjects in Part A, 
and up to the Month 8 visit for subjects in Part B. The Investigator will provide the 
information by completing the paper Pregnancy / Prenatal Exposure form, which will 
be provided to the Sponsor by email (pharmacovigilance@oxurion.com).  
• Pregnancies will be monitored until conclusion. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality) must be followed up and documented via the Pregnancy Follow-up 
form, including for subjects who discontinued from the study, or who completed the 
study. 
• Pregnancy in itself is not regarded as an AE unless there is a suspicion that the IMP 
may have interfered with the effectiveness of a contraceptive medication. Any 
pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE (and not the pregnancy itself). If an adverse 
condition that results from pregnancy is deemed serious, an SAE form must be 
completed. Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and will be 
reported as such. 
• The Investigator is not obliged to actively seek information on pregnancies after 
conclusion of the study participation. However, if he / she learns of any post-study 
pregnancy-related SAE, and he / she deems the event to be reasonably related to the 
study treatment, the Investigator must promptly notify the Sponsor by completing the 
paper Pregnancy / Prenatal Exposure form and providing it to the Sponsor by email 
(pharmacovigilance@oxurion.com).  
8.3.5.2. 
Men of Reproductive Potential 
As per the study eligibility criteria (refer to Section 5.2), men of reproductive potential must use 
contraception (where 1 method is barrier at the minimum) up to and including the Month 5 visit 
(for subjects participating in Part A), or up to and including the Month 8 visit (for subject 
participating in Part B). In the event of unexpected pregnancy in partners from male subjects 
participating in the study, the pregnancy will not be followed up, unless required by the local 
regulatory authorities or the IRB / IEC. 
8.4. 
Pharmacokinetics 
Blood samples (approximately 2mL) to assess THR-687 levels in plasma will be collected at the 
timepoints indicated in the SoAs, at sites that perform the sampling, from subjects who provide 
consent. This sampling is optional and sites / subjects do not need to consent to it to be part of 
the study (also refer to Section 10.1.3). The blood samples will be processed to plasma and 


 
 
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stored frozen until shipment to the central laboratory, where they will be stored until transfer to 
the testing laboratory (refer to Appendix 2). The samples will be stored for a maximum of 
5 years after the end of the study. 
Refer to the study-specific manual for more information about blood sampling, processing, 
storage and shipment. 
THR-687 levels in plasma can lead to unmasking and the results will therefore not be reported to 
the Investigator. 
8.5. 
Genetics 
Genetics are not evaluated in this study. 
8.6. 
Immunogenicity Assessments 
THR-687 is a small molecule that is not thought to be immunogenic. Immunogenicity 
assessments will therefore not be performed. 
8.7. 
Medical Resource Utilisation and Health Economics 
Health Economics / Medical Resource Utilisation and Health Economics parameters are not 
evaluated in this study. 


 
 
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9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis plan (SAP) will be finalised prior to the database lock (freeze) pertaining 
to the analysis that will be performed to support the benefit-risk assessment which will be 
conducted by the Steering Committee when all subjects in Part A have completed the Month 3 
visit. The SAP will include a more technical and detailed description of the statistical analyses 
described in this section, including the use of alternative estimands for the main endpoints to test 
the robustness of the results, and the description of sensitivity analyses. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints and provides the basis for the SAP. 
9.1. 
Statistical Hypotheses 
The study consists of 2 parts: a randomised, single-masked, dose-selection part (Part A), and a 
randomised, double-masked, active-controlled part (Part B). The THR-687 dose level selected in 
Part A will be compared to aflibercept in Part B. Statistical hypothesis testing only applies to 
Rx naïve subjects in Part B of the study. 
Based on the main estimand for the primary endpoint (defined in Section 3.2.2.1), THR-687 will 
be considered non-inferior to aflibercept if the lower limit of the 95% confidence interval (CI) 
for the difference in mean treatment between THR-687 and aflibercept is above the 
non-inferiority margin of -2 letters. If non-inferiority is established, THR-687 will be considered 
superior to aflibercept (i.e. null hypothesis to be tested is: THR-687 is not different from 
aflibercept) if the lower limit of the same 95% CI is greater than zero. Justification for the 
selected non-inferiority margin, as well as sensitivity analyses to examine the robustness of the 
primary efficacy analysis results will be specified in the SAP. 
9.1.1. 
Multiplicity Adjustment 
The comparison of the primary endpoint between the 2 study treatment arms is the only 
statistical inference applied in this study, controlling the overall type I error at 5%. While the 
difference between study treatment arms for other selected efficacy endpoints will also be 
assessed by study visit, in a similar manner as for the primary endpoint, the results of those 
endpoints will be described with nominal p values without any statement on statistical 
significance. 


 
 
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9.2. 
Analysis Sets 
Analysis sets will be defined for both parts of the study as presented in Table 7. For simplicity, 
reference to the study part is only done for Part A. Additional analysis sets (including the Per 
Protocol analysis set) will be defined in the SAP to perform confirmatory analyses where 
appropriate. 
Table 7: 
Analysis Sets 
Study Part 
Analysis Set  
Description 
Part A 
Randomised, 
single-
masked, 
dose-selection 
Enrolled in Part A  
Includes all enrolled subjects.  
Randomised in Part A 
Includes all enrolled subjects randomised to IMP. 
All Treated in Part A 
Includes all randomised subjects in Part A who received 
at least 1 injection with IMP.  
Subjects will be analysed according to the first IMP they 
actually received. 
Part B 
Randomised, 
double-
masked, 
active- 
controlled 
Enrolled  
Includes all enrolled subjects.  
Randomised 
Includes all enrolled subjects randomised to IMP. 
FAS 
Includes all randomised subjects who received at least 
1 injection with IMP.  
Subjects will be analysed according to the randomised 
IMP, regardless of IMP actually received. 
All Treated 
Includes all randomised subjects who received at least 
1 injection with IMP.  
Subjects will be analysed according to the first IMP they 
actually received. 
FAS = Full Analysis Set; IMP = investigational medicinal product  
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
9.3.1.1. 
Procedure for Accounting for Missing Data  
All reasonable efforts will be made to obtain complete data for all subjects. However, missing 
observations may occur due to subjects lost to follow-up or to noncompliance with required 
study visits and / or assessments. Management of dropouts and missing data will depend on their 
frequency and the nature of the outcome parameter. 
Unless otherwise specified, missing data for efficacy related endpoints will be imputed using a 
multiple imputation model in case of monotone missingness, and Last Observation Carried 
Forward (LOCF) in case of an intermediate missing value (i.e. between visits). In general, no 
missing data will be imputed for safety related parameters. 


 
 
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9.3.1.2. 
Analytical Methods Used in Part A 
In Part A, all analyses will be performed on the All Treated analysis set. All endpoints will be 
analysed descriptively within each THR-687 dose level, and overall. 
Summary statistics for continuous outcome measures will include number of available 
observations, mean, SD, standard error (SE), median, minimum, and maximum, and where 
applicable 95% CI for the mean. For endpoints assessed at different visits, these summaries will 
be presented by visit. 
Categorical data, including shifts from Baseline, will be summarised by presenting count and 
percentage, and where applicable 95% CI for the proportion (Clopper-Pearson method). 
9.3.1.3. 
Analytical Methods Used in Part B 
Efficacy analyses will be performed separately in each of the 2 subpopulations (Rx naïve 
subjects and previously treated subjects). For each of the subpopulations, the definition of the 
analysis sets in Table 7 equally applies. Where applicable, analyses presented within a 
subpopulation will be summarised by the stratification factors used at randomisation. The 
primary analysis set in Part B will be the FAS, in each subpopulation. For some selected 
efficacy endpoints, the analysis will be presented in the 2 subpopulations pooled. Details will be 
provided in the SAP. 
Safety analyses will be performed using the All Treated analysis set, overall and by 
subpopulation. All analyses will be presented by study treatment arm, and by study visit if 
applicable.  
For each of the subpopulations, summary statistics for continuous outcome measures (including 
number of available observations, mean, SD, SE, 95% CI for the mean, median, minimum, and 
maximum) will be presented in each of the study treatment arms, within and across strata, if 
applicable. For endpoints assessed at different visits, these summaries will be presented by visit. 
Selected continuous efficacy endpoints (including BCVA, and retinal thickness SD-OCT 
parameters as assessed by the CRC) will be analysed by fitting an ANCOVA model with factors 
for IMP, Baseline value of the endpoint, and the stratification factors used for randomisation. 
Least-square means and 95% CIs will be used to estimate the treatment effect, i.e. difference 
between THR-687 and aflibercept.  
For each of the subpopulations, categorical data, including shifts from Baseline, will be 
summarised (including count, proportion, and corresponding 95% CI where applicable) in each 
of the study treatment arms, within and across strata, if applicable. For endpoints assessed at 
different visits, these summaries will be presented by visit. For selected categorical endpoints, 
including those based on BCVA, proportions will be compared between study treatment arms 
using the Cochran-Mantel-Haenszel test, stratified by the stratification factors used for 
randomisation. 
Similar summary statistics will be applied to continuous and categorical endpoints selected to be 
presented for the 2 subpopulations pooled, irrespective of the strata. 


 
 
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9.3.2. 
Efficacy Analyses 
9.3.2.1. 
Primary Endpoint and Estimand Analysis; Rx Naïve Subjects (Part B) 
The main estimand for the primary endpoint is defined as the difference between the 2 study 
treatment arms in the mean change from Baseline in BCVA ETDRS letter score at Month 3, 
using the FAS. The intercurrent event ‘initiation of rescue treatment’ will be handled using the 
while-on-treatment strategy i.e. after initiation of rescue treatment, the last available value of 
BCVA prior to the intercurrent event will be carried forward. Other intercurrent events, 
including death or discontinuation from the study due to an AE related to IMP, will be handled 
by carrying forward the last available assessment of BCVA prior to the event. Secondary 
estimand(s) for the primary endpoint and sensitivity analyses will be defined in the SAP. 
9.3.2.2. 
Other Endpoints Analysis 
All efficacy endpoints in Part A will be summarised by THR-687 dose level, and all secondary 
and exploratory efficacy endpoints in Part B will be evaluated, by applying the respective 
statistical methodology described in Section 9.3.1. 
9.3.3. 
Safety Analyses 
Safety analyses will be performed using the All Treated analysis set. The safety analyses will be 
summarised descriptively. In Part A, data will be presented within and across the dose levels. In 
Part B, data will be presented by study treatment arm, overall and within the 2 subpopulations. 
Where applicable, data will be presented by study visit. In Part B, safety analyses will not be 
presented by the stratification factors used at randomisation. 
9.3.4. 
Other Analyses 
Subgroup analyses of the primary endpoint and key secondary endpoints will be made to assess 
consistency of the treatment effect across subgroups of clinical interest. Details on the statistical 
analysis will be provided in the SAP. 
9.4. 
Sequence of Analyses 
The following analyses will be performed: 
• An analysis supporting the benefit-risk assessment done by the Steering Committee 
will be conducted when all subjects in Part A completed the Month 3 visit 
• An analysis of all data pertaining to Part A, when all data up to Month 6 / End of 
Study is available for all subjects in Part A 
• A final analysis of the study when all data up to Month 8 / End of Study are available 
for all subjects in Part B 
9.5. 
Sample Size Determination 
The sample size in Part A is not based on statistical grounds. Approximately 12 subjects will be 
randomised to 2 different dose levels of THR-687 in a 1:1 ratio (no stratification). 


 
 
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Six (6) subjects per dose level are considered to provide sufficient information to assess the 
benefit-risk to select a dose level of THR-687 which warrants further investigation in Part B.  
The sample size in Part B is determined separately in each of the subpopulations: 
1. Rx naïve subjects: approximately 231 subjects will be randomly assigned to either 
THR-687 or aflibercept in a 2:1 ratio (i.e. approximately 154 and 77 subjects in the 
2 study treatment arms, respectively), stratified by study eye CST at Screening (< 400µm 
versus ≥ 400µm, on SD-OCT, as assessed by the CRC) and by study eye BCVA at Day 1 
(≤ 63 ETDRS letters versus > 63 ETDRS letters). Assuming a common SD of 10 and 
using a one-sided alpha of 2.5%, this sample size will allow, with 80% power, to 
establish that: 
• THR-687 is non-inferior to aflibercept, using a non-inferiority margin of -2 letters 
and assuming that THR-687 would be 2 letters better than aflibercept, and  
• THR-687 is superior to aflibercept assuming that THR-687 would be 4 letters better 
than aflibercept 
The sample size is based on the main estimand of the primary endpoint and takes into 
account a dropout rate of 3% by Month 3. The commercial software nQuery Advisor 7.0 
has been used to compute the sample size. 
2. Previously treated subjects: approximately 60 subjects will be randomised to either 
THR-687 or aflibercept in a 1:1 ratio, stratified by study eye BCVA at Day 1 
(≤ 63 ETDRS letters versus > 63 ETDRS letters). Analyses in this subpopulation will be 
exploratory in nature and no formal hypothesis testing will be performed to compare 
study treatment arms. A sample size of 30 subjects in each study treatment arm is 
considered appropriate to gain information on the treatment effect in this subpopulation. 
9.6. 
Committees 
9.6.1. 
Safety Monitoring Committee 
As this is the first study assessing multiple IVT injections of THR-687, an SMC will be 
established. The SMC will be composed of members of relevant functional areas who are not 
involved in the day-to-day execution, management or monitoring of the study.  
Three (3) scheduled SMC reviews will be conducted during Part A: 
• After 6 subjects in total have received their 2nd injection with IMP and data for these 
subjects have been collected at least up to Month 1. 
• After 3 subjects in total have received their 3rd injection and data for these subjects 
have been collected at least up to Month 2.  
• After 6 subjects in total have received their 3rd injection and data for these subjects 
have been collected at least up to Month 2.  
In addition, if there is a safety concern outside of the scheduled SMC meeting, an ad hoc SMC 
meeting will convene.  


 
 
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For this reason, the SMC must be notified if any of the following events occur in Part A, at any 
time post-injection up to Month 3:  
• Development of severe intraocular inflammation: ≥2+ inflammation on any of the 
intraocular inflammation grading scales (grading of anterior chamber cells, grading of 
anterior chamber flare, Nussenblatt chart for vitreous inflammation grading) 
• BCVA decrease of ≥ 10 ETDRS letter score from Day 1  
Moreover, the Investigator must alert the SMC if any event occurs, at any time during the 
study, that is deemed important enough to trigger an overall safety assessment.  
The Investigator will report such events immediately and no later than 24 hours after receipt of 
awareness of the information, by completing the SMC reporting form. The Investigator will 
send the completed form by email to the SMC. Refer to the study-specific manual for practical 
details on reporting of these events. 
Upon receipt of the information, the SMC will decide whether an ad hoc SMC meeting needs to 
be convened. 
The SMC will be empowered to make recommendations on further study conduct. 
The procedures that the SMC will follow during its review(s), as well as the information flow to 
and from the SMC, are described in the SMC Charter. 
9.6.2. 
Steering Committee 
A Steering Committee will be established, composed of members of relevant functional areas 
who are not involved in the day-to-day execution, management or monitoring of the study. 
The Steering Committee will assess the benefit-risk of the 2 dose levels assessed in Part A by 
reviewing all available safety and efficacy data collected by the time all subjects in Part A have 
completed the Month 3 visit. The objective of this review will be to select the dose level to use in 
Part B of the study.  
If there are insufficient data available to draw firm conclusions, the Steering Committee may 
request additional subjects to be recruited in Part A. This request can either be made prior to, or 
following the Steering Committee meeting. 
Safety will be reviewed first as follows:  
• All safety information, including, but not limited to, any SAEs, ocular AEs 
(frequency, location, severity, outcome, action taken) that are deemed related to the 
IMP by the Investigator and / or the SMC (of note: injection procedure-related risks 
are potential and expected risks, and include eye pain, intraocular and periocular 
haemorrhage, haematoma, ocular infection, transient increase in IOP, conjunctival 
swelling, conjunctival irritation, retinal detachment). 
Special attention will be given to the following events: 
• Development of severe intraocular inflammation: ≥2+ inflammation on any of the 
intraocular inflammation grading scales (grading of anterior chamber cells, grading of 


 
 
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anterior chamber flare, Nussenblatt chart for vitreous inflammation grading), at any 
time post-injection  
• BCVA decrease of ≥ 10 ETDRS letter score from Baseline, at any time post-injection 
To determine whether a dose level is considered safe, the Steering Committee will consider 
whether any event that occurred is related to the IMP, and / or whether the event could be 
effectively treated or resolved without treatment prior to the next visit. 
The assessment of efficacy will include the review of the following: 
• Mean change from Baseline in BCVA ETDRS letter score, by study visit, by dose 
level 
• Mean change from Baseline in CST, by study visit, by dose level 
• Individual subject data as needed 
The Steering Committee will select the dose level to be further assessed in Part B of the study, 
based on the benefit-risk assessment using their clinical judgement. 
The selected dose level will be the highest dose level that is considered safe based on the above 
assessments and, in addition, also shows clinically relevant sign(s) of efficacy at Month 3, e.g.: 
• Mean gain of ≥ 12 ETDRS letters from Baseline, or 
• Mean gain of ≥ 8 ETDRS letters from Baseline and a mean decrease of ≥ 15% in CST 
from Baseline  
A dose level that does not lead to a clinically relevant improvement from Baseline in BCVA 
and / or CST, despite being safe, will not be selected for further assessment in Part B of the 
study.  
The procedures that the Steering Committee will follow during its review, as well as the 
information flow to and from the Steering Committee, are described in the Steering Committee 
Charter. 


 
 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the study protocol and with the 
following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines. 
− Applicable ICH Good Clinical Practice (GCP) guidelines. 
− Applicable laws and regulations. 
• The Sponsor will obtain favourable opinion / approval to conduct the study from the 
appropriate regulatory agencies, in accordance with all local regulatory requirements. 
• The protocol, protocol amendments, patient information sheet (PIS) / ICF, 
Investigator’s Brochure and other relevant documents (e.g. subject recruitment 
materials) will be submitted to an IRB / IEC and reviewed and approved by the 
IRB / IEC. 
• Any substantial amendments to the protocol will require regulatory agency, 
IRB / IEC approval before implementation of changes made to the study design, 
except for changes necessary to eliminate an immediate hazard to study subjects.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB / IEC annually 
or more frequently in accordance with the requirements, policies, and procedures 
established by the IRB / IEC. 
− Notifying the IRB / IEC of SAEs or other significant safety findings as required 
by IRB / IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB / IEC, European regulation 
536/2014 and all other applicable local regulations. 
10.1.2. 
Financial Disclosure 
The Investigator and sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. The 
Investigator is responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 


 
 
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10.1.3. 
Informed Consent Process 
• Subjects are required to provide signed and dated informed consent prior to study 
participation. The authorised person obtaining the informed consent must also sign 
the ICF. A copy the PIS and the signed ICF will be provided to the subject. 
• Before signing of the ICF, the Investigator or his / her authorised representative will 
explain the nature, purpose, risks and benefits of the study to the subject, and answer 
all questions he / she has regarding the study. Subjects must be allowed sufficient 
time to consider the information provided. 
• Subjects must be informed that their participation is voluntary and that they are free 
to discontinue their participation in the study at any time.  
• The PIS / ICF will meet the requirements of 21 CFR Part 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and those from the IRB / IEC or study site. 
• A statement that written information consent was obtained prior to study 
participation, as well as the date the consent was obtained, must be included in the 
subject’s medical records. 
• Whenever applicable, subjects must be re-consented to the most current version of the 
PIS / ICF during their participation in the study. 
As described in Section 5.4, subjects can be re-screened once. A subject who is re-screened 
within 4 days from the first Screening is not required to sign a new ICF. If the re-screening is 
done more than 4 calendar days after the first Screening, the subject needs sign a new ICF. 
At sites that perform the sampling, subjects will be provided with (a) separate PIS / ICF(s) that 
addresses optional aqueous humour sampling / blood sampling for assessment of THR-687 
plasma levels. The Investigator will explain the nature, purpose, risks and benefits of the optional 
sampling to the subject and answer all questions he / she has. Subjects must be allowed sufficient 
time to consider the information provided. Subjects must be informed that the sampling is 
optional and that they can still participate in the study even if they decline or discontinue the 
optional sampling. 
10.1.4. 
Data Protection 
• At each site, a unique identifier (subject number) will be assigned to subjects who 
have consented to participate in the study. Any subject records or datasets that are 
transferred to the Sponsor will contain the subject number only; the name of the 
subject or any information which would make the subject identifiable will not be 
transferred. 
• The subject must be informed that his / her coded study-related data will be used by 
the Sponsor in accordance with local data protection laws. The level of disclosure 
must also be explained to the subject, who will be required to give consent for his / 
her data to be used as described in the PIS.  
• The subject must be informed that his / her medical records may be examined at the 
study site by Clinical Quality Assurance auditors, other authorised personnel from the 


 
 
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Sponsor or a delegate, IRB / IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
At the conclusion of the study, after the data are analysed, a clinical study report will be 
prepared.  
Summaries of the results of the study will be posted on publicly available clinical trial registries 
as required.  
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. Authorship will be 
determined by mutual agreement and in line with International Committee of Medical Journal 
Editors authorship requirements. 
10.1.6. 
Data Quality Assurance 
• All subject data relating to the study will be recorded in the eCRFs unless transmitted 
to the Sponsor or designee electronically (e.g. laboratory data). Refer to the 
study-specific manual for guidance on completion of the eCRF. 
• The Investigator is responsible for verifying that eCRF data entries are accurate and 
correct by electronically signing the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB / IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• Monitoring details describing strategy, including definition of study critical data 
items and processes, methods, responsibilities, and requirements, including handling 
of non-compliance issues and monitoring methods (central, remote, or on-site 
monitoring) will be described in the monitoring plan. 
• Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that 
can impact subject safety and / or reliability of study results. These pre-defined 
parameters will be monitored during the study, and important deviations from the 
QTLs and remedial actions taken will be summarised in the clinical study report. 
• The Sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (such 
as the contract research organisation [CRO] working on behalf of the Sponsor). 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator in a safe and secure location for at least 
25 years after study completion unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention 
period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 


 
 
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10.1.7. 
Source Documents 
• The Investigator must maintain accurate documentation (source documents) that 
supports the information recorded in the eCRF. 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s 
site. 
• Data recorded in the eCRF that are transcribed from source documents must be 
consistent with the source documents, or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• Study monitors from the CRO will perform ongoing source data verification to 
confirm that data recorded into the eCRF are accurate, complete, and verifiable from 
source documents; that the safety and rights of the subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
10.1.8. 
Study / Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. If the study is prematurely terminated or 
suspended, the Sponsor shall promptly inform the Investigators, the IECs / IRBs and the 
regulatory authorities of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subjects and will assure 
appropriate subject therapy and / or follow-up. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further THR-687 development. 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB / IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
subjects by the Investigator. 
• Total number of subjects included earlier than expected. 
A study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 


 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
Samples will not be labelled with information that directly identifies the subject but will be 
coded with the subject number assigned in this study. 
The Investigator cannot use the samples for any other purpose than what is described in the study 
protocol or its amendment(s). 
Table 8: 
Protocol-Required Laboratory Tests 
System 
Test 
Component 
Method 
Testing 
Laboratory 
Urine  
Pregnancy 
Human chorionic 
gonadotropin 
Commercial, highly 
sensitive urine 
pregnancy test 
provided by the central 
laboratory 
Local (site) 
Serum a 
Pregnancy 
Human chorionic 
gonadotropin 
Commercial 
Central laboratory 
Whole blood 
Haematology 
HbA1c 
Commercial 
Central laboratory 
a Only if a serum pregnancy test is required by local regulations or the IRB / IEC. 
HbA1c = glycated haemoglobin A 
The Investigator must document their review of each laboratory safety report. 
Table 9: 
Optional Laboratory Test 
System 
Component 
Method 
Testing Laboratory 
Plasma 
THR-687 
LC-MS/MS 
Charles River Laboratory or 
designated laboratory 
LC-MS/MS = liquid chromatography-tandem mass spectrometry 


 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
10.3.1. 
Definition of an Adverse Event 
AE Definition (ICH Guideline E2A Definition) 
• 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
• 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (haematology, clinical chemistry or urinalysis) or other 
safety assessments (e.g. electrocardiogram, radiological scans, vital signs measurements), 
including those that worsen from Baseline, deemed clinically significant in the medical and 
scientific judgment of the Investigator (i.e. not associated with the subject’s underlying 
disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and / or severity of the condition. 
• 
New conditions detected or diagnosed after IMP administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either the IMP or a 
concomitant medication. Overdose per se will not be reported as an AE / SAE unless it is an 
intentional overdose taken with possible suicidal / self-harming intent. Such overdoses must be 
reported regardless of sequelae. 
• 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalisation” occurred or was necessary, the AE will be considered serious. 
Lack of efficacy per se will not be reported as an AE or SAE. Such instances will be captured in the 
efficacy assessments. However, the signs, symptoms, and / or clinical sequelae resulting from lack of 
efficacy will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the subject’s condition. 
• 
The disease / disorder being studied or expected progression, signs, or symptoms of the 
disease / disorder being studied, unless more severe than expected for the subject’s condition. 


 
 
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• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and / or convenience 
admission to a hospital). 
• 
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
Baseline. 
10.3.2. 
Definition of a Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g. hospitalisation for signs / symptoms of the disease under study). 
SAE Definition (ICH guideline E2A definition) 
An SAE is defined as any untoward medical occurrence that, at any dose level: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation  
In general, hospitalisation signifies that the subject has been admitted (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and / or treatment that would not 
have been appropriate in the physician’s office or outpatient setting.  
d. Results in persistent disability / incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. 
sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
a. Is a congenital anomaly / birth defect 
b. Other situations: 
• 
Medical or scientific judgment will be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalisation but may jeopardise the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
events will also usually be considered serious. 
• 
Examples of such events include intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation; or 
development of drug dependency or drug abuse. 


 
 
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10.3.3. 
Recording, Assessment and Follow-Up of Adverse Events and Serious Adverse 
Events 
AE and SAE Recording 
• 
When an AE / SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g. hospital progress notes, laboratory reports, and diagnostics reports) related 
to the event. 
• 
The Investigator will then record all relevant AE / SAE information in the subject’s eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to 
the Sponsor in lieu of completion of the AE / SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor or the delegated Pharmacovigilance Service Provider. In this case, all subject 
identifiers, except for the subject number, will be redacted on the copies of the medical records 
before submission. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and / or other clinical information. Whenever possible, the diagnosis (not the individual signs / 
symptoms) will be documented as the AE / SAE. 
 
Assessment of Severity 
The Investigator will assess severity for each AE and SAE reported during the study and assign it to 1 
of the following categories:  
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. 
An AE that is assessed as severe must not be confused with a SAE. Severe is a category utilised for 
rating the severity of an event; and both AEs and SAEs can be assessed as severe. An event is defined 
as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the definition of an 
SAE, NOT when it is rated as severe. A severe AE can be of relatively minor medical significance / 
non-serious (e.g. severe itching). Similarly, an SAE can be of mild severity (e.g. mild chest pain). 
 


 
 
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Assessment of Causality  
• 
For each AE / SAE, the Investigator is obligated to assess whether there is a reasonable 
possibility that the event is related to: 
o The IMP 
o The IVT injection procedure 
o Any other study procedure (apart from IMP administration) 
The Investigator will use clinical judgement to determine the relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, and / or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to IMP administration will be considered and 
investigated. 
• 
The investigator will also consult the THR-687 Investigator’s Brochure and the aflibercept 
label in his / her assessment. 
• 
For each AE / SAE, the Investigator must document in the medical notes that he / she has 
reviewed the AE / SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial SAE report to the Sponsor. However, it is very important 
that the assessment of causality is made at the time of the initial SAE report because the 
causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The Investigator may change his/her opinion on relationship to IMP in light of 
follow-up information and send a SAE follow-up report with the updated causality assessment. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and / or evaluations as medically indicated or as requested by the Sponsor or the 
delegated Pharmacovigilance Service Provider to elucidate the nature and / or causality of the 
AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
Treatment of any AE or SAE is at the sole discretion of the Investigator and according to 
current good medical practice. The treatment / procedure will be recorded in the subject’s 
eCRF. 
• 
If a subject dies during participation in the study, the Investigator will provide a copy of any 
post-mortem findings including histopathology.  
• 
New or updated information on AEs or SAEs will be recorded in the originally completed 
eCRF. For SAEs, which need to be followed up until the event has resolved, stabilised, is 
otherwise explained, or the subject is lost to follow-up, if the eCRF has been locked at the time 
of receiving the new or updated information, the updated information will be provided by 
completing the paper SAE form and providing it to the Sponsor by email 
(pharmacovigilance@oxurion.com). 
• 
The Investigator will submit any updated SAE data within 24 hours of it being available. 


 
 
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10.3.4. 
Reporting of Serious Adverse Events 
SAE Reporting via the eCRF 
• 
The primary mechanism for reporting of SAEs will be the subject’s eCRF. 
• 
If the electronic system is unavailable, the site will use the paper SAE form (see next section) 
to report the event within 24 hours.  
• 
As soon as the eCRF is working again, the Investigator (or his / her designee) must complete 
the electronic SAE form. 
• 
After the study is completed and the source-verification and quality check of the data has been 
done, the database will be locked, i.e. the eCRF will be taken off-line to prevent the entry of 
new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study subject or receives updated data on a 
previously reported SAE after the eCRF has been taken off-line, then the site must report this 
information using the paper SAE form (see next section). 
 
SAE Reporting via the Paper SAE Form 
• 
In rare circumstances when the eCRF system does not work, SAEs can be reported to the 
Sponsor by email using the paper SAE form. This back-up system will only be used if the 
eCRF is not working and NOT if the system is slow. 
• 
Initial notification via the paper SAE form does not replace the need for the Investigator to 
complete and sign the SAE eCRF pages as soon as the eCRF is working again. 
• 
After the eCRF has been locked, SAE reporting will be done using the paper SAE form 
(follow-up information of SAEs that started during the study, or the reporting of new SAEs 
reasonably related to the IMP, the injection procedure or to any other study procedure). 


 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definition of Woman of Childbearing Potential 
Woman of Childbearing Potential 
• 
A woman is considered of childbearing potential, i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
• 
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed, additional evaluation should be considered. 
 
Women in the Following Categories are NOT Considered Women of Childbearing Potential: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For women with permanent infertility due to an alternate medical cause other than the above (e.g. 
mullerian agenesis, androgen insensitivity), Investigator discretion will be applied to determine the 
need for pregnancy testing. 
NOTE: Documentation can come from the site personnel: review of the subject’s medical records, 
medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required.  


 
 
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10.4.2. 
Definition of Highly Effective Birth Control Methods 
Highly Effective Birth Control Methods 
Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly 
are considered highly effective birth control methods. Such methods include: 
• 
combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
− 
oral 
− 
intravaginal 
− 
transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation: 
− 
oral 
− 
injectable 
− 
implantable  
• 
intrauterine device  
• 
intrauterine hormone-releasing system 
• 
bilateral tubal occlusion 
• 
vasectomised partner (provided that partner is the sole sexual partner of the study subject and 
that the vasectomised partner has received medical assessment of the surgical success) 
• 
sexual abstinence (defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the IMPs. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical study and the preferred and usual lifestyle of the subject) 
10.4.3. 
Collection of Pregnancy Information 
10.4.3.1. Female Subjects who Become Pregnant 
Refer to Section 8.3.5.1. 
10.4.3.2. Male Subjects with Partners who Become Pregnant 
Refer to Section 8.3.5.2. 


 
 
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10.5. 
Appendix 5: Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Curve 
BCVA 
Best-Corrected Visual Acuity 
°C 
Degrees Celsius 
CI 
Confidence Interval 
CI-DME 
Central-Involved Diabetic Macular Oedema 
CIOMS 
Council for International Organizations of Medical Sciences 
CNV 
Choroidal Neovascularisation 
CONSORT 
Consolidated Standards of Reporting Trials 
CRC 
Central Reading Centre 
CRO 
Contract Research Organisation 
CST 
Central Subfield Thickness 
D 
Diopter 
DME 
Diabetic Macular Oedema 
DR 
Diabetic Retinopathy 
eCRF 
electronic Case Report Form 
ETDRS 
International Clinical Diabetic Retinopathy Disease Severity Scale 
°F 
Degrees Fahrenheit 
FAS 
Full Analysis Set 
FSH 
Follicle Stimulating Hormone 
G 
Gauge 
GCP 
Good Clinical Practice 
HbA1c 
Glycated Haemoglobin A 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use  
IEC 
Independent Ethics Committee 
ILM 
Internal Limiting Membrane 
IMP 
Investigational Medicinal Product 
IOL 
Intraocular Lens 


 
 
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IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IVT 
Intravitreal 
IWRS 
Interactive Web Response System 
LC-MS/MS 
Liquid Chromatography-tandem Mass Spectrometry 
LOCF 
Last Observation Carried Forward 
mg 
Milligram 
µL 
Microlitre 
mL 
Millilitre 
µm 
Micrometre 
mm 
Millimetre 
mM 
Millimolar 
mmHg 
Millimetre of Mercury 
NEI VFQ-25 
National Eye Institute 25-Item Visual Function Questionnaire 
NOAEL 
No Observed Adverse Effect Level 
NZW Rabbit 
New Zealand White Rabbit 
OCTA 
Optical Coherence Tomography Angiography 
PDR 
Proliferative Diabetic Retinopathy 
PIS 
Patient Information Sheet 
PRN 
Pro Re Nata 
QTL 
Quality Tolerance Limit 
RPE 
Retinal Pigment Epithelium 
RTSM 
Randomisation and Trial Supply Management 
Rx 
Treatment 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SE 
Standard Error 
SMC 
Safety Monitoring Committee 
SoA 
Schedule of Activities 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
VEGF 
Vascular Endothelial Growth Factor 


 
 
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